Femtosecond laser-assisted cataract surgery compared with phacoemulsification: the FACT non-inferiority RCT

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Chapter 1 Introduction

Parts of this text have been reproduced with permission from Day et al. 1,2 © 2020 The Author(s). Published by Elsevier Ltd and Wolters Kluwer Health, Inc. This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/. The text below includes minor additions and formatting changes to the original text.

Cataract surgery is one of the most commonly performed operations in the Western world, with almost half a million procedures performed per year in the UK3 alone. The current standard method, phacoemulsification cataract surgery (PCS) (using ultrasound), was introduced > 50 years ago. 4

Complications can affect recovery, and some complications are serious and associated with long-term poor outcomes [e.g. posterior capsule rupture (PCR)/vitreous loss was reported to occur in 1.4% cases in the recent UK National Ophthalmology Database audit for the period 2016–17]. 5 Among patients who experience serious outcomes, one-third have complaints about their eye and vision 3.5 years after surgery. 6 One in five patients requires further surgery7 and they are at a risk of retinal detachment within 3 years that is 15 times higher than in those who do not have further surgery. 8 The surgical learning curve is associated with complications, with a 1.6 to 3.7 times higher risk of PCR for surgeries performed by non-consultant-grade doctors. 9 Other complications, the majority of which are less serious, may mean a longer operation duration and delayed healing, as well as additional appointments and the need to use eye drops. Patients can be devastated when suffering a complication and, because of the importance of vision for daily activities, can find even minor complications very distressing.

Femtosecond laser-assisted cataract surgery (FLACS) first became commercially available almost 10 years ago. The reported advantages include more accurate positioning, the shape and size of the capsulotomy when compared with a capsulorrhexis,10–12 and less intraocular lens (IOL) tilt13 with fewer higher-order aberrations. 14 In addition, by using a laser to fragment the crystalline lens, less ultrasound energy is required to complete the lens removal and reductions of 70–96% of effective phacoemulsification time (ultrasound power) have been reported,15–17 with zero effective phacoemulsification time being possible in 30% of operations in a recent series. 15 This study15 also reported a 36% lower endothelial cell loss in the laser-assisted procedures than when using manual phacoemulsification.

When introduced, laser cataract surgery platforms were marketed as bringing a stepwise improvement in surgical technique and were used as a differentiating factor between cataract surgery providers.

The timing of FACT (Femtosecond laser-Assisted Cataract Trial) was critical because FLACS was being rapidly adopted worldwide, despite the absence of any randomised controlled trials (RCTs) comparing its safety and efficacy with that of PCS. Although its potential advantages may be attractive to patients and surgeons, laser-assisted surgery is expensive and there are logistical and practical issues that need to be understood. The absence of good evidence for any advantage of laser-assisted surgery was highlighted in a 2013 review article by Trikha et al. 18 and also by the National Institute for Health Research (NIHR) Horizon Scanning Centre. 19 The topic was identified as a research priority by the national James Lind Alliance Sight Loss and Vision Priority Setting Partnership (see www.fightforsight.org.uk/sightlosspsp; accessed 1 January 2013).

The 2016 Cochrane review20 of FLACS compared with PCS concluded that there was limited evidence to determine equivalence or superiority and that large, adequately powered RCTs were needed. Three meta-analyses have been published;21–23 one found superior refractive outcomes with FLACS,23 whereas the others21,22 found no statistically significant differences in terms of patient-reported visual, refractive and complications. Two large RCTs have recently been completed, namely the French FEMCAT (FEMtosecond laser-assisted versus phacoemulsification CATaract surgery) trial,24 which found no difference in visual or refractive outcomes or complications between arms, and a UK trial of 400 eyes that found similar visual outcomes between treatment arms and a statistically significantly lower posterior capsule tear rate in the FLACS arm. 25

Overall, it was thought that the potential advantages of FLACS were broad and would translate to greater safety and better visual outcomes through greater precision and reproducibility. These systems are expensive but costs may potentially be mitigated by greater efficiency (faster surgery), fewer complications, less repeat surgery and better outcomes. At the time of funding FACT, there was already a demand for FLACS among NHS patients, and some NHS trusts, were tendering for FLACS platforms.

Currently, the cost of FLACS still remains high, which reflects the high development costs. For example, Alcon (Geneva, Switzerland) took over LenSx for US$744M in 201026 and Abbott Medical Optics (Abbott Park, IL, USA) purchased OptiMedicaCorp. for up to US$400M in 2013. 27

FACT will answer important questions about the potential introduction of laser cataract surgery platforms into NHS practice, and will also benchmark current surgical standards.

Chapter 2 Methods

Chapter 3 Results

Participant enrolment

Of the 3448 patients assessed, 785 participants were enrolled between May 2015 and September 2017 and 392 were randomly assigned to the FLACS arm and 393 were randomly assigned to the PCS arm (Figure 1). Of these 785 participants, 653 were enrolled from Moorfields St Ann’s, 100 were enrolled from New Cross Hospital and 32 were enrolled from Sussex Eye Hospital.

FIGURE 1.

The trial profile. DNA, did not attend. Reproduced from Day et al. 1,2 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/. The figure includes minor additions and formatting changes to the original figure.

Reproduced from Day et al. 1,2 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/. The figure includes minor additions and formatting changes to the original figure.

The main reasons participants were excluded (n = 1710) were not being sufficiently fluent in English for informed consent and trial questionnaire completion (n = 564), postoperative refractive target being outside ± 0.5 dioptre of emmetropia (n = 180), having poor pupil dilatation (n = 176) and not being willing to attend follow-up (n = 155). Of the 1738 patients eligible to participate, 770 declined to take part, 157 withdrew prior to randomisation and 26 were awaiting randomisation at recruitment closure.

