- Email: [email protected]
Comparison of Fibrin Glue versus Suture for Conjunctival Autografting in Pterygium Surgery: A Meta-Analysis
Comparison of Fibrin Glue versus Suture for Conjunctival Autografting in Pterygium Surgery: A Meta-Analysis Hong-Wei Pan, MD, PhD,1,2,3 Jing-Xiang Zhong, MD,1 Chun-Xia Jing, PhD4 Purpose: To evaluate the safety and clinical efficacy of fibrin glue in pterygium surgery with conjunctival autografting. Design: The use of fibrin glue has been introduced in the treatment of pterygium. However, its role versus traditional suturing is still a matter of debate. We performed a meta-analysis to compare the safety and clinical efficacy of fibrin glue with suture for conjunctival autograft attachment in pterygium surgery. Participants: A total of 342 participants with 366 eyes in 7 studies were analyzed. Methods: We searched Medline, EMBASE, Web of Science, Cochrane Central Register of Controlled Trials, and Google Scholar for relevant randomized controlled trials (RCTs). Main Outcome Measures: The methodological quality of all the included trials was assessed with the Jadad score. The meta-analysis was performed with the fixed-effects model for complication rate and recurrence rate, and random-effects model for operating time. Results: Fibrin glue was associated with a significantly decreased operating time (weighted mean difference ⫺17.61 minutes, 95% confidence interval [CI], ⫺26.03 to ⫺9.18, P ⬍ 0.0001) and was more effective in reducing the recurrence rate (Peto odds ratio [OR] 0.33, 95% CI, 0.15– 0.71, P ⫽ 0.004) compared with suture. There were no significant differences in the complication rate (Peto OR 1.82, 95% CI, 0.63–5.27, P ⫽ 0.27) between the 2 groups. Conclusions: Our meta-analysis supports the superiority of fibrin glue to suture in pterygium surgery with conjunctival autografting in that the use of fibrin glue can significantly reduce the recurrence rate without increasing the risk of complications. Ophthalmologists should consider the use of fibrin glue in pterygium surgery. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Ophthalmology 2011;118:1049 –1054 © 2011 by the American Academy of Ophthalmology.
Pterygium is a fibrovascular growth arising from the conjunctiva and extending onto the cornea. Surgical excision of the pterygium is the standard treatment, but the outcomes are compromised by postoperative recurrence. On the basis of simple excision of pterygium, many methods and techniques have been developed to reduce the recurrence rate, including beta-irradiation, mitomycin-C, human amniotic membrane grafting, and autologous conjunctival grafting. However, some adjunctive treatment for pterygium surgery might induce severe complications, such as scleral necrosis and corneal ulcer. Autologous conjunctival grafting or limbal-conjunctival autografting is demonstrated by many studies to be the best method with a low recurrence rate and high safety,1– 4 and limbalconjunctival autografting is considered to be more effective in recurrent pterygium.4 Traditionally, the conjunctival autograft is attached to the sclera by suturing, which prolongs operation time and is associated with drawbacks, such as postoperative discomfort and suture-related complications. Thus, fibrin glue, as an alternative for suturing for conjunctival closure, has been applied in © 2011 by the American Academy of Ophthalmology Published by Elsevier Inc.
pterygium surgery because of its advantage in decreasing operation time, improving postoperative comfort, and avoiding suture-related problems. Although many randomized controlled trials (RCTs) have compared the efficacy of fibrin glue and sutures in pterygium surgery, the results are not completely consistent. Moreover, the conclusion of a single RCT is limited by the small size, different population, follow-up period, and surgery technique. To the best of our knowledge, there is no meta-analysis on comparison of the efficacy of fibrin glue and suture for conjunctival autograft attachment in pterygium surgery. This study reviewed the published literature and performed a meta-analysis aimed to help oculists in choosing a better approach for the management of pterygium with lower recurrence and complications.
Materials and Methods Search Strategy We searched Medline, EMBASE, Web of Science, Cochrane Central Register of Controlled Trials, and Google Scholar for RCTs on comparison of the efficacy of fibrin glue versus suture for autolISSN 0161-6420/11/$–see front matter doi:10.1016/j.ophtha.2010.10.033
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Ophthalmology Volume 118, Number 6, June 2011 ogous conjunctival grafting in pterygium surgery. The keywords used in the search were “fibrin glue,” “suture,” “pterygium,” and “conjunctival autograft.” We performed the final search on August 25, 2010.
Inclusion Criteria Two reviewers independently screened the titles and abstracts of studies to identify those that fulfilled the inclusion criteria: RCT; patients with pterygium; pterygium surgery with conjunctival autograft; comparison on the efficacy of fibrin glue versus suture; and at least one of the following outcomes: operating time, complication rate, and recurrence rate. We applied no language restrictions.
Data Extraction and Quality Assessment Two reviewers independently performed the data extraction and methodological quality assessment of trials that were included. Any disagreement was resolved by discussion to reach consensus between the investigators. A customized form was used to record the author of the study, year of publication, sample size, mean age, gender, location of the trial, outcome measures, and duration of follow-up. We assessed the methodological quality of the studies included in the meta-analysis using the Jadad composite scale.5,6 The instrument assigned scores for reported randomization, blinding, and withdrawals. This is a 5-point scale with a score of 2 or less for low-quality studies and a score of at least 3 for high-quality studies.
