Efficacy and Adverse Event Profile of the iStent and iStent Inject Trabecular Micro-bypass for Open-angle Glaucoma: A Meta-analysis.

Aim: This meta-analysis explores the efficacy and adverse event profile of the iStent, an ab interno implant for the treatment of open-angle glaucoma.
Methods: A systematic literature search of Ovid MEDLINE and EMBASE was used to identify peer-reviewed original studies that provided efficacy data on the first or second generation iStent for at least five eyes. Intraocular pressure (IOP) was the primary efficacy endpoint, while the number of medication classes was the secondary outcome. Weighted mean differences were reported for continuous endpoints, while a relative risk was computed for dichotomous variables. Review
Results: The search revealed 545 results, of which 1767 eyes from 28 studies were included. The cohort age was 71.4 ± 5.4 years, and 44.9% of patients were male. There was a significantly greater IOP reduction after the use of two first-generation stents compared to one, irrespective of phacoemulsification status (p < 0.001). Additionally, there was a significantly greater IOP reduction following iStent alone relative to phaco-iStent for the first-generation iStent (p < 0.001) and the iStent inject (p < 0.001). For the first generation stent, combined phaco-iStent provided a greater level of IOP reduction (p < 0.001) and reduction in the number of medication classes relative to phacoemulsification alone (p < 0.001). In total, 22.5% of eyes that received iStent implantation sustained some type of adverse event. The most common adverse events were intraocular pressure elevation, stent blockage or obstruction, stent malposition and hyphema. Conclusion and Clinical Significance: Statistically significant differences in efficacy outcomes exist between different numbers of stents and the presence or absence of concurrent phacoemulsification.How to cite this article: Popovic M, Campos-Moller X, Saheb H, Ahmed IIK. Efficacy and Adverse Event Profile of the iStent and iStent Inject Trabecular Micro-bypass for Open-angle Glaucoma: A Meta-analysis. J Curr Glaucoma Pract 2018;12(2):67-84.

BACKGROUND

Given the irreversible retinal ganglion cell damage resulting from open-angle glaucoma (OAG), current treatment modalities are focused on preserving the structural integrity of the optic nerve and visual function.[1-3] Prospective evaluations in glaucoma have demonstrated that the reduction of IOP leads to significant sparing of vision: namely, every 1 mm Hg reduction of IOP is correlated with an approximate 10% decrease in the risk of glaucomatous progression.[4]

In OAG, IOP elevation is often a result of reduced aqueous humor flow through the trabecular meshwork[5] In early stages, ocular hypotensive medications and laser trabeculoplasty have been shown to attenuate glaucoma progression; however there are well known issues with compliance, tolerability, persistence, and difficulty of proper instillation.[35] In the situations in which these treatments are insufficient in reducing IOP to target pressures according to disease severity, ab externo filtering procedures are utilized to provide a more significant IOP reduction. Unfortunately, these techniques are higher risk options that may result in a bleb-related complication, hemorrhage, hyphema, hypotony, infection, inflammation, loss of vision or reoperation.[67]

Recently, there has been increasing interest in the ability of microinvasive glaucoma surgery (MIGS) devices to provide a significant level of IOP reduction with less severe postoperative adverse events.[8] One such device, the iStent ® (Glaukos Corporation, San Clemente, California), is the first ab interno glaucoma implant that has been approved for the management of mild-to-moderate OAG.[9] The iStent works by allowing aqueous humor to drain directly from the anterior chamber into Schlemm’s canal, thus bypassing a portion of the trabecular meshwork and reducing IOP.[10] Currently, the iStent has only received food and drug administration approval for use combined with cataract surgery.

Multiple randomized controlled trials and case series have investigated the efficacy and adverse event profile of the iStent device.[211-37] Some have directly compared the combination of iStent implantation and phacoemulsification to phacoemulsification alone.[3161719-2230] Others have been single-armed case series or have compared the iStent to ocular hypotensive medications.[11-151823-29] More recent research has focused on a second-generation trabecular micro-bypass device termed the iStent inject,[11142024293436] which consists of two heparin coated titanium stents that are both inserted ab interno through the trabecular mesh-work into Schlemm’s canal.[29] Differences in outcomes between single versus multiple iStents have also been investigated.[11131417202123-252931] In general, most studies have focused on patients with early stages of primary OAG [1114-16212227-2932]

There has been a rapid expansion of iStent research in recent years.[311-37] Given these new data, it is uncertain whether there are any differences in efficacy between single versus multiple stents or between phaco-iStent compared to either iStent alone or phacoemulsification alone. Additionally, the most frequently reported adverse events in the literature following iStent therapy should be identified. As such, the following meta-analysis aims to investigate the efficacy and adverse event profile of iStent implantation for the management of OAG.

METHODS

Literature Search and Data Collection

A systematic literature search was performed on Ovid MEDLINE (2006-Week 1 2018) and Ovid EMBASE (20062018 Week 3). The search strategy that was used can be found in Table 1A and B. Further, Google, Google Scholar and the reference lists of past reviews were manually searched to elicit further relevant literature. Any original prospective or retrospective clinical study that provided relevant efficacy data (i.e., IOP and number of medication classes) on the implantation of the iStent for at least five eyes was included. Only peer-reviewed journal articles were included. Non-english studies, letters to the editor, correspondences, editorials, reviews, opinions, case reports, articles reporting on other surgical procedures and studies that contained repeat data or less than 4 week follow-up were excluded. Studies were screened first by consulting titles and abstracts and afterwards by examining full-text versions. To assist with the screening process, a quality assessment of articles was performed. The Cochrane criteria were used in the assessment of randomized controlled trials, while the National Institute for Health and Care Excellence tool was used to evaluate case series.[3839] In both cases, studies were excluded if there was a high risk of bias in at least half of the assessment categories.

Table 1A: Search strategy for Ovid MEDLINE

#		Searches		Results
1		iStent.m_titl.		29
2		iStent.mp.		62
3		Trabecular micro-bypass.mp.		25
4		Glaukos.mp.		30
5		Microinvasive glaucoma surgery.mp.		12
6		Minimally invasive glaucoma surgery.mp.		38
7		Minimally Invasive Surgical Procedures/		24740
8		Ophthalmologic Surgical Procedures/		12012
9		7 and 8		86
10		Stents/		65102
11		Glaucoma/		37134
12		10 and 11		43
13		1 or 2 or 3 or 4 or 5 or 6 or 9 or 12		222
14		Limit 13 to yr = “2006-Current”		205

Table 1B: Search strategy for Ovid EMBASE

#		Searches		Results
1		iStent.m_titl.		47
2		iStent.mp.		158
3		Trabecular micro-bypass.mp.		52
4		Glaukos.mp.		125
5		Microinvasive glaucoma surgery.mp.		27
6		Minimally invasive glaucoma surgery.mp.		73
7		Minimally invasive surgery/		33752
8		Eye surgery/		66
9		1 and 8		66
10		Stent/		81559
11		Glaucoma/		51832
12		10 and 11		87
13		1 or 2 or 3 or 4 or 5 or 6 or 9 or 12		358
14		Limit 13 to yr = “2006-Current”		340

Variables that were included for the baseline demographic evaluation were country of origin, study design, distribution of right and left eyes, age, gender, ethnicity, cup-to-disc ratio, visual field, mean deviation and time of follow-up. The primary efficacy endpoint, IOP, was collected as a continuous variable (i.e., IOP postoperatively and reduction pre- to post-operatively). The postoperative number of hypotensive medication classes and pre- to post-operative reduction in the number of medication classes was the secondary endpoint. For the efficacy analysis, data on the number of iStents and phacoemulsification status (i.e., whether concomitant phacoemulsification was performed) were extracted. For adverse event analysis, the number of events and the four most prevalent events for each study arm were recorded. Postoperative outcomes were collected at last follow-up.