The 3-month outcomes

Overall, 353 out of 392 (90%) participants allocated to the FLACS arm and 317 out of 393 (81%) participants allocated to the PCS arm attended their follow-up visit at 3 months. Table 5 shows the postoperative results at 3 months by treatment arm for selected outcomes. The trial primary outcome was UDVA (logMAR). Additional outcomes for the study eye and all outcomes for the fellow eye can be found in Appendix 2.

TABLE 5 - Three-month outcomes in the study eye by treatment arm

SE, standard error.

In total, 353 FLACS patients were seen at 3 months, but one patient had a missing value for the primary outcome.

Outcome	Treatment arm		FLACS vs. PCS effect (95% CI)	p-value
	FLACS (N = 392)a	PCS (N = 393)
Primary outcome: UDVA logMAR, imputed, mean (SD); n	0.13 (0.23); 392	0.14 (0.27); 393	–0.01 (–0.05 to 0.03)	0.63
UDVA logMAR, complete case, mean (SD); n	0.13 (0.23); 352	0.14 (0.26); 317	–0.01 (–0.04 to 0.03)	0.70
UDVA logMAR, per protocol, mean (SD); n	0.13 (0.22); 334	0.14 (0.26); 317	–0.01 (–0.05 to 0.02)	0.54
CDVA logMAR mean (SD); n	–0.01 (0.19); 352	0.01 (0.21); 317	–0.01 (–0.05 to 0.02)	0.34
SE refraction within ± 0.5 dioptre of target, n (%)	250/352 (71)	224/316 (71)	1.01 (0.72 to 1.41)	0.95
SE refraction within ± 1.0 dioptre of target, n (%)	327/352 (93)	292/316 (92)	1.08 (0.60 to 1.94)	0.80
Change in endothelial cell count (cells/mm2): mean loss (SD); n	242 (416); 345	200 (369); 308	47 (–3 to 97)	0.06
Catquest 9-SF score, mean (SD); n	2.30 (1.31); 283	2.27 (1.30); 253	0.07 (–0.13 to 0.28)	0.49
EQ-5D-3L index score, mean (SD); n	0.84 (0.23); 351	0.82 (0.25); 323	0.0002 (–0.03 to 0.03)	0.88
I have no problems seeing, n (%)	235 (67)	220 (68)	–	–
I have some problems seeing, n (%)	114 (32)	100 (31)	–	–
I have extreme problems seeing, n (%)	3 (0.9)	3 (0.9)	–	–

Table 6 shows the intraoperative complications in the study eye by treatment arm.

TABLE 6 - Three-month intraoperative complications in the study eye by treatment arm

n/a, not applicable.

Complication	Treatment arm (n)
	FLACS	PCS
Anterior capsule tear	3	2
Posterior capsule tear with vitreous loss	0	0
Posterior capsule tear with no vitreous loss	0	2
Intraoperative pupil constriction needing intervention	3	1
Zonular dialysis with or without vitreous loss	1	0
Dropped lens fragments	0	0
Suprachoroidal haemorrhage	0	0
Incomplete laser capsulotomy	4	n/a

Table 7 shows the postoperative complications in the study eye by treatment arm.

TABLE 7 - Three-month postoperative complications in the study eye by treatment arm

Complication	Treatment arm, n (%)
	FLACS	PCS
Postoperative anterior uveitis	34 (9.7)	32 (8.2)
Endophthalmitis	0 (0)	0 (0)
Vitreous to wound	1 (0.3)	1 (0.3)
Steroid response ocular hypertension	4 (1.0)	3 (0.8)
Macular oedema	8 (2.0)	7 (1.8)
Retinal tear or detachment	1 (0.3)	1 (0.3)
Medication allergy or intolerance	4 (1.0)	3 (0.8)
Corneal oedema	4 (1.0)	2 (0.5)

Figures 2 and 3 show the standardised graphs for reporting the outcomes of IOL surgery. 53

FIGURE 2.

Outcomes of IOL surgery: PCS arm. (a) UDVA and CDVA; (b) difference between UDVA and CDVA; (c) accuracy of spherical equivalent refraction to target; and (d) refractive astigmatism.

FIGURE 3.

Outcomes of IOL surgery: FLACS arm. (a) UDVA; (b) UDVA vs. CDVA; (c) spherical equivalent refraction accuracy; and (d) refractive astigmatism.

The 12-month outcomes

Overall, 311 out of 392 (79%) participants allocated to the FLACS arm and 292 out of 393 (74%) participants allocated to the PCS arm attended their follow-up visit at 12 months.

The analysis of toric IOL use by arm showed that 22 toric lens were used in the FLACS arm (369 monofocal, one with data missing) and 19 toric lens were used in the PCS arm (370 monofocal, four with data missing). Table 8 shows the postoperative visual and refractive outcomes at 12 months. Borderline statistical significance was met for CDVA both eyes open, with a mean CDVA difference of –0.02 logMAR (95% CI –0.05 to –0.002; p = 0.036) favouring the FLACS arm. There were no significant differences between the arms for any other outcome. Additional outcomes for the study eye and all outcomes for the fellow eye can be found in Appendix 3.

TABLE 8 - The 12-month outcomes in the study eye by treatment arm

SE, standard error. Bold text indicates statistical significance.

Reproduced from Day et al. 1,2 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/. The table includes minor additions and formatting changes to the original table.