Surgical Techniques The surgical techniques were generally consistent with minor variation in different studies. Briefly, under a combination of topical and subconjunctival anaesthetic, the head of the pterygium was excised completely from the cornea. Blunt and sharp dissections were performed to separate the pterygium from the underlying sclera and surrounding conjunctiva. Abnormal scar tissue on the corneal and scleral surface was removed. The dimensions of the bare sclera bed were measured with a caliper, and a free graft with an additional 1.0 mm of length and width was then obtained from the bulbar conjunctiva. Care was taken to include as little as possible of Tenon’s tissue under the graft. In the fibrin glue group, a drop of fibrinogen solution was placed on the bare sclera, and thrombin solution was applied to activate the sealant. The graft was then immediately transferred onto the bare sclera in correct orientation. After a drying period of several minutes, the lid retractors were removed. The fibrin glues used in these studies were all commercially available products. Tisseel (Baxter, Vienna, Austria) was used in the studies by Koranyi et al,7 Hall et al,8 Karalezli et al,9 Ozdamar et al,10 and Ratnalingam et al,11 Full Link (LIKORY, Shanghai, China) was used in the study by Jiang et al,12 and Beriplast P (Aventis Behring, King of Prussia, PA) was used in the study by Uy et al.13 In the suture group, the graft was attached to the adjacent conjunctiva and episclera with interrupted 8-0 Vicryl sutures or 10-0 nylon sutures. Care was taken to maintain the spatial orientation of the graft in relation to the limbus. Study-to-study variations in the surgical steps within each technique were not taken into consideration during this analysis.
Outcome Measurement The outcome measure was the operating time, complication rate, and recurrence rate. For the operating time, mean and standard deviation were obtained from the text. In absence of the standard deviation, the maximum and minimum values were available, and we estimate the standard deviation by the following formula:
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共 Max ⫺ Mean兲2 ⫹ 共 Min ⫺ Mean兲2 4
.
For complication rate, because the criteria of complication identification varied in different studies, we set up a uniform standard to minimize individual variation among all the studies. We analyzed those complications with remarkable signs, including the dehiscence, displacement or loss of the autograft, infection, hemorrhage, and other indications that required special treatment, and excluded those manifestations that are common inflammatory reactions of the surgery, such as edema, fibrosis, and retraction. For recurrence rate, we calculated the number of recurrences at the end of follow-up in each study.
Statistical Methods and Assessment of Heterogeneity The statistical analysis was performed by RevMan 4.2.7 software (The Cochrane Collaboration, Oxford, England). The complication rate and recurrence rate were treated as dichotomous variables, whereas operating time was treated as continuous variable. Dichotomous data were presented as Peto odds ratio (OR) with 95% confidence interval (CI). Weighted mean differences with 95% CI were calculated for continuous variables. A P value less than 0.05 was considered statistically significant. Heterogeneity between studies was assessed by review of trial reports, and statistical heterogeneity was analyzed using a chisquare test. The I2 statistic was calculated to assess inconsistency between studies (P⬍0.05 was considered representative of significant statistical heterogeneity). If there was heterogeneity between studies, a random-effects model was used; otherwise, a fixedeffects model was used for pooling the data. Recent reports have commented on limitations and potential misleading results of funnel plot graphs, so we did not use this method to examine the possibility of publication bias.14 –16
Summary of Evidence Study Selection and Evaluation. Forty-six relevant studies were identified through a literature search. Of these, 15 were excluded for noncomparative studies and 18 were excluded for unqualified intervention. Five studies were excluded for nonrandomized controlled trials.17–21 One study was excluded for unqualified outcome measures.22 Thus, 7 randomized controlled trials comparing the efficacy of fibrin glue versus suture for conjunctival autograft fixation in pterygium surgery were included in the meta-analysis. The selection of the studies is summarized in Figure 1. Study Characteristics. A total of 342 participants with 366 eyes in 7 included studies were enrolled in this meta-analysis. More than 55% of participants were male. Sample sizes in these studies ranged from 22 to 137. Two studies were carried out in Turkey, and one study each was carried out in Sweden, the Philippines, Malaysia, New Zealand, and China. All of the studies included at least one of the following outcome measures: operating time, complication rate, and recurrence rate. The follow-up period ranged from 2 to 12 months. The characteristics of the included trials are summarized in Table 1 (available at http://aaojournal.org). The quality of the included studies was assessed by the Jadad score. The Jadad score of the 7 studies included was fairly good; a score of 5 for 2 studies, a score of 3 for 4 trials, and a score of 2 for 1 trial (Table 2, available at http://aaojournal.org). Outcome Measures. The pooled data (OR and weighted mean difference) for the 3 outcomes are summarized in Figures 2 to 4. Six
Pan et al 䡠 Fibrin Glue vs Suture in Pterygium Surgery
Figure 1. Selection of publications for inclusion in this meta-analysis.
studies reported operating time. Because statistically significant heterogeneity was evident for the outcome of operating time, a randomeffects model was used to combine the data. Fibrin glue was associated with a significantly shorter operating time (weighted mean difference ⫺17.61 minutes, 95% CI, ⫺26.03 to ⫺9.18, P⬍0.0001). For analysis of complication rate and recurrence rate, there was no significant heterogeneity between studies; thus, a fixed-effects model
was used for pooling the data. Fibrin glue was more effective in reducing the recurrence rate (Peto OR 0.33, 95% CI, 0.15– 0.71, P ⫽ 0.004) compared with suture. There were no significant differences in complication rate (Peto OR 1.82, 95% CI, 0.63–5.27, P ⫽ 0.27) between the 2 groups. Sensitivity analysis for those studies with short follow-up (Koranyi et al,7 Ozdamar et al,10 and Uy et al13) did not change the results of recurrence rate.
Figure 2. The effect of fibrin glue versus suture on the combined outcome “operating time.” Results are expressed as weighted mean difference with a random-effect model. In the graph, squares indicate point estimates of treatment effect (mean difference, i.e., mean for fibrin glue group–mean for suture group), with the size of the squares representing the weight attributed to each study. The horizontal lines represent 95% CI for means differences. The pooled estimate of operating time (min) is the weighted mean difference, obtained by combining all means differences using the inverse weighted method, and is represented by the diamond, with the size of the diamond depicting the 95% CI. Values to the left of the vertical line at zero favor fibrin glue. CI ⫽ confidence interval; SD ⫽ standard deviation; WMD ⫽ weighted mean difference.
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Figure 3. The effect of fibrin glue versus suture on the combined outcome “recurrence rate.” Results are expressed as OR with a fixed-effect model. In the graph, squares indicate point estimates of treatment effect (OR for fibrin glue over suture groups), with the size of the squares representing the weight attribute to each study. The horizontal lines represent 95% CI for OR. The pooled estimate for recurrence rate is the pooled OR obtained by combining all OR of the 7 studies using the inverse weighted method and is represented by the diamond, with the size of the diamond depicting the 95% CI. Values to the left of the vertical line at 1 favor fibrin glue. CI ⫽ confidence interval; OR ⫽ odds ratio.