Statistical Analysis

Weighted mean differences (WMD) and corresponding 95% confidence intervals (95% CI) were reported in the analysis of primary and secondary endpoints. Throughout the analysis, the number of eyes (i.e., sample size) was used as a weighted variable. Alongside a random effects model, the inverse variance method was used in the meta-analysis. The weighted mean was defined as

while the weighted standard deviation was computed using the formula

Due to the differential reporting of included studies, each unique endpoint contains data from a different collection of studies. A consequence of this is that the WMDs of IOP and medication class reduction will likely not equal the difference between the preoperative and postoperative values for IOP and medication class count.

In the test for overall effect, a p-value of less than 0.05 was considered statistically significant. The main analysis was performed based on whether patients had 1, 2 or 3 iStents implanted and whether they did or did not receive combined phacoemulsification and iStent. All statistical analyses were performed using Review Manager (RevMan 5.3; The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark) and Microsoft ® Excel (Microsoft Corporation, Redmond, Washington).

REVIEW RESULTS

Study Inclusions and Baseline Demographics

The systematic search revealed 545 results. Upon title and abstract screening, the number of potential articles was reduced to 135. Afterwards, full-text screening resulted in 28 studies that met al.l inclusion criteria (Fig. 1).[311-37] Baseline characteristics and the results of quality assessment for included studies are reported on Table 2A. Within the cohort of 1773 eyes for which there was relevant demographic information, the mean age was 71.4 ± 5.4 years (n = 1606; cohort range: 54.4-78.8 years), and 747 out of 1662 eyes were male (44.9%). Most eyes came from Caucasian patients (870 out of 1089 eyes, 79.9%). Generally, studies were moderate to high quality (Tables 2B and C). No study met the a priori condition for exclusion based on the quality assessment.

Fig. 1:

Modified preferred reporting Items for systematic reviews and meta-analysis (PRISMA) flow diagram

Table 2A: Baseline demographics of included trials

Study

Country

Single center or multicenter

Study design

2016 journal 2-year cites per document

Number of eyes

Age

Number of males

Number of Caucasians

Mean cup-to-disk ratio

Mean visual field (MD, dB)

Samuelson et al., 2011

United States

Multicenter

Prospective randomized controlled trial

Ophthalmology; 7.40

117

74 ±8

46

83

n/a

–3.75 ± 3.03

Fea etal., 2014

Europe

Multicenter

Prospective randomized controlled trial

Clinical ophthalmology; 1.86

94

64.5 ± 10.3

37

94

n/a

n/a

Buchacra et al., 2011

Spain

Single center

Prospective case series

Clinical ophthalmology; 1.86

10

54.4 ±7.9

9

n/a

n/a

n/a

Ahmed etal., 2014

Armenia

Single center

Prospective case series

Journal of Cataract and Refractive Surgery; 2.69

39

62.8 ± 12.6

21

39

0.7 ±0.1

–6.47 ± 7.2

Voskanyan et al., 2014

Europe

Multicenter

Prospective case series

Advances in therapy; 2.98

99

66.4 ± 10.9

43

95

0.7 ±0.2

n/a

Vandewalle et al., 2009

Belgium

Single center

Prospective case series

Bulletin de la Societe Beige d’Ophtalm ologie; 0.158 (2015)

10

69

n/a

n/a

n/a

–13.7

Fea, 2010

Italy

Single center

Prospective randomized controlled trial

Journal of Cataract and Refractive Surgery; 2.69

12

64.5 ±3.4

4

n/a

n/a

n/a

Belovay etal., 2012

Canada

Single center

Prospective case series

Journal of Cataract and Refractive Surgery; 2.69

26

78.8 ± 7

7

18

0.76 ±0.16

–12.6 ±7.1

2nd study arm

Canada

Single center

Prospective case series

Journal of Cataract and Refractive Surgery; 2.69

23

75 ± 7.3

9

11

0.71 ±0.17

.-10.2 ±8.1

Patel etal., 2013

United Kingdom

Single center

Prospective case series

Clinical and Experimental Ophthalmology; 2.93

44

76.8

n/a

n/a

n/a

n/a

Arriola- Villalobos et al., 2012)