Outcome	Treatment arm		FLACS vs. PCS effect (95% CI)	p-value
	FLACS (N = 311)	PCS (N = 292)
UDVA logMAR, study eye, mean (SD); n	0.14 (0.22); 310	0.17 (0.25); 291	–0.03 (–0.06 to 0.01)	0.17
UDVA logMAR, both eyes open, mean (SD); n	0.05 (0.16); 310	0.07 (0.20); 292	–0.03 (–0.05 to 0.003)	0.08
CDVA logMAR, study eye, mean (SD); n	0.003 (0.18); 311	0.03 (0.23); 292	–0.03 (–0.06 to 0.01)	0.11
CDVA logMAR, both eyes, mean (SD)	–0.05 (0.11); 310	–0.03 (0.17); 291	–0.02 (–0.05 to 0.002)	0.036
SE refraction within ± 0.5 dioptre of target, n (%)	230/307 (75)	218/290 (75)	0.99 (0.68 to 1.43)	0.94
SE refraction within ± 1.0 dioptre of target, n (%)	292/307 (95)	279/290 (96)	0.76 (0.34 to 1.69)	0.50
Catquest 9-SF score, mean (SD); n	2.94 (1.05); 318	2.96 (1.09); 300	0.01 (–0.15 to 0.17)	0.91
EQ-5D-3L index score, mean (SD); n	0.83 (0.23); 318	0.82 (0.25); 299	0.001 (–0.03 to 0.03)	0.95
I have no problems seeing, n (%)	242 (76)	231 (77)	–	–
I have some problems seeing, n (%)	70 (22)	62 (21)	–	–
I have extreme problems seeing, n (%)	6 (2)	6 (2)	–	–

Figures 4 and 5 show the standardised graphs for reporting the outcomes of IOL surgery. 53

FIGURE 4.

Standardised graphs: PCS arm at 12 months. (a) UDVA; (b) UDVA vs. CDVA; (c) spherical equivalent refraction; and (d) refractive cylinder. Reproduced from Day et al. 1,2 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/. The figure includes minor additions and formatting changes to the original figure.

Reproduced from Day et al. 1,2 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/. The figure includes minor additions and formatting changes to the original figure.

FIGURE 5.

Standardised graphs: FLACS arm at 12 months. (a) UDVA; (b) UDVA vs. CDVA; (c) spherical equivalent refraction; and (d) refractive cylinder. Reproduced from Day et al. 1,2 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/. The figure includes minor additions and formatting changes to the original figure.

Reproduced from Day et al. 1,2 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/. The figure includes minor additions and formatting changes to the original figure.

Table 9 shows the postoperative complications at 12 months.

TABLE 9 - The 12-month postoperative complications in the study eye by treatment arm

Participants may have had more than one event.

Reproduced from Day et al. 1,2 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/. The table includes minor additions and formatting changes to the original table.

Complications	Treatment arm, n (%)
	FLACS	PCS
Postoperative anterior uveitis	38 (9.7)	33 (8.4)
Endophthalmitis	0 (0)	0 (0)
Vitreous to wound	1 (0.3)	1 (0.3)
Steroid response ocular hypertension	7 (1.8)	3 (0.8)
Macular oedema	9 (2.3)	14 (3.6)
Posterior vitreous detachment	3 (0.8)	2 (0.5)
Retinal tear or detachment	2 (0.5)	3 (0.8)
Medication allergy or intolerance	4 (1.0)	3 (0.8)
Corneal oedema	8 (2.0)	2 (0.5)
Posterior capsule opacification	4 (1.0)	6 (1.5)

Table 10 shows the corneal endothelial cell measures at 12 months. There was no significant difference between the arms.

TABLE 10 - The 12-month corneal endothelial cell count in the study eye by treatment arm

Reproduced from Day et al. 1,2 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/. The table includes minor additions and formatting changes to the original table.

Corneal endothelial cell count (cells/mm2)	Treatment arm, mean (SD); n		FLACS vs. PCS effect (95% CI)	p-value
	FLACS (N = 307)	PCS (N = 286)
Corneal endothelial cell count	2404 (434); 307	2412 (406); 286	40 (–8 to 89)	0.10
Change in endothelial cell count, mean loss	228 (353); 304	175 (312); 284	40 (–8 to 89)	0.10

Health economic results

Cost of the FLACS and PCS interventions

Based on the Association for Perioperative Practice guidance and evidence from the observational study,46 the following staff were involved in delivering both the FLACS and PCS interventions:

• two nurses (one band 5 and one band 6)

• one operating department practitioner

• one health-care assistant

• one surgeon

• one anaesthetist.

A technician was also present when patients were allocated to the FLACS arm, but only for the duration of the actual FLACS treatment. The total staff and overhead cost per minute was £9.59 per minute in the FLACS arm during the actual FLACS treatment and £9.02 per minute in the FLACS and PCS arms during the time in the operating theatre.

In the FLACS arm, surgery took a mean of 17.1 minutes (SD 7.4 minutes). FLACS laser took an additional 3.9 minutes (SD 3.5 minutes), with a total time of 20.8 minutes (SD 8.2 minutes). In the PCS arm, surgery took 17.8 minutes (SD 8.0 minutes).

At a cost of £232,500 for the machine, and an annual maintenance cost of £16,221, the cost per patient for the machine, annuitising for a 5-year lifespan, is £26 if one assumes that each site sees 3000 patients per year for cataract surgery and 90.5% of patients are able to receive FLACS based on the exclusion criteria seen in the trial. There is also a per-patient cost of £130 for the patient interface, with a total machine cost per patient for FLACS of £156. If an 8-year lifespan is assumed, the cost per patient for the machine is £18, with a total cost per patient of £148 including the patient interface.