Discussion Fibrin glue is a blood-derived product that consists of 2 components: fibrinogen and thrombin. When the 2 components are mixed and fibrinogen is activated by thrombin, an adhesive fibrin network is formed. Fibrin glue has been applied in ophthalmology for a variety of surgeries, including strabismus surgery, corneal surgery, and glaucoma surgery. Recent studies demonstrated that the use of fibrin glue in pterygium surgery might be an optimal alternative for suturing because of the following advantages: it saves time, it’s easy to use, and it’s associated with less postoperative discomfort and recurrence. We performed the meta-analysis to evaluate the use of fibrin glue with more convincing evidence.
Operating Time Six the trials reported the duration of operation. Without exception, all the RCTs clearly showed a longer operating time for suture compared with fibrin glue. Our meta-analysis revealed statistically significant longer operating time for suture than for fibrin glue (Fig 2). Longer operating time is considered to be closely associated with enhanced postoperative reaction and increased risk of infection; thus, reduction of operating time has important implications for both patients and healthcare providers. For the surgeons, the use of fibrin glue will shorten the learning curve and make the surgery easier; for the patients, conjunctival autografting will be better accepted because the use of fibrin glue produces significantly less symptoms. Moreover, reduction in surgical time would make it cost-effective compared with sutures according to the analysis by Hall et al.8
Complication Rate All 7 studies reported complications. In general, the occurrence of complications was at a relatively low level.
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In 2 studies, no complication was found in both groups. The highest complication rate, 9% in both the fibrin glue group (1/11) and suture group (1/11), was reported in the same study by Uy et al.13 The complications reported in the studies included graft dehiscence or loss, conjunctival cysts, granuloma, and hemorrhage. The most important complication reported in the studies was related to the stability of the graft. Graft dehiscence or loss was found in both groups, more commonly in the fibrin glue group. All the complications reported in these studies were successfully managed and did not influence the visual acuity. Another potential complication for fibrin glue, viral transmission, was not reported in all the studies. The results of meta-analysis for complication rate showed no significant difference between the 2 groups, suggesting fibrin glue has a safety similar to suture. As far as safety is concerned, we think the use of fibrin glue is superior to many adjunctive treatments in pterygium surgery, such as mitomycin-C and beta-irradiation, because it does not induce severe complications. We did not analyze the postoperative discomfort because it was difficult to quantitatively evaluate subjective symptoms. All the included studies7–13 have compared the major symptoms, including postoperative pain, foreign body sensation, and tearing, by a questionnaire method. The results were generally consistent and showed that total discomfort was considerably less in the fibrin group than in the suture group.
Recurrence of Pterygium Recurrence is the most important issue for pterygium surgery and is a source of frustration for both patients and surgeons. Theoretically, the use of fibrin glue can decrease the recurrence rate through its ability to reduce inflammation. Postoperative inflammation is closely associated with the surgical outcome23 and the risk of pterygium recurrence,24 and the use of sutures can induce inflammation and
Pan et al 䡠 Fibrin Glue vs Suture in Pterygium Surgery
Figure 4. The effect of fibrin glue versus suture on the combined outcome “complication rate.” Results are expressed as OR with a fixed-effect model. In the graph, squares indicate point estimates of treatment effect (OR for fibrin glue over suture groups), with the size of the squares representing the weight attribute to each study. The horizontal lines represent 95% CI for OR. The pooled estimate for complication rate is the pooled OR obtained by combining all OR of the 7 studies using the inverse weighted method and is represented by the diamond, with the size of the diamond depicting the 95% CI. Values to the left of the vertical line at 1 favor fibrin glue. CI ⫽ confidence interval; OR ⫽ odds ratio.
migration of Langerhans’ cells to the cornea.25 A prospective blinded study by Srinivasan et al22 quantified the postoperative inflammation with scoring parameters and found the degree of inflammation with fibrin glue was significantly less than with sutures at 1 and 3 months. So it can be inferred that replacement of suture with fibrin glue, which can reduce the migration of fibroblast cells by rapid adhesion of the graft, might inhibit postoperative inflammation and in turn decrease the recurrence rate. A relatively large retrospective study demonstrated a statistically significant decreased recurrence rate with the use of fibrin glue when compared with the use of sutures.20 All 7 studies in this meta-analysis reported recurrence rate. Of these, 4 studies7–9,12 revealed no significant difference in the recurrence rate between fibrin glue and suture, 1 study11 revealed the recurrence rate in the fibrin glue group was significantly lower than in the suture group, and 2 studies10,13 reported no recurrence in both groups probably because of the short follow-up period (2 and 6 months, respectively) and small sample size. Pooling the data from these trials showed a significantly reduced recurrence rate in the fibrin glue group compared with the suture group. There are a number of explanations for the inconsistent results from different studies. First, the sample sizes of most of these RCTs are relatively small, which may have masked the true difference in recurrence rate. Second, the follow-up period varied in different trials. Recurrence of pterygium after surgical treatment is usually seen within 6 months in most cases, but sometimes occurs later, so a 12-month follow-up period is recommended.26 Among the 7 studies that reported recurrence rate, the follow-up period was 2 months in 1 study,13 6 months in 2 studies,7,10 and 12 months in 4 studies.8,9,11,12 Therefore, the result of our meta-analysis based on the previously published literature is more convincing than the result from a single RCT.
Study Limitations The present study has limitations that result from the quality of the individual trials and the methods of the meta-analysis itself. First, our research was restricted to studies published in indexed journals or in certain trial registers and conference proceedings. We did not search for unpublished studies or original data. Second, the included studies were different in terms of design, population, surgical technique, postoperative management, and outcome investigated. For example, limbal-conjunctival autografting was the surgical technique used by Ozdamar et al,10 whereas conjunctival autografting was used in other studies. Moreover, the suture and fibrin glue used in these studies were not consistent. Third, the few published trials comparing fibrin with suture is a significant limitation of this analysis, and the numbers of participants in the trials also are limited (range, 22–137). Finally, publication bias is inevitable, because it is unlikely that any article would have been accepted for publication if it did not show a high success rate.