Spain

Single center

Prospective case series

British Journal of Ophthalmology; 3.52

19

74.63 ± 8.44

9

19

n/a

n/a

Arriola-Villalobos et al., 2013

Spain

Single center

Prospective case series

British Journal of Ophthalmology; 3.52

20

75.1 ± 8.6

9

20

n/a

n/a

Fernandez-Barrientos et al., 2010

Spain

Single center

Prospective randomized controlled trial

Investigative Ophthalmology and Visual Science; 3.15

17

75.2 ±7.2

6

n/a

n/a

n/a

Spiegel etal., 2009

Europe

Multicenter

Prospective case series

European Journal of Ophthalmology; 1.15

47

76.2 ±6.7

18

46

n/a

n/a

Wang etal., 2015

Canada

Single center

Retrospective case series

Journal of Ophthalmology; 1.79

96

70.6 ±2.8

53

86

n/a

–7.3 ±2.1

Klamann etal., 2015

Germany

Single center

Retrospective case series

Graefe’s Archive for Clinical and Experimental Ophthalmology; 2.42

35

61.3 ±3.5

15

n/a

n/a

n/a

Khan etal., 2015

Canada and United States

Multicenter

Retrospective case series

Journal of Cataract and Refractive Surgery; 2.69

49

77.5 ±11.9

20

34

n/a

–11.5 ±8.0

Seibold etal., 2016

United States

Single center

Retrospective case series

Journal of Cataract and Refractive Surgery; 2.69

64

73.9 ±8.8

23

34

n/a

n/a

Gallardo etal., 2016

United States

Single center

Retrospective case series

Clinical Ophthalmology; 1.86

100

74.6 ±8.9

37

14

0.7 ±0.2

n/a

Ferguson et al., 2016

United States

Single center

Retrospective case series

Clinical Ophthalmology; 1.86

350

74.1 ± 9.0

133

n/a

n/a

n/a

Lindstrom et al., 2016

Armenia

Single center

Prospective case series

Advances in Therapy; 2.98

57

65.3 ±9.0

30

57

0.7 ±0.1

–4.9 ±5.3

El Wardani etal., 2015

Switzerland

n/a

Retrospective case series

Klinische Monatsblatter fur Augenheilkunde; 0.52

31

n/a

n/a

n/a

n/a

n/a

2nd Study Arm

Switzerland

n/a

Retrospective case series

Klinische Monatsblatter fur Augenheilkunde; 0.52

22

n/a

n/a

n/a

n/a

n/a

Katzetal., 2015

Armenia

Single center

Prospective randomized controlled trial

Clinical Ophthalmology; 1.86

38

68.1 ± 9.1

27

38

0.68 ±0.11

–4.72 ± 4.42

2nd Study Arm

Armenia

Single center

Prospective randomized controlled trial

Clinical Ophthalmology; 1.86

41

67.8 ±9.3

19

41

0.71 ±0.14

–5.20 ± 5.65

3rd Study Arm

Armenia

Single center

Prospective randomized controlled trial

Clinical Ophthalmology; 1.86

40

60.9 ±8.1

19

40

0.70 ±0.12

–4.81 ± 4.22

Shiba etal., 2017

Japan

Single center

Prospective case series

Journal of Ophthalmology; 1.79

10

64.6 ± 10.7

7

0

n/a

–15.4 ±8.1

Zheng etal., 2017

USA

Single center

Retrospective case series

International Journal of Ophthalmology; 1.30

34

74

9 of 30

21 of 30

n/a

n/a

Berdahl etal., 2017

Armenia

Single center

Prospective case series

Clinical & Experimental Ophthalmology; 2.93

53

64.7 ±9.6

27

53

0.7 ±0.1

n/a

Ferguson et al., 2017

USA

Single center

Retrospective case series

Journal of Cataract and Refractive Surgery; 2.69

115

77.42 ±8.51

86

n/a

0.68 ±0.11

n/a

Gonnermann et al., 2017

Germany

Single center

Retrospective case series

Graefe’s Archivefor Clinical and Experimental Ophthalmology; 2.42

27

73.8 ±7.8

13

27

n/a

n/a

Kurji etal., 2017

Canada

Single center

Retrospective case series

Canadian Journal of Ophthalmology; 1.57

34

75.02 ± 10.34

11

n/a

n/a

n/a

*MD = Mean deviation; dB = Decibels; n/a = Not available.

Table 2B: Quality assessment of included randomized controlled trials (Cochrane criteria)

Study

Year

Random sequence generation (Selection bias)

Allocation concealment (Selection bias)

Blinding of participants and personnel (Performance bias)

Blinding of outcome assessment (Detection bias)

Incomplete outcome data (Attrition bias)

Selective reporting (Reporting bias)

Other bias

Samuelson et al.

2011

Low

Unclear

High

Low

High

Low

Low

Fea et al.

2014

Unclear

Unclear

High

High

Low

Low

Low

Fea

2010

Low

Unclear

Low

Low

Low

Low

Low

Fernandez-Barrientos et al.

2010

Low

Unclear

Unclear

Low

Low

Low

Low

Katz et al.

2015

Unclear

Unclear

High

High

Low

Low

Low

Table 2C: Quality assessment of included case series (National Institute for Health and Care Excellence Criteria)

Study

Year

Multicen-tered

Study objective described

Inclusion and exclusion criteria reported

Outcomes definition reported

Prospective

Consecutive recruitment

Description of study findings

Stratification of out-omes

Buchacra et al.

2011

No

Yes

Yes

No

Yes

Unclear

Yes

No

Ahmed et al.

2014

No

Yes

No

Yes

Yes

Unclear

Yes

No

Voskanyan et al.

2014

Yes

Yes

Yes

Yes

Yes

Unclear

Yes

No

Vandewalle et al.

2009

No

Yes

Yes

Yes

Yes

Unclear

Yes

No

Belovay et al.

2012

No

Yes

Yes

No

Yes

Unclear

Yes

No

Patel et al.

2013

No

Yes

Yes

No

Yes

Unclear

Yes

No

Arriola- Villalobos et al.

2012

No

Yes

Yes

No

Yes

Unclear

Yes

No

Arriola- Villalobos et al.

2013

No

Yes

Yes

No

Yes

Yes

Yes

No

Spigel et al.

2009

Yes

Yes

Yes

No

Yes

Unclear

Yes

No

Wang et al.

2015

No

Yes

No

Yes

No

Yes

Yes

Yes

Klamann et al.

2015

No

Yes

Yes

Yes

No

Yes

Yes

No

Khan et al.

2015

Yes

Yes

Yes

No

No

Unclear

Yes

Yes

Seibold et al.

2016

No

Yes

Yes

Yes

No

Unclear

Yes

No

Gallardo et al.

2016

No

Yes

Yes

Yes

No

Yes

Yes

Yes

Ferguson et al.

2016

No

Yes

Yes

Yes

No

Yes

Yes

Yes

Lindstrom et al.

2016

No

Yes

Yes

Yes

Yes

Unclear

Yes

No

El Wardani et al.

2015

No

Yes

Yes

Yes

No

Yes

Yes

Yes

Shiba et al.

2017

No

Yes

Yes

Yes

Yes

Yes

Yes

No

Zheng et al.

2017

No

Yes

Yes

No

No

Unclear

Yes

No

Berdahl et al.

2017

No

Yes

Yes

Yes

Yes

Unclear

Yes

No

Ferguson et al.

2017

No

No

Yes

Yes

Yes

Yes

Yes

Yes

Gonnermann et al.

2017

No

Yes

Yes

Yes

No

Unclear

Yes

No

Kurji et al.

2017

No

Yes

Yes

Yes

No

Yes

Yes

Yes

Of the 1767 eyes included in the efficacy and adverse event analysis, a total of 1217 (68.9%) underwent combined iStent implantation and phacoemulsification, while 497 eyes (28.1%) underwent iStent implantation alone (Table 3). More than half of included eyes had one iStent implanted (999, 56.5%), while 685 eyes had two (38.8%) and 63 eyes received three (3.6%). Overall, the vast majority of eyes (1398, 79.1%) received a first generation iStent, while only 369 eyes (20.9%) received an iStent inject. The distribution of relevant clinical features between groups is presented in Table 4.

Table 3: Efficacy endpoints and stratification characteristics of included trials

Study

Numbei of Eyes

IOP ’ reduction

IOP Preoperative

IOP Postopera-tively

Reduction in medications

Number of Medica-tions Preopera-tively

Number of Medications Postopera-tively

Follow-up (months)