There was no significant difference in the use of anaesthetic drugs or consumables between treatment arms except for VisionBlue^® [D.O.R.C. (Dutch Ophthalmic Research Center) (International) B.V., Zuidland, the Netherlands; used for staining the anterior capsule to increase visibility, 43 patients in the PCS arm compared with three patients in the FLACS arm] at a cost per vial of £8.65.

Surgeon training for FLACS comprised 10 sessions of using the laser. At a cost per minute of £1.80 for surgeon time and an average time of using the lasert in FLACS of 4 minutes, the total cost of training per surgeon is £70. Given a caseload of approximately 1000 cataracts per year (from professional opinion), the cost of training is very close to zero and hence has been excluded from the total cost.

The average total patient cost of surgery was £363.21 (95% CI £347.65 to £378.77) in the FLACS arm, compared with £174.58 (95% CI £163.24 to £185.92) in the PCS arm (Table 11). The analysis is intention to treat, in line with the analysis plan. As a result, it includes 20 patients who were randomised to the FLACS arm but received standard cataract surgery and so are costed as PCS. Five patients had missing surgery data and, therefore, are not included in the analysis. Details on adverse events are also reported in Table 11.

TABLE 11 - Total cost of surgery (£)

Cost	Treatment arm, mean cost (SD)
	FLACS (n = 391)	PCS (n = 389)
Surgery staff cost	199.70 (78.38)	160.95 (72.26)
FLACS machine	146.70 (35.95)	0
Consumables: VisionBlue	0.11 (0.97)	0.90 (2.65)
Adverse events	14.12 (112.06)	8.90 (77.13)
Surgery medication	3.72 (1.41)	3.82 (1.80)
Total per patient	363.21 (156.5)	174.58 (113.78)

Health, social care and societal costs

Complete-case health and social care and societal costs and MICE total costs are reported in Tables 12 and 13. There were no significant differences between the two arms in any health and social care or societal costs. For societal costs, missing carer costs were imputed as zero because otherwise the missing data created issues in the analysis, as a patient who was missing data at multiple time points had skewed carer costs. The carer costs should be interpreted with caution as they are calculated from a single question: ‘How many hours per week on average did [friends or relatives] help you over the last 3 months?’

TABLE 12 - Health and social care costs (£)

A&E, accident and emergency; GP, general practitioner; SE, standard error.

Adjusted for baseline costs, site, the number of eyes that were eligible and random surgeon effects.

Cost	Treatment arm						Adjusteda mean difference	95% CI	p-value
	FLACS			PCS
	n	Mean	SD	n	Mean	SD
GP
Baseline	383	45	61	375	48	57
3 months	354	28	37	323	31	44
6 months	265	35	44	242	42	65
12 months	318	31	40	298	32	46
Total cost	220	86	84	196	100	124	–0.080	–21.823 to 21.663	0.994
Community nurse
Baseline	383	6	21	374	10	55
3 months	353	7	57	323	23	274
6 months	266	5	14	242	10	49
12 months	318	8	35	298	6	30
Total cost	221	21	84	195	20	50	1.637	–8.729 to 12.002	0.748
Occupational therapist
Baseline	382	14	187	374	3	25
3 months	353	1	16	323	4	27
6 months	265	2	18	242	4	36
12 months	318	3	24	298	5	34
Total cost	220	6	39	195	11	57	–8.215	–17.578 to 1.147	0.083
Physiotherapist
Baseline	381	14	127	375	8	48
3 months	353	9	47	323	8	43
6 months	265	4	28	242	9	41
12 months	318	17	155	298	20	96
Total cost	220	29	96	195	28	82	0.389321	–15.015 to 15.794	0.959
Other community
Baseline	382	57	482	374	27	247
3 months	352	8	63	322	38	460
6 months	263	24	124	240	26	169
12 months	318	9	72	298	24	198
Total cost	218	36	123	193	121	716	–70.747	–156.78 to 15.286	0.103
Total community
Baseline	383	135	589	375	95	283
3 months	354	53	111	323	103	548
6 months	266	69	141	243	89	234
12 months	318	67	189	298	87	236
Total cost	221	177	253	196	278	773	–89.789	–185.006 to 5.429	0.063
A&E
Baseline	383	18	64	374	9	47
3 months	354	20	61	323	22	69
6 months	262	13	62	241	14	61
12 months	318	14	50	298	15	77
Total cost	217	41	101	193	45	118	–7.047	–26.578 to 12.48	0.464
Outpatient
Baseline	383	65	176	374	98	321
3 months	354	63	270	323	55	179
6 months	262	63	163	241	68	160
12 months	318	88	211	298	100	280
Total cost	217	209	445	193	235	446	–22.879	–110.509 to 64.751	0.596
Inpatient
Baseline	383	40	320	375	37	236
3 months	354	72	518	323	45	418
6 months	265	51	383	243	73	519
12 months	318	104	757	298	89	422
Total cost	219	248	1204	195	198	783	97.360	–86.520 to 281.250	0.286
Social care
Baseline	382	3	44	375	3	34
3 months	354	5	4	323	11	154
6 months	267	2	27	244	4	38
12 months	319	2	24	298	2	18
Total cost	222	6	45	196	20	201	–16.578	–46.287 to 13.130	0.261
Total NHS and social care
Baseline	383	262	750	375	289	958
3 months	354	215	757	323	239	751
6 months	267	201	495	244	262	743
12 months	319	365	1444	298	304	641
Total cost	222	750	1970	196	807	1477	–28.743	–290.488 to 233.002	0.823
MICE NHS and social care
	n	Mean	SE	n	Mean	SE
3 months (MICE)	383	215	43	375	226	40
6 months (MICE)	383	196	29	375	210	34
12 months (MICE)	383	312	60	375	304	37
Total cost	383	723	88	375	741	74	–10.890	–234.124 to 212.344	0.924

TABLE 13 - Societal costs

Adjusted for baseline costs, site, the number of eyes that were eligible and random surgeon effects.