Clinical Recommendation This meta-analysis of RCTs supports the superiority of fibrin glue to suture for conjunctival autografting in pterygium surgery in that the use of fibrin glue can significantly reduce the recurrence rate without an apparent increased risk of complications. Fibrin glue is more effective in reducing the recurrence rate of pterygium compared with suture, so patients would benefit from the use of fibrin glue[A,II]. The complication rate of fibrin glue is not significantly different from that of suture, suggesting fibrin glue has a similar safety compared with suture[B,II]. Although the possibility of transmitting infectious agents is considerably low, and so far there is no report yet, the risk cannot be completely ruled out.
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Ophthalmology Volume 118, Number 6, June 2011 Fibrin glue can significantly reduce the operating time for conjunctival autografting surgery. The use of fibrin glue makes pterygium surgery easier and less time-consuming[C,I]. In conclusion, ophthalmologists should consider the use of fibrin glue in pterygium surgery to obtain a better surgical outcome. Further research should be carried out on the cost-effectiveness analysis of fibrin glue, and efforts should be dedicated to making fibrin glue available and affordable to more patients.
References 1. Kenyon KR, Wagoner MD, Hettinger ME. Conjunctival autograft transplantation for advanced and recurrent pterygium. Ophthalmology 1985;92:1461–70. 2. Chen PP, Ariyasu RG, Kaza V, et al. A randomized trial comparing mitomycin C and conjunctival autograft after excision of primary pterygium. Am J Ophthalmol 1995;120: 151– 60. 3. Prabhasawat P, Barton K, Burkett G, Tseng SC. Comparison of conjunctival autografts, amniotic membrane grafts, and primary closure for pterygium excision. Ophthalmology 1997; 104:974 – 85. 4. Al Fayez MF. Limbal versus conjunctival autograft transplantation for advanced and recurrent pterygium. Ophthalmology 2002;109:1752–5. 5. Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996;17:1–12. 6. Moher D, Pham B, Jones A, et al. Does quality of reports of randomised trials affect estimates of intervention efficacy reported in meta-analyses? Lancet 1998;352:609 –13. 7. Koranyi G, Seregard S, Kopp ED. Cut and paste: a no suture, small incision approach to pterygium surgery. Br J Ophthalmol 2004;88:911– 4. 8. Hall RC, Logan AJ, Wells AP. Comparison of fibrin glue with sutures for pterygium excision surgery with conjunctival autografts. Clin Experiment Ophthalmol 2009;37:584 –9. 9. Karalezli A, Kucukerdonmez C, Akova YA, et al. Fibrin glue versus sutures for conjunctival autografting in pterygium surgery: a prospective comparative study. Br J Ophthalmol 2008;92:1206 –10. 10. Ozdamar Y, Mutevelli S, Han U, et al. A comparative study of tissue glue and Vicryl suture for closing limbal-conjunctival autografts and histologic evaluation after pterygium excision. Cornea 2008;27:552– 8.
11. Ratnalingam V, Eu AL, Ng GL, et al. Fibrin adhesive is better than sutures in pterygium surgery. Cornea 2010;29:485–9. 12. Jiang J, Yang Y, Zhang M, et al. Comparison of fibrin sealant and sutures for conjunctival autograft fixation in pterygium surgery: one-year follow-up. Ophthalmologica 2008;222:105– 11. 13. Uy HS, Reyes JM, Flores JD, Lim-Bon-Siong R. Comparison of fibrin glue and sutures for attaching conjunctival autografts after pterygium excision. Ophthalmology 2005;112:667–71. 14. Tang JL, Liu JL. Misleading funnel plot for detection of bias in meta-analysis. J Clin Epidemiol 2000;53:477– 84. 15. Lau J, Ioannidis JP, Terrin N, et al. The case of the misleading funnel plot. BMJ 2006;333:597– 600. 16. Terrin N, Schmid CH, Lau J. In an empirical evaluation of the funnel plot, researchers could not visually identify publication bias. J Clin Epidemiol 2005;58:894 –901. 17. Ayala M. Results of pterygium surgery using a biologic adhesive. Cornea 2008;27:663–7. 18. Farid M, Pirnazar JR. Pterygium recurrence after excision with conjunctival autograft: a comparison of fibrin tissue adhesive to absorbable sutures. Cornea 2009;28:43–5. 19. Kim HH, Mun HJ, Park YJ, et al. Conjunctivolimbal autograft using a fibrin adhesive in pterygium surgery. Korean J Ophthalmol 2008;22:147–54. 20. Koranyi G, Seregard S, Kopp ED. The cut-and-paste method for primary pterygium surgery: long-term follow-up. Acta Ophthalmol Scand 2005;83:298 –301. 21. Miranda-Rollon MD, Perez-Gonzalez LE, SentieriOmarrementeria A, et al. Pterygium surgery: comparative study of conjunctival autograft with suture versus fibrin adhesive [in Spanish]. Arch Soc Esp Oftalmol 2009;84:179 – 84. 22. Srinivasan S, Dollin M, McAllum P, et al. Fibrin glue versus sutures for attaching the conjunctival autograft in pterygium surgery: a prospective observer masked clinical trial. Br J Ophthalmol 2009;93:215– 8. 23. Kheirkhah A, Casas V, Sheha H, et al. Role of conjunctival inflammation in surgical outcome after amniotic membrane transplantation with or without fibrin glue for pterygium. Cornea 2008;27:56 – 63. 24. Ti SE, Tseng SC. Management of primary and recurrent pterygium using amniotic membrane transplantation. Curr Opin Ophthalmol 2002;13:204 –12. 25. Suzuki T, Sano Y, Kinoshita S. Conjunctival inflammation induces Langerhans cell migration into the cornea. Curr Eye Res 2000;21:550 –3. 26. Hirst LW, Sebban A, Chant D. Pterygium recurrence time. Ophthalmology 1994;101:755– 8.