Number of iStents

Combined Phacoe– mulsification

iStent Generation

Type of Glaucoma

Samuelson et al., 2011

117

8.4± 3.6

25.2 ±3.5

n/a

1.4±0.8

1.5 ±0.7

0.2±0.6

12

1

Yes

First

Any

Fea et al., 2014

94

12.2± 2.5

25.2 ±1.4

13.0±2.3

n/a

1.0±0

n/a

12

2

No

Second

Primary

Buchacra et al., 2011

8

6.6±5.4

26.5± 7.9

17.0±2.5

1.1±0.6

2.9±0.7

2

12

1

No

First

Secondary

Ahmed et al., 2014

39

13.5

25.3 ±1.8

11.8±2.1

1.0±0

2.0±0

1.0±0

18

2

No

First

Any

Voskanyan et al., 2014

88

10.4±3.2

26.3± 3.5

15.7±3.7

n/a

2.21±0.44

n/a

12

2

No

Second

Pseudoexfol iative

Vandewalle et al., 2009

9

4.2

20

15.8

1

2.7

1.7

12

1

Mixed

First

Primary

Fea, 2010

12

3.2±3

17.9± 2.6

14.8±1.2

1.6

2±0.9

0.4±0.7

15

1

Yes

First

Primary

Belovay et al., 2012

28

3.5

17.3±4

13.8±4

1.8

2.8±0.8

1.0±1.1

12

2

Yes

First

Primary, mixed

2nd study arm

25

3.9

18.6±4

14.8±3

2.2

2.6±1.2

0.4±0.5

12

3

Yes

First

Primary, mixed

Patel et al., 2013

44

5

21.5 ±5

16.5±3

1.7

2.3±0.9

0.6±1.0

6

1

Mixed

First

Any

Arriola Villalobos et al., 2012

19

3.16±3.9

19.42±1.89

16.26±4.23

0.47±0.96

1.32±0.48

0.84±0.89

Mean: 53.68±9.26

1

Yes

First

Any

Arriola-Villalobos et al., 2013

20

9.42±3

26±3.11

16.75±2.24

1±0.79

1.3±0.66

0.3±0.57

12

1 or 2

Yes

Second

Any open angle

Fernandez-Barrientos et al., 2010

17

6.6±3.0

24.2±1.8

17.6±2.8

1.1

1.1±0.5

0

12

2

Yes

First

Primary

Spiegel et al., 2009

42

4.4±4.54

21.7±3.98

17.4±2.99

1.2±0.7

1.6±0.8

0.4±0.62

12

1

Yes

First

Primary

Wang et al., 2015

96

2.50±5.80

n/a

n/a

1.38±1.43

2.14±0.16

0.76

3

2

Yes

First

Any

Klamann et al., 2015

32

7.67

22.39±1.81

14.72±0.80

1.3

2.26±0.1

0.96±0.11

6

2

No

Second

Primary, pseudoexfol iative, pigmentary

Khan et al., 2015

49

n/a

19.6±5.2

14.3±3.1

n/a

2.86±0.91

1.22±1.28

12

2

Yes

First

Primary, pseudoexfol iative, pigmentary

Seibold et al., 2016

64

1.5

14.7±3.2

13.2±2.8

0.4

1.8±1.1

1.4±1.5

12

1

Yes

First

Any

Gallardo et al., 2016

134

3.6

16.5±3.7

12.9±2.1

1.4

2.3±1.1

0.9±1.2

12

1

Yes

First

Primary

Ferguson et al., 2016

350

4.0

19.1±6.3

15.2±3.5

0.6

1.2±1.0

0.6±1.0

24

1

Yes

First

Primary

Lindstrom et al., 2016

57

10.0

24.4±1.3

14.4±2.1

1.0

1.0±0

0.02

18

2

No

Second

Primary

El Wardani et al., 2015

31

1.6

16.7

15.1

1.7

2.5

0.8

6

1

Yes

First

N/a

2nd Study Arm

22

3.2

17

13.8

1.1

2.1

1

6

2

Yes

First

N/a

Katz et al., 2015

37

10.6

25.0±1.1

14.4 ±1.2

1.6

1.71± 0.61

0.11

12

1

No

First

Primary, pseudoexfol iative, pigmentary

2nd study arm

41

12.2

25.0±1.7

12.8 ±1.4

1.66

1.76±0.54

0.10

12

2

No

First

Primary, pseudoexfol iative, pigmentary

3rd study arm

38

12.9

25.1±1.9

12.2 ±1.5

1.43

1.51± 0.69

0.08

12

3

No

First

Primary, pseudoexfol iative, pigmentary

Shiba et al., 2017

10

5.1

22.0±3.0

16.9 ±3.6

0

3± 0

3±0

6

2

No

First

Primary

Zheng et al., 2017

17

3

19.7±4.1

16.7 ±2.1

1.4

2.2± 1.2

0.8±1.3

6

1

Yes

First

Any

Berdahl et al., 2017

53

6.8

19.7±1.5

12.9 ±2.1

1±0

2± 0

1±0

18

2

No

Second

Any

Ferguson et al., 2017

115

5.49

20.00 ±6.95

14.51 ±2.79

0.7

1.41± 1.04

0.71

24

1

Yes

First

Pseudoexfol iative

Gonnerman n et al., 2017

25

7.8

21.3±4.1

0. 13.5 ±5

0.72

2.0± 0.9

1.28±1.17

12

2

Yes

Second

Primary, pseudoexfol iative

Kurji et al., 2017

34

3.87

17.47 ±4.87

13.6 ±3.4

0.32±0.59

2.15± 1.21

1.83±1.2

6

2

yes

First

Primary, pseudoexfol iative

* IOP = intraocular pressure.

Table 4: Distribution of clinical features for first generation studies by type of analysis

Type of analysis		Baseline feature		Comparator 1		Comparator 2		Proportion of baseline feature in comparator 1 (%)		Proportion of baseline feature in comparator 2
Number of iStents-reduction in IOP		Phacoemulsification status		One iStent		Two iStents		iStent alone: 45/999 (4.5%)		iStent alone: 90/287 (31.4%)
Number of iStents-preoperative IOP		Phacoemulsification status		One iStent		Two iStents		iStent alone: 45/999 (4.5%)		iStent alone: 90/240 (37.5%)
Number of iStents-postoperative IOP		Phacoemulsification status		One iStent		Two iStents		iStent alone: 45/882 (5.1%)		iStent alone: 90/240 (37.5%)
Number of iStents-reduction in medications		Phacoemulsification status		One iStent		Two iStents		iStent alone: 45/999 (4.5%)		iStent alone: 90/287 (31.4%)
Number of iStents-preoperative medications		Phacoemulsification status		One iStent		Two iStents		iStent alone: 45/999 (4.5%)		iStent alone: 90/336 (26.8%)
Number of iStents- postoperative medications		Phacoemulsification status		One iStent		Two iStents		iStent alone: 45/999 (4.5%)		iStent alone: 90/336 (26.8%)
Number of iStents-reduction in IOP		Phacoemulsification status		One iStent		Three iStents		iStent alone: 45/999 (4.5%)		iStent alone: 38/63 (60.3%)
Number of iStents-preoperative IOP		Phacoemulsification status		One iStent		Three iStents		iStent alone: 45/999 (4.5%)		iStent alone: 38/63 (60.3%)
Number of iStents-postoperative IOP		Phacoemulsification status		One iStent		Three iStents		iStent alone: 45/882 (5.1%)		iStent alone: 38/63 (60.3%)
Number of iStents-reduction in medications		Phacoemulsification status		One iStent		Three iStents		iStent alone: 45/999 (4.5%)		iStent alone: 38/63 (60.3%)
Number of iStents-preoperative medications		Phacoemulsification status		One iStent		Three iStents		iStent alone: 45/999 (4.5%)		iStent alone: 38/63 (60.3%)
Number of iStents - postoperative medications		Phacoemulsification status		One iStent		Three iStents		iStent alone: 45/999 (4.5%)		iStent alone: 38/63 (60.3%)
Number of iStents -reduction in IOP		Phacoemulsification status		Two iStents		Three iStents		iStent alone: 90/287 (31.4%)		iStent alone: 38/63 (60.3%)
Number of iStents -preoperative IOP		Phacoemulsification status		Two iStents		Three iStents		iStent alone: 90/240 (37.5%)		iStent alone: 38/63 (60.3%)
Number of iStents -postoperative IOP		Phacoemulsification status		Two iStents		Three iStents		iStent alone: 90/240 (37.5%)		iStent alone: 38/63 (60.3%)
Number of iStents -reduction in medications		Phacoemulsification status		Two iStents		Three iStents		iStent alone: 90/287 (31.4%)		iStent alone: 38/63 (60.3%)
Number of iStents -preoperative medications		Phacoemulsification status		Two iStents		Three iStents		iStent alone: 90/336 (26.8%)		iStent alone: 38/63 (60.3%)
Number of iStents - postoperative medications		Phacoemulsification status		Two iStents		Three iStents		iStent alone: 90/336 (26.8%)		iStent alone: 38/63 (60.3%)
Phacoemulsification status - IOP reduction		Number of iStents		iStent alone		Phaco-iStent		One iStent: 45/173 (26.0%)		One iStent: 901/1123 (80.2%)
Phacoemulsification status - preoperative IOP		Number of iStents		iStent alone		Phaco-iStent		One iStent: 45/173 (26.0%)		One iStent: 901/1076 (83.7%)
Phacoemulsification status - postoperative IOP		Number of iStents		iStent alone		Phaco-iStent		One iStent: 45/173 (26.0%)		One iStent: 784/959 (81.8%)
Phacoemulsification status - reduction in medications		Number of iStents		iStent alone		Phaco-iStent		One iStent: 45/173 (26.0%)		One iStent: 901/1123 (80.2%)
Phacoemulsification status -preoperative medications		Number of iStents		iStent alone		Phaco-iStent		One iStent: 45/173 (26.0%)		One iStent: 901/1172 (76.9%)
Phacoemulsification status -postoperative medications		Number of iStents		iStent alone		Phaco-iStent		One iStent: 45/173 (26.0%)		One iStent: 901/1172 (76.9%)