Cost	Treatment arm						Adjusteda mean difference	95% CI	p-value
	FLACS			PCS
	n	Mean	SD	n	Mean	SD
Home help private
Baseline	382	0.69	8.47	375	0.21	2.56
3 months	354	0.23	2.9	323	0.17	3.06
6 months	266	0.42	5.5	244	0.25	3.93
12 months	318	0.2	2.86	298	1.11	14.48
Total cost	220	0.68	6.88	196	1.92	25.85	–1.75055	–6.19982 to 2.698725	0.425405
Unpaid carers
Baseline	381	703	3834	373	667	2484
3 months	353	623	2557	321	761	3799
6 months	263	448	1857	239	755	2469
12 months	319	669	3831	298	824	4485
Total cost	373	1477	5732	357	1878	6911	–559.751	–1394.57 to 275.0671	0.179873
Reducing hours
Baseline	383	11.18	66.81	375	8.58	54.47
3 months	354	5.84	40.19	323	5.85	46.31
6 months	266	0.3	4.95	244
12 months	319			299	1.08	18.69
Total cost	221	4.83	41	197	6.32	50.83	–1.41168	–12.1063 to 9.282926	0.787964
All societal
Baseline	383	711	3830	375	672	2478
3 months	354	627	2556	323	762	3787
6 months	267	442	1845	244	740	2446
12 months	319	669	3831	299	824	4478
Total cost	374	1480	5726	358	1880	6901	–566.077	–1342.95 to 210.7933	0.146231
MICE all societal costs
3 months	383	587	131	375	700	193
6 months	383	337	85	375	824	154
12 months	383	612	193	375	754	223
Total cost	383	1537	308	375	2279	423	–761.396	–1783.597 to 260.804	0.144

Quality-adjusted life-years

There were no significant differences between the FLACS and PCS arms for the complete-case analysis of QALYs (Table 14) or for the MICE analysis of QALYs (Table 15).

TABLE 14 - Utilities and QALYs

EQ-5D	Treatment arm						Adjusted mean difference	95% CI	p-value
	FLACS			PCS
	n	Mean	SD	n	Mean	SD
EQ-5D-3L
Baseline	380	0.795	0.236	373	0.783	0.25
6 weeks	280	0.81	0.271	254	0.813	0.253
3 months	351	0.835	0.23	323	0.822	0.245
6 months	262	0.824	0.26	234	0.812	0.255
12 months	318	0.833	0.231	299	0.819	0.253
QALYs	179	0.825	0.206	143	0.832	0.165	–0.011	–0.037 to 0.016	0.416
EQ-5D-3L vision bolt-on
Baseline	380	0.769	0.249	373	0.759	0.26
6 weeks	280	0.801	0.279	254	0.805	0.26
3 months	351	0.829	0.232	323	0.816	0.25
6 months	262	0.818	0.265	234	0.805	0.26
12 months	318	0.828	0.233	299	0.814	0.257
QALYs	179	0.819	0.209	143	0.826	0.169	–0.012	–0.038 to 0.014	0.360

TABLE 15 - Multiple imputation by chained equations utilities and QALYs

EQ-5D	Treatment arm						Adjusted mean difference	95% CI	p-value
	FLACS			PCS
	n	Mean	SD	n	Mean	SD
EQ-5D-3L
6 weeks	380	0.819	0.015	373	0.827	0.014
3 months	380	0.844	0.012	373	0.835	0.013
6 months	380	0.828	0.015	373	0.827	0.014
12 months	380	0.839	0.012	373	0.827	0.014
QALYs	380	0.815	0.010	373	0.810	0.001	0.0004	–0.022 to 0.023	0.974
EQ-5D-3L vision bolt-on
6 weeks	380	0.810	0.015	373	0.818	0.014
3 months	380	0.838	0.013	373	0.830	0.013
6 months	380	0.822	0.015	373	0.822	0.014
12 months	380	0.834	0.013	373	0.821	0.015
QALYs	380	0.811	0.012	373	0.804	0.011	–0.004	–0.0284 to 0.0203	0.744

Primary economic evaluation

The primary economic evaluation was a within-trial cost-effectiveness analysis over 12 months from a health and social care cost perspective using the EQ-5D-3L to calculate QALYs and using MICE for missing cost and utility data. Seemingly unrelated regression was used to account for correlation between costs and outcomes, with adjustment for baseline, site and the number of eyes that were eligible.

The mean cost difference (FLACS minus PCS) for the imputed, bootstrapped, adjusted data was £167.62 per patient (95% of iterations between -£14.12 and £341.67). The mean QALY difference (FLACS minus PCS) was 0.001 (95% of iterations between –0.011 and 0.015). This equates to an ICER (cost difference divided by QALY difference) of £167,620. The CEAC and cost-effectiveness planes are reported in Figures 6 and 7, respectively. There is a 24% probability that FLACS is cost-effective compared with PCS at a WTP threshold of £20,000 for a QALY gained and 30% probability at a £30,000 WTP threshold. As shown in Figure 7, the incremental mean cost of FLACS is greater than that of PCS for 97% of iterations, and in 53% of iterations FLACS has greater incremental mean QALYs.

FIGURE 6.

Cost-effectiveness acceptability curve of FLACS compared with PCS from a health and social care cost perspective: bootstrapped, adjusted with MICE.

FIGURE 7.

Cost-effectiveness plane of FLACS compared with PCS from a health and social care cost perspective: bootstrapped, adjusted with MICE.