Footnotes and Financial Disclosures Originally received: May 25, 2010. Final revision: October 21, 2010. Accepted: October 21, 2010. Available online: February 3, 2011.
Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Manuscript no. 2010-722
1
Department of Ophthalmology, the First Affiliated Hospital of Jinan University, Guangzhou, China.
2
Department of Ophthalmology, Medical College, Jinan University, Guangzhou, China.
3
Key Laboratory for Regenerative Medicine of Ministry of Education, Jinan University, Guangzhou, China.
4
Department of Epidemiology, Medical College, Jinan University, Guangzhou, China.
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Supported by the National Natural Science Foundation of China (81000368), Fundamental Research Funds for the Central Universities (21609315), and Medical Scientific Research Foundation of Guangdong Province, China (B2008091). Correspondence: Hong-Wei Pan, MD, PhD, Department of Ophthalmology, Medical College, Jinan University, 601 West Huangpu Avenue, Guangzhou, 510632, China. E-mail: [email protected].
Pterygium is a fibrovascular growth arising from the conjunctiva and extending onto the cornea. Surgical excision of the pterygium is the standard treatment, but the outcomes are compromised by postoperative recurrence. On the basis of simple excision of pterygium, many methods and techniques have been developed to reduce the recurrence rate, including beta-irradiation, mitomycin-C, human amniotic membrane grafting, and autologous conjunctival grafting. However, some adjunctive treatment for pterygium surgery might induce severe complications, such as scleral necrosis and corneal ulcer. Autologous conjunctival grafting or limbal-conjunctival autografting is demonstrated by many studies to be the best method with a low recurrence rate and high safety,1– 4 and limbalconjunctival autografting is considered to be more effective in recurrent pterygium.4 Traditionally, the conjunctival autograft is attached to the sclera by suturing, which prolongs operation time and is associated with drawbacks, such as postoperative discomfort and suture-related complications. Thus, fibrin glue, as an alternative for suturing for conjunctival closure, has been applied in © 2011 by the American Academy of Ophthalmology Published by Elsevier Inc.
pterygium surgery because of its advantage in decreasing operation time, improving postoperative comfort, and avoiding suture-related problems. Although many randomized controlled trials (RCTs) have compared the efficacy of fibrin glue and sutures in pterygium surgery, the results are not completely consistent. Moreover, the conclusion of a single RCT is limited by the small size, different population, follow-up period, and surgery technique. To the best of our knowledge, there is no meta-analysis on comparison of the efficacy of fibrin glue and suture for conjunctival autograft attachment in pterygium surgery. This study reviewed the published literature and performed a meta-analysis aimed to help oculists in choosing a better approach for the management of pterygium with lower recurrence and complications.
Materials and Methods Search Strategy We searched Medline, EMBASE, Web of Science, Cochrane Central Register of Controlled Trials, and Google Scholar for RCTs on comparison of the efficacy of fibrin glue versus suture for autolISSN 0161-6420/11/$–see front matter doi:10.1016/j.ophtha.2010.10.033
1049
Ophthalmology Volume 118, Number 6, June 2011 ogous conjunctival grafting in pterygium surgery. The keywords used in the search were “fibrin glue,” “suture,” “pterygium,” and “conjunctival autograft.” We performed the final search on August 25, 2010.
Inclusion Criteria Two reviewers independently screened the titles and abstracts of studies to identify those that fulfilled the inclusion criteria: RCT; patients with pterygium; pterygium surgery with conjunctival autograft; comparison on the efficacy of fibrin glue versus suture; and at least one of the following outcomes: operating time, complication rate, and recurrence rate. We applied no language restrictions.
Data Extraction and Quality Assessment Two reviewers independently performed the data extraction and methodological quality assessment of trials that were included. Any disagreement was resolved by discussion to reach consensus between the investigators. A customized form was used to record the author of the study, year of publication, sample size, mean age, gender, location of the trial, outcome measures, and duration of follow-up. We assessed the methodological quality of the studies included in the meta-analysis using the Jadad composite scale.5,6 The instrument assigned scores for reported randomization, blinding, and withdrawals. This is a 5-point scale with a score of 2 or less for low-quality studies and a score of at least 3 for high-quality studies.
Surgical Techniques The surgical techniques were generally consistent with minor variation in different studies. Briefly, under a combination of topical and subconjunctival anaesthetic, the head of the pterygium was excised completely from the cornea. Blunt and sharp dissections were performed to separate the pterygium from the underlying sclera and surrounding conjunctiva. Abnormal scar tissue on the corneal and scleral surface was removed. The dimensions of the bare sclera bed were measured with a caliper, and a free graft with an additional 1.0 mm of length and width was then obtained from the bulbar conjunctiva. Care was taken to include as little as possible of Tenon’s tissue under the graft. In the fibrin glue group, a drop of fibrinogen solution was placed on the bare sclera, and thrombin solution was applied to activate the sealant. The graft was then immediately transferred onto the bare sclera in correct orientation. After a drying period of several minutes, the lid retractors were removed. The fibrin glues used in these studies were all commercially available products. Tisseel (Baxter, Vienna, Austria) was used in the studies by Koranyi et al,7 Hall et al,8 Karalezli et al,9 Ozdamar et al,10 and Ratnalingam et al,11 Full Link (LIKORY, Shanghai, China) was used in the study by Jiang et al,12 and Beriplast P (Aventis Behring, King of Prussia, PA) was used in the study by Uy et al.13 In the suture group, the graft was attached to the adjacent conjunctiva and episclera with interrupted 8-0 Vicryl sutures or 10-0 nylon sutures. Care was taken to maintain the spatial orientation of the graft in relation to the limbus. Study-to-study variations in the surgical steps within each technique were not taken into consideration during this analysis.
Outcome Measurement The outcome measure was the operating time, complication rate, and recurrence rate. For the operating time, mean and standard deviation were obtained from the text. In absence of the standard deviation, the maximum and minimum values were available, and we estimate the standard deviation by the following formula:
1050
冑
共 Max ⫺ Mean兲2 ⫹ 共 Min ⫺ Mean兲2 4
.