IOP = intraocular pressure.

In terms of study design, the majority (19/28; 67.9%) of studies were case series, while another 17.9% (5/28) were randomized controlled trials. A total of 60.7% of studies were prospective (17/28), while the rest (11/28, 39.3%) were retrospective. Most studies (22/27; 81.5%) extracted data from a single center while a smaller number were multicentered (5/27; 18.5%).

Number of iStents-First Generation

Not accounting for phacoemulsification status, meta-analysis was only possible to evaluate the effect of the number of stents on IOP and medication class reduction for first generation iStents (Table 5A-C, Figs 2A and B). When examining IOP reduction, there was a significantly greater decrease after two stents compared to one [WMD = -1.36 mm Hg, 95% CI = (-1.92 mm Hg, -0.80 mm Hg), p < 0.001]. This may have been influenced by the fact that two-stent patients had a significantly greater preopera-tive IOP than one-stent patients [WMD = -1.35 mm Hg, 95% CI = (-1.85 mm Hg, -0.85 mm Hg), p < 0.001]. At the same time, implantation of two stents led to a lesser postoperative IOP when compared to one [WMD = 1.02 mm Hg, 95% CI = (0.80 mm Hg, 1.24 mm Hg), p < 0.001]. There was a greater IOP reduction [WMD= -4.66 mm Hg, 95% CI = (-6.20 mm Hg, -3.12 mm Hg), p < 0.001], higher preoperative IOP [WMD = -2.80 mm Hg, 95% CI = (-3.93 mm Hg, -1.67 mm Hg), p < 0.001] and lower postoperative IOP [WMD = 1.57 mm Hg, 95% CI = (1.12 mm Hg, 2.02 mm Hg), p < 0.001] following three stents relative to one. There was a greater IOP reduction [WMD = -3.30 mm Hg, 95% CI = (-4.93 mm Hg, -1.67 mm Hg), p < 0.001], higher preoperative IOP [WMD = -1.45 mm Hg, 95% CI = (-2.65 mm Hg, -0.25 mm Hg), p = 0.02] and a lower postoperative IOP [WMD = 0.55 mm Hg, 95% CI =(0.06 mm Hg, 1.04 mm Hg), p = 0.03] after three stents relative to two.

Table 5A: Efficacy outcomes of one versus two first generation iStent implantation

		One iStent						Two iStents						Meta-analysis
Outcome		Mean		Standard deviation		Number of eyes		Mean		Standard deviation		Number of eyes		Weighted mean difference		95% CI - lower bound		95% CI – upper bound		p-value
IOP reduction		4.67		2.18		999		6.03		4.66		355		–1.36		–1.86		–0.86		p <0.001
Preoperati ve IOP		19.72		3.06		999		21.07		3.66		240		–1.35		–1.85		–0.85		p <0.0
Postopera tive IOP		14.80		1.25		882		13.78		1.62		240		1.02		0.80		1.24		p <0.001
Reduction in medications		0.97		0.46		999		1.20		0.51		287		–0.23		–0.30		–0.16		p <0.001
Preoperati ve medicatio ns		1.62		0.48		999		2.21		0.48		336		–0.59		–0.65		–0.53		p <0.0 01
Postopera tive medications		0.67		0.34		999		0.95		0.64		336		–0.28		–0.35		–0.21		p <0.001

*IOP = Intraocular pressure. CI = Confidence interval

Table 5C: Efficacy outcomes of two versus three first generation iStent implantation

		Two iStents						Three iStents						Meta-Analysis
Outcome		Mean		Standard deviation		Number of eyes		Mean		Standard deviation		Number of eyes		Weighted mean difference		95%CI –Lower bound		95%CI –Upper bound		p-value
IOP reduction		6.03		4.66		287		9.33		6.23		63		–3.30		–4.93		–1.67		p <0.001
Preoperative IOP		21.07		3.66		240		22.52		4.50		63		–1.45		–2.65		–0.25		p = 0.02
Postoperative IOP		13.78		1.62		240		13.23		1.80		63		0.55		0.06		1.04		p = 0.03
Reduction in medications		1.20		0.51		287		1.74		0.53		63		–0.54		–0.68		–0.40		p <0.001
Preoperative medications		2.21		0.48		336		1.94		0.75		63		0.27		0.08		0.46		p = 0.006
Postoperative medications		0.95		0.64		336		0.21		0.22		63		0.74		0.65		0.83		p <0.001

*IOP = Intraocular pressure. CI = Confidence interval. n/a = Not available. Note: Red text denotes endpoints that substantially differed from those of the original analysis.

Fig. 2A:

Number of first generation iStents-IOP

Fig. 2B:

Number of First Generation iStents-number of medication classes

For the number of hypotensive medication classes, there was a greater reduction in medication classes following two iStents relative to one [WMD = -0.23, 95% CI = (-0.30, -0.16), p < 0.001]. There was a significantly greater number of medication classes in two stent patients compared to one both preoperatively [WMD = -0.59, 95% CI = (-0.65, -0.53), p < 0.001] and postoperatively [WMD = -0.28, 95% CI = (-0.35, -0.21), p < 0.001]. Comparing between one and three stents, there was a significantly higher number of medication classes [WMD = -0.32, 95%CI = (-0.51, -0.13), p < 0.001] in the three stent cohort preoperatively, as well as a greater reduction in medication class number [WMD = -0.77, 95% CI = (-0.90, -0.64), p < 0.001). Postoperatively, the three stent group had a significantly lower medication class count [WMD = 0.46, 95% CI = (0.40, 0.52), p < 0.001]. There was a greater reduction in medication classes [WMD = -0.54, 95% CI = (-0.68, -0.40), p < 0.001], lower preoperative [WMD = 0.27, 95% CI = (0.08, 0.46), p = 0.006] and lower postoperative medication class count [WMD = 0.74, 95% CI = (0.65, 0.83), p < 0.001] following three stents relative to two.