Secondary and sensitivity analyses

Using the 3-month data only to calculate cost-effectiveness, in the MICE, bootstrapped and adjusted analysis, FLACS is dominated by PCS (mean cost difference of £171.70, 95% CI £57.59 to £285.80; mean QALY difference of –0.001, 95% CI –0.006 to 0.004).

When the vision bolt-on is included in the MICE, bootstrapped, adjusted results, PCS dominates FLACS, in that there is a mean cost difference of £234.94 (95% of iterations between £56.44 and £455.83) and the mean QALY difference is –0.003 (95% of iterations between –0.016 and 0.011). There is an 11% probability that FLACS is cost-effective compared with PCS at a WTP threshold of £20,000 for a QALY gained and a 16% probability at a £30,000 WTP threshold.

If two theatres are used at the same time, as opposed to just one, in the MICE, bootstrapped, adjusted results the ICER is £149,830, in that there is mean cost difference of £149.83 (95% of iterations between –£31.64 and £232.80) and the mean QALY difference is –0.001 (95% of iterations between –0.011 and 0.015). There is a 26% probability that FLACS is cost-effective compared with PCS at a WTP threshold of £20,000 for a QALY gained and a 32% probability at a £30,000 threshold.

In the societal analysis using MICE for missing data, and with the bootstrapped adjusted results, FLACS dominates PCS, with a mean cost saving of £623.53 per patient (95% of iterations between –£1431.27 and £203.24) and a mean QALY difference of 0.0004 (95% of iterations between –0.013 and 0.015). There is an 87% probability that FLACS is cost-effective compared with PCS at a £20,000 WTP for a QALY gained and an 86% probability at a £30,000 WTP threshold (Figure 8). The downwards slope of the CEAC is because of the very small number of additional negative incremental QALYs compared with positive incremental QALYs (50.2% vs. 49.8%, respectively).

FIGURE 8.

Cost-effectiveness acceptability curve of FLACS compared with conventional cataract surgery from a societal cost perspective: bootstrapped, adjusted with MICE.

For the threshold analysis from a health and social care cost perspective, assuming that FLACS results in an additional 0.001 QALYs per patient, FLACS needs to cost £138 less than it currently does to potentially be cost-effective at a WTP threshold of £30,000 for a QALY gained.

Chapter 4 Discussion

The result of FACT is that FLACS is not inferior to PCS for UDVA 3 months postoperatively (the primary outcome). In addition, we found no significant difference in any of our secondary outcome measures by treatment arm with follow-up to 12 months, with the exception of binocular CDVA, which, although statistically significant, was not clinically significant.

Overall, our complication rates were lower than or comparable to previously published data from big data sets on cataract surgery outcomes. 38 Specifically, the PCR rates were 0.0% for FLACS and 0.5% for PCS, compared with a reported UK benchmark rate of 2.0%. 38 Reported PCR rates in the FEMCAT study were 1.4% for FLACS compared with 1.6% for PCS. 24 A RCT of 400 eyes of 400 patients from St Thomas’ Hospital (London, UK) undergoing either FLACS or PCS found a statistically significantly lower PCR rate in the FLACS than in the PCS arm (0.0% vs. 3.0%). 25 Previously, there had been some concern over possible higher anterior capsule tear rates with FLACS because of the ‘postage-stamp’ edge pattern following laser capsulotomy creation, with rates of 1.9% reported for laser capsulotomy compared with 0.1% for standard capsulorrhexis in a comparative case series of 1626 surgeries. 54 In our trial, anterior capsule tear rates were 0.8% (3/392) for laser capsulotomy compared with 0.5% (2/393) for standard capsulorrhexis, and this difference did not reach statistical significance. In the St Thomas’ laser cataract RCT,25 the anterior capsule tear rate was 3.0% for FLACS cases and 1.5% for PCS, which did not reach statistical significance. In view of the low event rates of posterior capsule tears and anterior capsule tears, a meta-analysis of RCT outcomes is required to investigate this further.

For refractive outcomes, 75% of both FLACS and PCS cases were within ± 0.5 dioptre target, and 95% of FLACS cases and 96% of PCS cases within ± 1.0 dioptre target at 1 year, compared with 73% and 93% of eyes being within ± 0.5 dioptre and ± 1.0 dioptre target in a recent large EUREQUO (European Registry of Quality Outcomes for Cataract and Refractive Surgery) analysis of 282,811 cataract surgeries. 55 Comparative values from another recent large RCT of FLACS compared with standard PCS were 71% and 77% of eyes, respectively, within ± 0.5 dioptre, and 94% and 95% of eyes, respectively, within ± 1.0 dioptre. 25

This trial was designed to have adequate power to detect important differences in vision and to minimise possible bias. It was publicly funded and designed to be representative of the publicly funded NHS in the UK. Masking the operating surgeon was not possible because of the surgery methodology, and, although trial participants were not masked to their allocated arm, we do not believe that this was a significant source of bias in the outcome measures. Interestingly, we did observe a small difference in the 3-month follow-up rates for those who underwent FLACS compared with those who underwent PCS, with 90% of FLACS patients attending follow-up compared with 80% of PCS patients. Participants who did not attend were contacted by identical methods to rebook within trial timescales and an additional sensitivity analysis does not suggest a difference in the characteristics of those who were lost to follow-up. A surgical learning curve effect is possible for FLACS, as all trial surgeons had performed hundreds to thousands of PCS compared with a minimum of 10 FLACS to meet trial surgeon eligibility. We have previously published data on the learning curve for FLACS and found that complications attributable to FLACS tend to occur in the first few patients,56 but correspondence suggests that the learning curve may include the first 100 patients undergoing FLACS. 57 Even if the FLACS learning curve is 100 patients, the complication rate in the FLACS arm is low and so it is difficult to see how this would materially affect our findings. Another limitation is that the majority of patients were recruited from a high-volume cataract day surgery unit (St Ann’s, Moorfields Eye Hospital, London, UK) and this may not be fully representative of the set-up in other areas of the UK. Trial recruitment (785 participants) was slightly below the planned 808 total; however, based on the pre-recruitment power calculation, the 95% CI for the difference in visual acuity (95% CI –0.05 to 0.03 logMAR) did not include our non-inferiority margin of 0.1 logMAR that was considered to be appropriate for cataract drug efficacy trials. 58 FACT was not powered to identify differences in complications such as PCR that happen infrequently, and an additional meta-analysis of the available evidence is required to investigate possible differences in rare events.