For complication rate, because the criteria of complication identification varied in different studies, we set up a uniform standard to minimize individual variation among all the studies. We analyzed those complications with remarkable signs, including the dehiscence, displacement or loss of the autograft, infection, hemorrhage, and other indications that required special treatment, and excluded those manifestations that are common inflammatory reactions of the surgery, such as edema, fibrosis, and retraction. For recurrence rate, we calculated the number of recurrences at the end of follow-up in each study.
Statistical Methods and Assessment of Heterogeneity The statistical analysis was performed by RevMan 4.2.7 software (The Cochrane Collaboration, Oxford, England). The complication rate and recurrence rate were treated as dichotomous variables, whereas operating time was treated as continuous variable. Dichotomous data were presented as Peto odds ratio (OR) with 95% confidence interval (CI). Weighted mean differences with 95% CI were calculated for continuous variables. A P value less than 0.05 was considered statistically significant. Heterogeneity between studies was assessed by review of trial reports, and statistical heterogeneity was analyzed using a chisquare test. The I2 statistic was calculated to assess inconsistency between studies (P⬍0.05 was considered representative of significant statistical heterogeneity). If there was heterogeneity between studies, a random-effects model was used; otherwise, a fixedeffects model was used for pooling the data. Recent reports have commented on limitations and potential misleading results of funnel plot graphs, so we did not use this method to examine the possibility of publication bias.14 –16
Summary of Evidence Study Selection and Evaluation. Forty-six relevant studies were identified through a literature search. Of these, 15 were excluded for noncomparative studies and 18 were excluded for unqualified intervention. Five studies were excluded for nonrandomized controlled trials.17–21 One study was excluded for unqualified outcome measures.22 Thus, 7 randomized controlled trials comparing the efficacy of fibrin glue versus suture for conjunctival autograft fixation in pterygium surgery were included in the meta-analysis. The selection of the studies is summarized in Figure 1. Study Characteristics. A total of 342 participants with 366 eyes in 7 included studies were enrolled in this meta-analysis. More than 55% of participants were male. Sample sizes in these studies ranged from 22 to 137. Two studies were carried out in Turkey, and one study each was carried out in Sweden, the Philippines, Malaysia, New Zealand, and China. All of the studies included at least one of the following outcome measures: operating time, complication rate, and recurrence rate. The follow-up period ranged from 2 to 12 months. The characteristics of the included trials are summarized in Table 1 (available at http://aaojournal.org). The quality of the included studies was assessed by the Jadad score. The Jadad score of the 7 studies included was fairly good; a score of 5 for 2 studies, a score of 3 for 4 trials, and a score of 2 for 1 trial (Table 2, available at http://aaojournal.org). Outcome Measures. The pooled data (OR and weighted mean difference) for the 3 outcomes are summarized in Figures 2 to 4. Six
Pan et al 䡠 Fibrin Glue vs Suture in Pterygium Surgery
Figure 1. Selection of publications for inclusion in this meta-analysis.
studies reported operating time. Because statistically significant heterogeneity was evident for the outcome of operating time, a randomeffects model was used to combine the data. Fibrin glue was associated with a significantly shorter operating time (weighted mean difference ⫺17.61 minutes, 95% CI, ⫺26.03 to ⫺9.18, P⬍0.0001). For analysis of complication rate and recurrence rate, there was no significant heterogeneity between studies; thus, a fixed-effects model
was used for pooling the data. Fibrin glue was more effective in reducing the recurrence rate (Peto OR 0.33, 95% CI, 0.15– 0.71, P ⫽ 0.004) compared with suture. There were no significant differences in complication rate (Peto OR 1.82, 95% CI, 0.63–5.27, P ⫽ 0.27) between the 2 groups. Sensitivity analysis for those studies with short follow-up (Koranyi et al,7 Ozdamar et al,10 and Uy et al13) did not change the results of recurrence rate.
Figure 2. The effect of fibrin glue versus suture on the combined outcome “operating time.” Results are expressed as weighted mean difference with a random-effect model. In the graph, squares indicate point estimates of treatment effect (mean difference, i.e., mean for fibrin glue group–mean for suture group), with the size of the squares representing the weight attributed to each study. The horizontal lines represent 95% CI for means differences. The pooled estimate of operating time (min) is the weighted mean difference, obtained by combining all means differences using the inverse weighted method, and is represented by the diamond, with the size of the diamond depicting the 95% CI. Values to the left of the vertical line at zero favor fibrin glue. CI ⫽ confidence interval; SD ⫽ standard deviation; WMD ⫽ weighted mean difference.
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Figure 3. The effect of fibrin glue versus suture on the combined outcome “recurrence rate.” Results are expressed as OR with a fixed-effect model. In the graph, squares indicate point estimates of treatment effect (OR for fibrin glue over suture groups), with the size of the squares representing the weight attribute to each study. The horizontal lines represent 95% CI for OR. The pooled estimate for recurrence rate is the pooled OR obtained by combining all OR of the 7 studies using the inverse weighted method and is represented by the diamond, with the size of the diamond depicting the 95% CI. Values to the left of the vertical line at 1 favor fibrin glue. CI ⫽ confidence interval; OR ⫽ odds ratio.
Discussion Fibrin glue is a blood-derived product that consists of 2 components: fibrinogen and thrombin. When the 2 components are mixed and fibrinogen is activated by thrombin, an adhesive fibrin network is formed. Fibrin glue has been applied in ophthalmology for a variety of surgeries, including strabismus surgery, corneal surgery, and glaucoma surgery. Recent studies demonstrated that the use of fibrin glue in pterygium surgery might be an optimal alternative for suturing because of the following advantages: it saves time, it’s easy to use, and it’s associated with less postoperative discomfort and recurrence. We performed the meta-analysis to evaluate the use of fibrin glue with more convincing evidence.