Phacoemulsification Status-First Generation

Next, studies were categorized by whether phacoemulsification was performed, irrespective of the number of first-generation iStents (Table 6A, Figs 3A and B). Data revealed that the iStent alone group produced a significantly more pronounced reduction in IOP than the phaco-iStent cohort [WMD = -7.44 mm Hg, 95% CI = (-7.82 mm Hg, -7.06 mm Hg), p < 0.001]. The iStent alone group also had a significantly greater preoperative IOP than the phaco-iStent cohort [WMD = -5.72 mm Hg, 95% CI = (-5.93 mm Hg, -5.51 mm Hg), p < 0.001]. Nonetheless, the iStent alone cohort had a lower postoperative IOP relative to the phaco-iStent cohort [WMD = 1.42 mm Hg, 95% CI = (1.15 mm Hg, 1.69 mm Hg), p < 0.001].

Table 6A: First Generation iStent - Efficacy Outcomes of Phaco-iStent versus iStent Implantation Alone

		Phaco-istent						Istent implantation alone						Meta-analysis
Outcome		Mean		Standard deviation		Number of eyes		Mean		Standard deviation		Number of eyes		Weighted mean difference		95% CI –Lower bound		95% CI –Upper bound		P-value
IOP reduction Preoperative		4.20		1.82		1123		11.64		2.47		173		–7.44		–7.82		–7.06		p <0.001
IOP Postoperative		19.27		2.78		1076		24.99		0.88		173		–5.72		–5.93		–5.51		p <0.001
IOP Reduction in		14.64		1.21		959		13.22		1.72		173		1.42		1.15		1.69		p <0.001
medications		0.99		0.49		1123		1.33		0.46		173		–0.34		–0.41		–0.27		p <0.001
Preoperative medications		1.62		0.60		1172		1.87		0.44		173		–0.25		–0.32		–0.18		p <0.001
Postoperative medications		0.73		0.36		1172		0.55		0.87		173		0.18		0.05		0.31		p = 0.007

*IOP = Intraocular pressure. CI = Confidence interval. Note: Red text denotes endpoints that substantially differed from those of the original analysis.

Fig. 3A:

First generation phaco-iStent versus iStent alone-IOP

Fig. 3B:

First generation phaco-iStent versus iStent alone-number of medication classes

Preoperatively, patients receiving combined phaco-iStent were taking significantly fewer medication classes relative to the iStent alone group [WMD = -0.25 mm Hg, 95% CI = (-0.32 mm Hg, -0.18 mm Hg), p < 0.001]. There was a significantly greater reduction in medication class number following iStent alone [WMD=-0.34mmHg, 95% CI = (-0.41 mm Hg, -0.27 mm Hg), p < 0.001] along with a significantly lower postoperative medication class number in the iStent alone arm relative to phaco-iStent [WMD = 0.18 mm Hg, 95% CI = (0.05 mm Hg, 0.31 mm Hg), p = 0.007].

The combination of phacoemulsification and a first generation iStent was also compared to phacoemulsification alone (Table 6B, Figs 4A and B). This comparison only included studies that contained both a phaco-iStent arm and a phacoemulsification alone arm. For this analysis, there was a significantly greater IOP reduction [WMD = 1.68 mm Hg, 95% CI = (1.11 mm Hg, 2.25 mm Hg), p < 0.001] and a higher preoperative IOP [WMD = 2.15 mm Hg, 95% CI = (1.35 mm Hg, 2.95 mm Hg), p < 0.001] following phaco-iStent relative to phacoemulsification alone. However, there was no significant difference between comparators for postoperative IOP (p = 0.07). Phaco-iStent resulted in a significantly more pronounced reduction in medication class number [WMD = 0.80 mm Hg, 95% CI = (0.75 mm Hg, 0.85 mm Hg), p < 0.001] and lower postoperative number of medication classes [WMD = -0.69 mm Hg, 95% CI = (-0.78 mm Hg, -0.60 mm Hg), p < 0.001] relative to phacoemulsification alone. Preoperatively, there was no significant difference between comparators (p = 0.78).

Table 6B: First Generation iStent-Efficacy Outcomes of Phaco-iStent versus Phacoemulsification Alone

		Phaco-istent						Phacoemulsification alone						Meta-analysis
Outcome		Mean		Standard deviation		Number eyes		of Mean		Standard deviation		Number of eyes		Weighted mean difference		95%Ci –Lower bound		95%Ci –Upper bound		P-value
IOP reduction		6.30		3.10		199		4.62		3.47		319		1.68		1.11		2.25		p <0.001
Preoperative IOP		22.44		4.24		199		20.29		4.93		319		2.15		1.35		2.95		p <0.001
Postoperative IOP		15.23		1.53		82		14.84		1.80		196		0.39		–0.03		0.81		p = 0.07
Reduction in medications		1.40		0.21		199		0.60		0.36		319		0.80		0.75		0.85		p <0.001
Preoperative medications		1.72		0.47		199		1.71		0.25		319		0.01		–0.06		0.08		p = 0.78
Postoperative medications		0.38		0.36		199		1.07		0.63		319		–0.69		–0.78		–0.60		p <0.001

*IOP = Itraocular pressure. CI = Confidence interval. Note: Red text denotes endpoints that substantially differed from those of the original analysis.

Fig. 4A:

First generation phaco-iStent versus phacoemulsification alone-IOP

Fig. 4B:

First generation phaco-iStent versus phacoemulsification alone-number of medication classes

Phacoemulsification Status-Second Generation

For the second generation iStent inject, studies reporting on iStent alone had a significantly greater IOP reduction [WMD = -1.47 mm Hg, 95% CI = (-1.88 mm Hg, -1.06 mm Hg), p < 0.001] and a greater preoperative IOP [WMD = -0.79 mm Hg, 95% CI = (-1.54 mm Hg, -0.04 mm Hg), p = 0.04] compared to studies reporting on phaco-iStent (Table 7, Fig. 5A). Postoperatively, the phaco-iStent cohort had a significantly higher IOP relative to iStent alone [WMD = 0.81 mm Hg, 95% CI = (0.13 mm Hg, 1.49 mm Hg), p < 0.001]. There was a significantly greater reduction in medication classes [WMD=-0.22, 95% CI = (-0.28, -0.16), p < 0.001], higher number of pre-operative medication classes [WMD = 0.20, 95% CI = (0.04, 0.36), p = 0.01] and a lower number of postoperative medication classes [WMD = 0.24, 95% CI = (0.02, 0.46), p = 0.03] following iStent alone relative to phaco-iStent (Fig. 5B).

Table 7: Second generation iStent - efficacy outcomes of phaco-iStent versus iStent implantation alone

		Phaco-iStent						iStent i mplantation Alone						Meta-analysis
Outcome		Mean		Standard deviation		Number of eyes		Mean		Standard deviation		Number of eyes		Weighted mean difference		95% CI –Lower bound		95% CI– Upper bound		p-value
IOP reduction		8.52		1.14		45		9.99		2.14		324		–1.47		–1.88		–1.06		p <0.001
Preoperative IOP		23.39		2.39		45		24.18		2.53		324		–0.79		–1.54		–0.04		p = 0.04
Postoperative IOP		14.94		2.28		45		14.13		1.29		324		0.81		0.13		1.49		p = 0.02
Reduction in medications		0.84		0.20		45		1.06		0.16		142		–0.22		–0.28		–0.16		p <0.001
Preoperative medications		1.69		0.49		45		1.49		0.64		324		0.20		0.04		0.36		p = 0.01
Postoperative medications		0.84		0.69		45		0.60		0.58		142		0.24		0.02		0.46		p = 0.03

*IOP = Intraocular pressure. CI = Confidence interval.