FLACS automates cataract surgery steps, including capsulorrhexis, which can typically take < 1 minute to complete. This is a key step in surgical training, and delegating this step to a machine may have an impact on training, potentially affecting surgical cases that are unsuitable for FLACS and, therefore, by definition, technically more complex. In FACT, eligible surgeons were those who had completed 10 or more FLACS cases, and, although the trial was open to surgeons of all grades, we found that, anecdotally, specialist trainees were often not keen to take part as this would give them less experience of all the steps completed by hand in PCS.

The within-trial analysis conducted as part of FACT provides the best evidence that we are aware of to date of the cost-effectiveness of FLACS compared with PCS. Given that FLACS costs £216 more than PCS (£168 when any potential cost benefits from health and social care costs are included) and that the study has found no evidence of any additional benefit as a result of FLACS, there is a low probability that implementing FLACS is cost-effective for the NHS.

Based on the threshold analysis, FLACS would need to cost at least £138 less than it currently does to potentially be cost-effectiveness at a WTP threshold of £30,000 for a QALY gained (£168 if the non-significant difference in QALYs is not included). This cost is very close to that of the FLACS patient user interface. Even with a more efficient use of theatres, using two theatres at the same time, and hence saving some cost on staff that can work across theatres, FLACS has a 26% probability of being cost-effective at the upper NICE WTP threshold of £30,000 per QALY gained. Similar conclusions have been drawn by Roberts et al. ,47 who explored how FLACS could be implemented in the NHS so that it is cost neutral, using the model of two theatres functioning in parallel and staff working between the two. They came to the conclusion that either theatres would need to increase their list size by 100% or the cost of the patient interface would need to decrease by 70% for FLACS to approach cost saving. Based on the results of a decision model, Abell et al. 59 came to the conclusion that FLACS would need to significantly improve patient outcomes to be cost-effective in an Australian setting. The recent FEMCAT study concluded that FLACS was not cost-effective for the French health-care system. 24

There was some evidence that FLACS is potentially cost-effective from a societal perspective. However, this result is predicated on the single question about time spent caring for a partner and, hence, should be interpreted with caution. There is a slight possibility that this question captured an impact on patients that is not captured elsewhere in the analysis, but there is limited evidence for this. Any future health economic evaluations in this area should continue to measure the impact on carers but should ensure that this is done using a validated measure of carer time, such as iMTA Valuation of Informal Care Questionnaire (iVICQ),60 to ensure a more robust analysis. We may have underestimated the FLACS and PCS costs of surgeons for FLACS and PCS as these are based on the PSSRU44 cost per hour, including overheads, but do not include an adjustment for additional activities conducted outside face-to-face time with patients.

Although the EuroQol-5 Dimensions (EQ-5D) is generally not recommended in trials involving eyes because it has been found to be unreliable at capturing changes in vision,36 we included the vision bolt-on in an attempt to overcome this. The QALYs for the vision bolt-on are not significantly different from those for the EQ-5D-3L, although the mean is in a different direction (negative mean QALYs for the vision bolt-on compared with positive mean QALYs for the standard EQ-5D-3L). Given the results reported elsewhere in this report, it is unlikely that a condition-specific measure would have detected a change that the EQ-5D-3L and its vision bolt-on have failed to capture. We have not explored the cost-effectiveness for any of the other outcomes in the trial because there were no significant differences between arms and hence these analyses would have provided limited additional information.

Chapter 5 Conclusions

In summary, the results of FACT showed that FLACS is not inferior to PCS. The methods appear to be similar in terms of vision, patient-reported health and safety outcomes after 12 months’ follow-up. FLACS is not cost-effective. Additional RCT data and meta-analyses are required to further investigate possible differences between the surgical methods due to the low complication rates and apparently similar efficacy.

Acknowledgements

The trial was funded by the NIHR Health Technology Assessment programme (project reference number 13/04/46) and was sponsored by University College London (UCL).

We thank the NIHR Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust for supporting the trial and Moorfields Eye Charity (grant references GR000233 and GR000449 for the endothelial cell counter and femtosecond laser used). Alexander C Day was supported by the NIHR Biomedical Research Centre based at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology. Catey Bunce is part funded/supported by the NIHR Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London.

We thank the patient panel at Moorfields Eye Hospital who contributed to the design of the trial, and also all FACT participants and recruiting sites.

We are also grateful to the following.

Members of the Trial Steering Committee (TSC):

• TSC: chairperson Professor David Spalton, Mr Andrew Elders, Mr Larry Benjamin and Mr Horace Cheung.

Independent members of the Data Monitoring Committee:

• Independent Data Monitoring Committee: chairperson Dr Chris Rogers, Miss Emma Hollick and Professor Augusto Azuara-Blanco.

• Non-independent TSC member: Professor Anne Schilder.