Operating Time Six the trials reported the duration of operation. Without exception, all the RCTs clearly showed a longer operating time for suture compared with fibrin glue. Our meta-analysis revealed statistically significant longer operating time for suture than for fibrin glue (Fig 2). Longer operating time is considered to be closely associated with enhanced postoperative reaction and increased risk of infection; thus, reduction of operating time has important implications for both patients and healthcare providers. For the surgeons, the use of fibrin glue will shorten the learning curve and make the surgery easier; for the patients, conjunctival autografting will be better accepted because the use of fibrin glue produces significantly less symptoms. Moreover, reduction in surgical time would make it cost-effective compared with sutures according to the analysis by Hall et al.8
Complication Rate All 7 studies reported complications. In general, the occurrence of complications was at a relatively low level.
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In 2 studies, no complication was found in both groups. The highest complication rate, 9% in both the fibrin glue group (1/11) and suture group (1/11), was reported in the same study by Uy et al.13 The complications reported in the studies included graft dehiscence or loss, conjunctival cysts, granuloma, and hemorrhage. The most important complication reported in the studies was related to the stability of the graft. Graft dehiscence or loss was found in both groups, more commonly in the fibrin glue group. All the complications reported in these studies were successfully managed and did not influence the visual acuity. Another potential complication for fibrin glue, viral transmission, was not reported in all the studies. The results of meta-analysis for complication rate showed no significant difference between the 2 groups, suggesting fibrin glue has a safety similar to suture. As far as safety is concerned, we think the use of fibrin glue is superior to many adjunctive treatments in pterygium surgery, such as mitomycin-C and beta-irradiation, because it does not induce severe complications. We did not analyze the postoperative discomfort because it was difficult to quantitatively evaluate subjective symptoms. All the included studies7–13 have compared the major symptoms, including postoperative pain, foreign body sensation, and tearing, by a questionnaire method. The results were generally consistent and showed that total discomfort was considerably less in the fibrin group than in the suture group.
Recurrence of Pterygium Recurrence is the most important issue for pterygium surgery and is a source of frustration for both patients and surgeons. Theoretically, the use of fibrin glue can decrease the recurrence rate through its ability to reduce inflammation. Postoperative inflammation is closely associated with the surgical outcome23 and the risk of pterygium recurrence,24 and the use of sutures can induce inflammation and
Pan et al 䡠 Fibrin Glue vs Suture in Pterygium Surgery
Figure 4. The effect of fibrin glue versus suture on the combined outcome “complication rate.” Results are expressed as OR with a fixed-effect model. In the graph, squares indicate point estimates of treatment effect (OR for fibrin glue over suture groups), with the size of the squares representing the weight attribute to each study. The horizontal lines represent 95% CI for OR. The pooled estimate for complication rate is the pooled OR obtained by combining all OR of the 7 studies using the inverse weighted method and is represented by the diamond, with the size of the diamond depicting the 95% CI. Values to the left of the vertical line at 1 favor fibrin glue. CI ⫽ confidence interval; OR ⫽ odds ratio.
migration of Langerhans’ cells to the cornea.25 A prospective blinded study by Srinivasan et al22 quantified the postoperative inflammation with scoring parameters and found the degree of inflammation with fibrin glue was significantly less than with sutures at 1 and 3 months. So it can be inferred that replacement of suture with fibrin glue, which can reduce the migration of fibroblast cells by rapid adhesion of the graft, might inhibit postoperative inflammation and in turn decrease the recurrence rate. A relatively large retrospective study demonstrated a statistically significant decreased recurrence rate with the use of fibrin glue when compared with the use of sutures.20 All 7 studies in this meta-analysis reported recurrence rate. Of these, 4 studies7–9,12 revealed no significant difference in the recurrence rate between fibrin glue and suture, 1 study11 revealed the recurrence rate in the fibrin glue group was significantly lower than in the suture group, and 2 studies10,13 reported no recurrence in both groups probably because of the short follow-up period (2 and 6 months, respectively) and small sample size. Pooling the data from these trials showed a significantly reduced recurrence rate in the fibrin glue group compared with the suture group. There are a number of explanations for the inconsistent results from different studies. First, the sample sizes of most of these RCTs are relatively small, which may have masked the true difference in recurrence rate. Second, the follow-up period varied in different trials. Recurrence of pterygium after surgical treatment is usually seen within 6 months in most cases, but sometimes occurs later, so a 12-month follow-up period is recommended.26 Among the 7 studies that reported recurrence rate, the follow-up period was 2 months in 1 study,13 6 months in 2 studies,7,10 and 12 months in 4 studies.8,9,11,12 Therefore, the result of our meta-analysis based on the previously published literature is more convincing than the result from a single RCT.
Study Limitations The present study has limitations that result from the quality of the individual trials and the methods of the meta-analysis itself. First, our research was restricted to studies published in indexed journals or in certain trial registers and conference proceedings. We did not search for unpublished studies or original data. Second, the included studies were different in terms of design, population, surgical technique, postoperative management, and outcome investigated. For example, limbal-conjunctival autografting was the surgical technique used by Ozdamar et al,10 whereas conjunctival autografting was used in other studies. Moreover, the suture and fibrin glue used in these studies were not consistent. Third, the few published trials comparing fibrin with suture is a significant limitation of this analysis, and the numbers of participants in the trials also are limited (range, 22–137). Finally, publication bias is inevitable, because it is unlikely that any article would have been accepted for publication if it did not show a high success rate.
Clinical Recommendation This meta-analysis of RCTs supports the superiority of fibrin glue to suture for conjunctival autografting in pterygium surgery in that the use of fibrin glue can significantly reduce the recurrence rate without an apparent increased risk of complications. Fibrin glue is more effective in reducing the recurrence rate of pterygium compared with suture, so patients would benefit from the use of fibrin glue[A,II]. The complication rate of fibrin glue is not significantly different from that of suture, suggesting fibrin glue has a similar safety compared with suture[B,II]. Although the possibility of transmitting infectious agents is considerably low, and so far there is no report yet, the risk cannot be completely ruled out.