Fig. 5A:

Second generation phaco-iStent versus iStent alone-IOP

Fig. 5B:

Second generation phaco-iStent versus iStent alone-number of medication classes

Adverse Event Analysis

Overall, a total of 261 out of 1159 eyes (22.5%) that received iStent implantation sustained some type of adverse event (Table 8). In order from most to least common, the following adverse events were reported: IOP elevation or spike (reported in 12 of 27 papers; 44.4%), stent blockage or obstruction (8/27; 29.6%), stent malposition (7/27; 25.9%), hyphema (6/27; 22.2%), progression of cataract (3/27; 11.1%), blood reflux (3/27; 11.1%), corneal event (3/27; 11.1%), early postoperative event (2/27; 7.4%), stent not visible (2/27; 7.4%), formation of peripheral anterior synechiae (2/27; 7.4%), need for additional surgery (2/27, 7.4%), hypotony (1/27; 3.7%), posterior capsular opacification (1/27; 3.7%), replacement applicator (1/27; 3.7%), patients soreness/discomfort (1/27; 3.7%), transient visual acuity loss (1/27; 3.7%), intraoperative hemorrhage (1/27; 3.7%) and subconjunctival hemorrhage (1/27, 3.7%). Most studies reported either stable or improved visual acuity at last follow-up.

Table 8: Safety endpoints of included trials

Study

Number ofeyes

Complications

Adverse event 1

Adverse event 2

Adverse event 3

Adverse event 4

Visual acuity change

Samuelson et al., 2011

111

37

Anticipated early postoperative event

Stent obstruction

Posterior capsular opacification

Stent malposition

97% BCVA improvement

Fea et al., 2014

94

3

IOP elevation

Soreness/ discomfort

Stent not visible

n/a

Five people experienced decrease

Buchacra et al., 2011

8

17

Hyphema

IOP elevation

Corneal edema

n/a

No significant change

Ahmed et al., 2014

39

7

Hypotony

Progression of cataract

Transient visual acuity loss

n/a

CDVA maintained in most eyes

Voskanyan et al., 2014

88

18

IOP elevation

Stent obstruction

Progression of cataract

Stent not visible

Slight improvement

Vandewalle et al., 2009

9

10

IOP elevation

Stent malposition

Corneal Erosion

Blood reflux

Stable/improved

Fea, 2010

12

n/a

n/a

n/a

n/a

n/a

n/a

Belovay et al., 2012

28

n/a

Stent blockage

Hyphema

Stent malposition

IOP elevation

Stable/improved

2nd study arm

25

n/a

Stent blockage

Hyphema

Stent Malposition

IOP elevation

Stable/improved

Patel et al., 2013

44

1

Hyphema

n/a

n/a

n/a

Mean improved

Arriola-villalobos et al., 2012

19

12

Stent malposition

Stent blockage

Replacement applicator

IOP elevation

Significantly improved

Arriola-villalobos et al., 2013

20

10

Stent malposition

Stent blockage

Iop elevation

n/a

Significantly improved

Fernandez-barrientos et al., 2010

17

n/a

Stent malposition

n/a

n/a

n/a

n/a

Spiegel et al., 2009

42

22

Stent blockage

Stent malposition

Iop elevation

Cataract surgery Complication

Significantly improved

Wang et al., 2015

96

0

n/a

n/a

n/a

n/a

n/a

Klamann et al., 2015

32

32

Blood reflux

n/a

n/a

n/a

No decrease

Khan et al., 2015

49

26

Peripheral anterior synechiae formation

IOP spike

Early postoperative interventions

Hyphema

n/a

Seibold et al., 2016

64

n/a

n/a

n/a

n/a

n/a

Significant improvement

Gallardo et al., 2016

134

0

n/a

n/a

n/a

n/a

83% of eyes achieved a BCVA of 20/40 or better after surgery relative to 20% preoperatively

Ferguson et al., 2016

350

n/a

IOP spike

n/a

n/a

n/a

n/a

Lindstrom et al.

57

1

Progression of cataract

n/a

n/a

n/a

Stable

El wardani et al.

31

n/a

n/a

n/a

n/a

n/a

n/a

2nd study arm

22

n/a

n/a

n/a

n/a

n/a

n/a

Katz et al.

37

0

n/a

n/a

n/a

n/a

76% of eyes achieved a BCVA of 20/40 or better after surgery relative to 68%

2nd study arm

41

0

n/a

n/a

n/a

n/a

Preoperatively 66% of eyes achieved a BCVA of 20/40 or better after surgery relative to 61%

3rd study arm

38

0

n/a

n/a

n/a

n/a

Preoperatively 80% of eyes achieved a BCVA of 20/40 or better after surgery relative to 73% preoperatively

Shiba et al., 2017

12

Hyphema

Peripheral anterior synechiae

Occlusion by iris

Iop spike

n/a

n/a

Berdahl et al, 2017

n/a

n/a

n/a

n/a

n/a

n/a

Stable

Ferguson et al., 2017

8

Iop spike

Need for additional surgery

n/a

n/a

n/a

n/a

Gonnermann et al 2017

29

Reflux bleeding

Trabulectomy

n/a

n/a

n/a

n/a

Kurji et al., 2017

3

Blocked istent

n/a

n/a

n/a

n/a

Approximate 2 line gain on snellen chart

* BCVA = Best corrected visual acuity; CDVA = Corrected distance visual acuity; IOP = Intraocular pressure.

DISCUSSION

The efficacy and adverse event profile of the iStent device have been explored in a variety of different settings. To evaluate the efficacy and adverse events following iStent implantation based on the consolidation of all peer-reviewed research on the iStent, the present meta-analysis was undertaken.

In a recent meta-analysis by Malvankar-Mehta et al., the efficacy of the iStent without adjunctive phacoemulsification was analyzed in 248 patients from five studies.[40] Meta-analysis revealed a significant reduction in IOP after implantation of one [standardized mean difference (SMD) = -1.68, 95% CI = (-2.7, -0.61)], two [SMD = -1.88, 95% CI = (-2.2, -1.56)] and three iStents [SMD = -2, 95%CI = (-2.62, -1.38)]. Glaucoma medication class number was reduced by a mean of 1.2 bottles after one iStent implant, 1.45 bottles after two iStents and one bottle after three iStents.

Another meta-analysis by the same team aimed to investigate the reduction of IOP after phaco-iStent compared to phacoemulsification alone.[41] A total of 396 patients from 10 studies received phaco-iStent and 1768 patients from 26 studies received phacoemulsification alone. Phaco-iStent produced a significantly greater reduction in IOP relative to cataract extraction alone [SMD = -0.46, 95%CI = (-0.87, -0.06)]. Relative to phacoemulsification alone, phaco-iStent demonstrated a statistically significantly greater reduction in glaucoma medication class number [SMD = -0.65, 95% CI = (-1.18, -0.12)]. Relative to the two studies by Malvankar-Mehta and colleagues, 20 of our 28 included peer reviewed articles have not been reported in previous meta-analyses.[4041]

The greater IOP reduction with multiple iStents compared to one has been documented in previous laboratory studies and was also confirmed by the findings of the present meta-analysis.[42] For instance, both postoperative IOP and IOP reduction were significantly improved in the two-stent comparator relative to one. We hypothesize that a selection bias may have influenced these findings, as the higher initial IOP or more severe disease seen in the two-stent comparator may have contributed to the greater IOP reduction following stent implantation. For patients with high preoperative IOP (average of 22.5 mm Hg), three stents provided a more pronounced level of

IOP reduction (9.3 mm Hg) relative to one or two stents. However, interpretations of the three-stent data should be made with caution, as data from only 63 eyes existed for this comparison.