Collaborators on behalf of the FACT group:

• Francesco Aiello, Muna Ali, Walter Andreatta, Bruce Allan, Hayley Boston, Torsten Chandler, Sandeep Dhallu, Matthew Edmunds, Ahmed Elkarmouty, Joanna Gambell, Felicia Ikeji, Balasubramaniam Ilango, Emma Jones, Gemma Jones, John Koshy, Nicola Lau, Vincenzo Maurino, Victoria McCudden, Kirithika Muthusamy, Anna Quartilo, Gary Rubin, Jeffrey Round, Jasmin Singh, Yvonne Sylvestre, Richard Wormald and Yit Yang.

Staff facilitating recruitment and data collection:

• Moorfields Eye Hospital –

  • Ahmed Al Maskari, Ahmed Elkarmouty, Alex Day, Alexa King, Aljazy Jaber, Bruce Allan, Chameen Samarawickrama, Chrysostomos Dimitriou, Darlene Catalan, Deborah Horney, Eme Chan, Emma Jones, Farah Mawji, Fransesco Alello, Giovanni Cillino, Harendra Thillaiampalam, Hayley Boston, James Byers, Jasmin Singh, John Koshy, Kareemah Adiatu, Konstantina Prapa, Krithika Muthusamy, Lena Potiwal, Marcus Ang, Mark Wilkins, Mohammed Ziaei, Muna Ali, Nick Taylor, Nicola Lau, Oluwatoyin Adenuga, Qasiem Nasser, Rajesh Deshmukh, Rasha Jorany, Rima Hussain, Samiul Rahman, Sandeep Dhallu, Sanjina Kathwiria, Sara Maio, Satvir Hansi, Scott Robbie, Sharona Hattersley, Simranjit Mehta, Steve Tuft, Tulsi Parekh, Victoria Grayson, Vincenzo Maurino, Vito Romano, William Kabanda and Yoganand Jeetun.

• Sussex Eye Hospital staff –

  • Alfonso V Perez, Andrew Simpson, Campbell Keir, Carla Henrique, Carlos Garcia, Catherine Offer, Florence Winterflood, Jennifer Reid, Lisa Taylor, Lorraine Bennett, Luke Bromilow, Mayank Nanavaty, Nicola Sabokbar, Paul Frattarolli and Steven Borkum.

• New Cross Hospital staff –

  • Balasubramaniam Ilango, Bhogal S Bhogal, Caz Ranford-Law, Claire Parkes, Donna Butler, Donna Jones, Gemma Edwards, Hafsa Iqbal, Imogen Hawthorne, Jas Purewal, Jose Maya, Kamaljit Balaggan, Matthew Edmunds, Meena Karpoor, Nick Denyer, Niro Narendran, Richard Webb, Sara Simmons, Sharon Hughes, Susan Massey, Walter Andreatta, Yit Yang, Jennie Green and Ian Bowen.

• UCL Comprehensive Clinical Trials Unit staff –

  • Ana Quartilho, Caroline Doré, Emilia Caverly, Felicia Ikeji, Gemma Jones, Jade Dyer, Jeff Round, Kate Bennett, Michelle Tetlow, Philip Bakobaki, Pranitha Veeramalla, Rachael Hunter, Sophie Connor, Steve Hibbert, Tabassum Khan, Tola Erinle, Torsten Chandler, Victoria McCudden, Yvonne Sylvestre, Zainib Shabir and Gemma Jones.

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Appendix 1 Protocol deviations

Tables 16–18 detail the protocol deviations.

Appendix 2 Full 3-month outcomes

Table 19 shows the number of patients screened by centre and Table 20 shows the number of patients randomised by centre. Figure 9 shows the number of patients consented and randomised each month. Tables 21 and 22 show the baseline characteristics of trial patients by allocated treatment – study eye. Tables 23 and 24 show the baseline characteristics of trial patients by treatment received – fellow eye. Table 25 shows the frequency of intraoperative complications by treatment allocated (study eye) or by treatment received (fellow eye), and Table 26 shows the results of the regression models (adjusted for stratification variables and baseline values) and safety events at 3 months in the study eye. Table 27 shows the results of the regression models (adjusted for stratification variables) and safety events at 3 months in the fellow eye.

FIGURE 9.

Number of patients consented and randomised each month.

Appendix 3 Full 12-month outcomes

Table 28 shows the results of the regression models for secondary outcomes at 12 months in the study eye and Table 29 shows the results of the regression models for secondary outcomes at 12 months in the fellow eye.

List of abbreviations

CDVA

corrected distance visual acuity

CEAC

cost-effectiveness acceptability curve

CI

confidence interval

EQ-5D

EuroQol-5 Dimensions

EQ-5D-3L

EuroQol-5 Dimensions, three-level version

ETDRS

Early Treatment Diabetic Retinopathy Study

FACT

Femtosecond laser-Assisted Cataract Trial

FEMCAT

FEMtosecond laser-assisted versus phacoemulsification CATaract surgery

FLACS

femtosecond laser-assisted cataract surgery

ICER

incremental cost-effectiveness ratio

IOL

intraocular lens

logMAR

logarithm of the minimum angle of resolution

MICE

multiple imputation by chained equations

NICE

National Institute for Health and Care Excellence

NIHR

National Institute for Health Research

OCT

optical coherence tomography

PCR

posterior capsule rupture

PCS

phacoemulsification cataract surgery

PSSRU

Personal Social Services Research Unit

QALY

quality-adjusted life-year

RCT

randomised controlled trial

SD

standard deviation

TSC

Trial Steering Committee

UCL

University College London

UDVA

uncorrected distance visual acuity

WTP

willingness to pay