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Ophthalmology Volume 118, Number 6, June 2011 Fibrin glue can significantly reduce the operating time for conjunctival autografting surgery. The use of fibrin glue makes pterygium surgery easier and less time-consuming[C,I]. In conclusion, ophthalmologists should consider the use of fibrin glue in pterygium surgery to obtain a better surgical outcome. Further research should be carried out on the cost-effectiveness analysis of fibrin glue, and efforts should be dedicated to making fibrin glue available and affordable to more patients.
References 1. Kenyon KR, Wagoner MD, Hettinger ME. Conjunctival autograft transplantation for advanced and recurrent pterygium. Ophthalmology 1985;92:1461–70. 2. Chen PP, Ariyasu RG, Kaza V, et al. A randomized trial comparing mitomycin C and conjunctival autograft after excision of primary pterygium. Am J Ophthalmol 1995;120: 151– 60. 3. Prabhasawat P, Barton K, Burkett G, Tseng SC. Comparison of conjunctival autografts, amniotic membrane grafts, and primary closure for pterygium excision. Ophthalmology 1997; 104:974 – 85. 4. Al Fayez MF. Limbal versus conjunctival autograft transplantation for advanced and recurrent pterygium. Ophthalmology 2002;109:1752–5. 5. Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996;17:1–12. 6. Moher D, Pham B, Jones A, et al. Does quality of reports of randomised trials affect estimates of intervention efficacy reported in meta-analyses? Lancet 1998;352:609 –13. 7. Koranyi G, Seregard S, Kopp ED. Cut and paste: a no suture, small incision approach to pterygium surgery. Br J Ophthalmol 2004;88:911– 4. 8. Hall RC, Logan AJ, Wells AP. Comparison of fibrin glue with sutures for pterygium excision surgery with conjunctival autografts. Clin Experiment Ophthalmol 2009;37:584 –9. 9. Karalezli A, Kucukerdonmez C, Akova YA, et al. Fibrin glue versus sutures for conjunctival autografting in pterygium surgery: a prospective comparative study. Br J Ophthalmol 2008;92:1206 –10. 10. Ozdamar Y, Mutevelli S, Han U, et al. A comparative study of tissue glue and Vicryl suture for closing limbal-conjunctival autografts and histologic evaluation after pterygium excision. Cornea 2008;27:552– 8.
11. Ratnalingam V, Eu AL, Ng GL, et al. Fibrin adhesive is better than sutures in pterygium surgery. Cornea 2010;29:485–9. 12. Jiang J, Yang Y, Zhang M, et al. Comparison of fibrin sealant and sutures for conjunctival autograft fixation in pterygium surgery: one-year follow-up. Ophthalmologica 2008;222:105– 11. 13. Uy HS, Reyes JM, Flores JD, Lim-Bon-Siong R. Comparison of fibrin glue and sutures for attaching conjunctival autografts after pterygium excision. Ophthalmology 2005;112:667–71. 14. Tang JL, Liu JL. Misleading funnel plot for detection of bias in meta-analysis. J Clin Epidemiol 2000;53:477– 84. 15. Lau J, Ioannidis JP, Terrin N, et al. The case of the misleading funnel plot. BMJ 2006;333:597– 600. 16. Terrin N, Schmid CH, Lau J. In an empirical evaluation of the funnel plot, researchers could not visually identify publication bias. J Clin Epidemiol 2005;58:894 –901. 17. Ayala M. Results of pterygium surgery using a biologic adhesive. Cornea 2008;27:663–7. 18. Farid M, Pirnazar JR. Pterygium recurrence after excision with conjunctival autograft: a comparison of fibrin tissue adhesive to absorbable sutures. Cornea 2009;28:43–5. 19. Kim HH, Mun HJ, Park YJ, et al. Conjunctivolimbal autograft using a fibrin adhesive in pterygium surgery. Korean J Ophthalmol 2008;22:147–54. 20. Koranyi G, Seregard S, Kopp ED. The cut-and-paste method for primary pterygium surgery: long-term follow-up. Acta Ophthalmol Scand 2005;83:298 –301. 21. Miranda-Rollon MD, Perez-Gonzalez LE, SentieriOmarrementeria A, et al. Pterygium surgery: comparative study of conjunctival autograft with suture versus fibrin adhesive [in Spanish]. Arch Soc Esp Oftalmol 2009;84:179 – 84. 22. Srinivasan S, Dollin M, McAllum P, et al. Fibrin glue versus sutures for attaching the conjunctival autograft in pterygium surgery: a prospective observer masked clinical trial. Br J Ophthalmol 2009;93:215– 8. 23. Kheirkhah A, Casas V, Sheha H, et al. Role of conjunctival inflammation in surgical outcome after amniotic membrane transplantation with or without fibrin glue for pterygium. Cornea 2008;27:56 – 63. 24. Ti SE, Tseng SC. Management of primary and recurrent pterygium using amniotic membrane transplantation. Curr Opin Ophthalmol 2002;13:204 –12. 25. Suzuki T, Sano Y, Kinoshita S. Conjunctival inflammation induces Langerhans cell migration into the cornea. Curr Eye Res 2000;21:550 –3. 26. Hirst LW, Sebban A, Chant D. Pterygium recurrence time. Ophthalmology 1994;101:755– 8.
Footnotes and Financial Disclosures Originally received: May 25, 2010. Final revision: October 21, 2010. Accepted: October 21, 2010. Available online: February 3, 2011.
Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Manuscript no. 2010-722
1
Department of Ophthalmology, the First Affiliated Hospital of Jinan University, Guangzhou, China.
2
Department of Ophthalmology, Medical College, Jinan University, Guangzhou, China.
3
Key Laboratory for Regenerative Medicine of Ministry of Education, Jinan University, Guangzhou, China.
4
Department of Epidemiology, Medical College, Jinan University, Guangzhou, China.
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Supported by the National Natural Science Foundation of China (81000368), Fundamental Research Funds for the Central Universities (21609315), and Medical Scientific Research Foundation of Guangdong Province, China (B2008091). Correspondence: Hong-Wei Pan, MD, PhD, Department of Ophthalmology, Medical College, Jinan University, 601 West Huangpu Avenue, Guangzhou, 510632, China. E-mail: [email protected].