Regardless of the number of implanted iStents, the cohort that underwent first-generation iStent implantation alone saw a more pronounced IOP reduction and lower postoperative IOP than the phaco-iStent group. However, this comparison considers two different patient populations, namely (1) patients receiving iStent alone, who normally do not have cataracts and are receiving the device specifically for IOP reduction, and (2) patients undergoing combined phacoemulsification and iStent, who are receiving the treatment for both their cataracts and an elevated IOP. As such, the finding of a higher preoperative IOP in the iStent alone group may have influenced the difference in IOP reduction between comparators. Even though some included studies contained both patients who received phaco-iStent and iStent alone, subgroup analysis analyzing the differences in outcomes between these two groups was never performed in individual studies.[1518] As such, the conclusions derived from comparing phaco-iStent versus iStent alone have not been previously established.

Analysis of phaco-iStent compared to phacoemul-sification alone revealed that there was a greater IOP reduction following phaco-iStent relative to phaco-emulsification alone. This aligns with the findings of Malvankar-Mehta et al., who also showed that there was a significantly greater IOP reduction following phaco-iStent relative to phacoemulsification alone [SMD = -0.46, 95% CI = (0.87, -0.06)].[41] Despite the similarity, it is important to note that uncontrolled, one-armed studies examining the efficacy of phacoemulsification alone were included in the previous analysis but were excluded in the present article.[41] Instead, we limited our analysis of phaco-iStent versus phacoemulsification only to the studies that had a phaco-iStent arm and a phacoemulsification only comparator, thus resulting in a more controlled analysis. Beyond analysis of IOP, both meta-analyses concluded that phaco-iStent was statistically superior relative to phacoemulsification alone in the reduction of medication class number pre- to post-operatively.

The adverse event analysis revealed that fewer than 25% of eyes carried some type of adverse event postoperatively, most of which were not serious nor visually threatening. This compares favorably with the postoperative adverse event rates of both trabeculec-tomy and the Baerveldt glaucoma implant.[43] However, due to differential reporting of adverse events between individual studies, caution should be used when interpreting these findings. In our cohort, IOP elevation, stent blockage or obstruction, stent malposition and hyphema were the most common adverse events following iStent implantation.

Beyond the efficacy and adverse event profile, the cost-effectiveness of the iStent relative to topical glaucoma medications has been studied by Iordanous and colleagues.[44] Following implantation of two iStents, the authors analyzed cost differences at 6 years postop-eratively. At 6 years, the iStent was $20.77 more expensive relative to monodrug therapy but was cheaper by $1272.55 compared to bidrug treatment and $2124.71 versus tridrug therapy. The authors concluded that the iStent may offer a modest cost saving when compared to glaucoma medications.

Given that past meta-analyses included lower numbers of eyes receiving iStent implantation (first article: 5 studies, n = 248; second article: 10 studies, n = 396), the present work (28 studies, n = 1767) represents the largest quantitative synthesis of efficacy and adverse event data for the iStent device.[4041] The large statistical power provided by such a high sample size allowed us to conduct certain analyses that were novel to the published literature; for example, an analysis comparing phaco-iStent to iStent alone. We only included published articles, thus ensuring that the rigors of peer-review were met for each included study.

Limitations of the analysis include the fact that there was no restriction of studies based on design. As such, baseline values for included endpoints were significantly different between comparator arms. As shown in Table 4, the relevant clinical features were often not balanced between groups. As noted by Kaplowitz et al., variation in study design and implementation such as length of follow-up, etiology of disease and baseline clinical indicators may account for the high degree of heterogeneity upon meta-analysis.[45] Further, since some articles did not include sociodemographic and clinical characteristics of their study cohorts (e.g. surgeon experience), it is uncertain whether there was a balance of these factors between comparator arms. For instance, there

is variable reporting of surgeon experience in the literature: two articles[1920] noted that the study surgeon was in an early stage in the learning curve, one noted that the data incorporate the surgeon learning curve,[3] and another hypothesized how the learning curve influenced the greater number of adverse events in an initial set of patients.[22] Two studies reported that their surgeons were experienced,[2430] while another found no significant difference in outcomes between initial and late procedures.[28] Another limitation was that the lack of available studies prevented us from performing a robust meta-analysis for some endpoints, such as IOP reduction following three stents, where there was only 63 included patients. Limited reporting of adverse event severity across studies prevented us from analyzing severity in the adverse event analysis. Studies were variable in how they handled medication washout before stent implantation, which made it impossible to analyze the effect of preoperative medications on baseline IOP. Given that data was extracted from study cohorts, conclusions should be limited to the level of the cohort.

CONCLUSION AND CLINICAL SIGNIFICANCE

The following meta-analysis has shown that there may be differences in treatment response for the iStent due to varying parameters, including the number of iStents and phaco-iStent compared to either iStent alone or phaco-emulsification alone. In our analysis, two stents delivered a greater response in terms of IOP reduction relative to one and iStent alone had a significantly greater IOP reduction compared to phaco-iStent. Combined phaco-iStent was statistically superior relative to phacoemulsification alone in the reduction of IOP and medication classes pre-to post-operatively. Future research should determine whether similar conclusions are reached following meta-analysis in a more controlled environment.

ETHICAL APPROVAL

This article does not contain any studies with human participants or animals performed by any of the authors. As such, there was no informed consent process needed for this study.

Conception and design of study: M.P., X.C.M., I.I.K.A.

Acquisition of data: M.P., X.C.M.

Analysis and interpretation of data: M.P., X.C.M., H.S., I.I.K.A.

Drafting and revising article: M.P., X.C.M., H.S., I.I.K.A.

Final approval of the version to be submitted: M.P., X.C.M., H.S., I.I.K.A.

Table 5B: Efficacy outcomes of one versus three first generation iStent implantation

		One iStent						Three iStents						Meta-Analysis
Outcome		Mean		Standard deviation		Number of eyes		Mean		Standard deviation		Number of eyes		Weighted mean difference		95%CI –Lower bound		95%CI –Upper bound		p-value
IOP reduction Preoperative		4.67		2.18		999		9.33		6.23		63		–4.66		–6.20		–3.12		p <0.001
IOP Postoperative		19.72		3.06		867		22.52		4.50		63		–2.80		–3.93		–1.67		p <0.001
IOP Reduction in		14.80		1.25		882		13.23		1.80		63		1.57		1.12		2.02		p <0.001
medications Preoperative		0.97		0.46		999		1.74		0.53		63		–0.77		–0.90		–0.64		p <0.001
medications		1.62		0.48		999		1.94		0.75		63		–0.32		–0.51		–0.13		p <0.001
Postoperative medications		0.67		0.34		999		0.21		0.22		63		0.46		0.40		0.52		p <0.001

*IOP = Intraocular pressure. CI = Confidence interval. n/a = Not available. Note: red text denotes endpoints that substantially differed from those of the original analysis.