The results of the model fit used to investigate the influence exerted by patient and procedure-related variables (mesh type, sex, age, WHO obesity classification, ASA score, defect size, defect localization, defect closure, mesh size, fixation technique, recurrent operation, preoperative pain, and risk factors) on the outcome variables are presented. The multivariable analyses of intraoperative, postoperative surgical, and postoperative general complications, and also complication-related re-operations and pain at rest, showed no influence of the mesh type on the outcome.
Table 3 shows the multivariable analysis results of the factors impacting onset of recurrences on 1-year follow-up (model fit: P < 0.001). The recurrence rate was highly significantly influenced by the mesh type used (P < 0.001). If Physiomesh was used, it led to an increase in the recurrence rate on 1-year follow-up (OR 2.570, 95% CI 2.057, 3.210). A recurrent operation (OR 1.499, 95% CI 1.166, 1.926, P = 0.002), and also larger defect sizes (W3 vs W1: OR 1.831, 95% CI 1.245; 2.692, P = 0.002; W2 vs W1: OR 1.471, 95% CI 1.117, 1.937, P = 0.006) were significantly associated with a higher recurrence risk. Differences were also observed with regard to the EHS classification, with the majority of recurrences found for lateral hernias (lateral vs combined: OR 1.657, 95% CI 1.070, 2.567, P = 0.024; lateral vs medial: OR 1.546, 95% CI 1.166, 2.051, P = 0.002). Likewise, a larger mesh (10-point: OR 1.006, 95% CI 1.000, 1.011, P = 0.040) was conducive to recurrence and obesity versus normal weight (OR 1.621, 95% CI 1.138, 2.309, P = 0.007) was also associated with a higher recurrence risk although BMI classification was not be found to be a significant predictor of recurrence.
Pain on Exertion
The multivariable analysis results of pain on exertion on 1-year follow-up are shown in Table 4 (model fit: P < 0.001). Likewise, pain on exertion was primarily and negatively influenced by preoperative pain (preoperative pain yes vs no: OR 1.808, 95% CI 1.531, 2.133, P < 0.001). Female sex (female vs male: OR 1.557, 95% CI 1.345, 1.801, P < 0.001), lateral EHS classification (lateral vs medial: OR 1.587, 95% CI 1.319, 1.908, P < 0.001), the use of Physiomesh (Physiomesh vs other meshes: OR 1.194, 95% CI 1.022, 1.395, P = 0.026), mesh size (10-point: OR 1.004, 95% CI 1.000, 1.008, P = 0.037), and recurrent operation (yes vs no: OR 1.187, 95% CI 1.004, 1.402, P = 0.044) were also associated with a higher risk of pain on exertion. A higher age reduced the risk of pain on exertion (10-year: OR 0.787, 0.742, 0.835, P < 0.001).
Chronic Pain Requiring Treatment
The multivariable results of pain requiring treatment are illustrated in Table 5 (model fit: P < 0.001). Chronic pain requiring treatment was primarily influenced by female sex (female vs male: OR 1.706, 95% CI 1.374, 2.118, P < 0.001). Likewise, preoperative pain (yes vs no: OR 1.651, 95% CI 1.272, 2.067, P < 0.001), the use of Physiomesh (Physiomesh vs other meshes: OR 1.321, 95% CI 1.060, 1.648, P = 0.013), lateral vs medial EHS classification (lateral vs medial: OR 1.410, 95% CI 1.083, 1.837, P = 0.011), and the mesh size (10-point: OR 1.005, 95% CI 1.000, 1.011, P = 0.045) increased the risk of chronic pain requiring treatment. By contrast, a higher age reduced the risk of chronic pain requiring treatment (10-year: OR 0.818, 95% CI 0.751, 0.890, P < 0.001).
Univariable and multivariable analyses of the Herniamed data showed that the mesh used in laparoscopic IPOM had no detectable impact on the intraoperative, postoperative surgical, and postoperative general complications, complication-related reoperations, and pain at rest, but did have an influence on recurrence, pain on exertion, and chronic pain requiring treatment.
Furthermore, multivariable analysis of the recurrence rate revealed that Physiomesh compared with the other meshes recommended in the guidelines did present a highly significantly higher risk of onset of a recurrence on 1-year follow-up, with a P value <0.001 and an OR of 2.570. Other variables revealed by multivariable analysis to have had a significant influence on the recurrence rate were recurrent operation, larger defect size, lateral EHS classification, obesity, and larger mesh size. Whereas there was evidence that the use of Physiomesh impacted the risk of pain on exertion and of chronic pain requiring treatment, with an OR of 1.194 and 1.321, respectively, this was lower than the influence exerted by preoperative pain, female sex, and lateral EHS classification.
The Laparoscopic Intraperitoneal Onlay Mesh Augmentation trial, sponsored by Ethicon, was designed to standardize surgical technique for laparoscopic IPOM, that is, mesh fixation with absorbable tacks in double crown technique and transfascial sutures at the edges of mesh, along with the use of Physiomesh alone in incisional hernia repair. Compliance with specified criteria by the participating study sites was strictly monitored.22 Using this standard operative procedure, the recurrence rate after 1 year in 85 enrolled patients, of whom 75 presented for 1-year follow-up examination, was 4.1% (95% CI 0.9–11.9).23
A single-arm observational study by the International Hernia Mesh Registry sponsored by Ethicon did not find any evidence of an increased recurrence rate for laparoscopic IPOM repair of ventral hernias with Physiomesh.24,25 The role of the sponsor must, however, be taken into account with regard to that finding since both studies23,25 were sponsored by Ethicon and this may have impacted the findings. A Cochrane review suggests the existence of an industry bias that cannot be explained by standard “risk of bias” assessment. Sponsorship of device studies by the manufacturing company merely leads to favorable efficacy results.26
One possible explanation for the significantly higher recurrence rate associated with Physiomesh could be its burst strength. Measurements of the burst strength of the nonabsorbable portion of the Physiomesh yielded the sufficient value of 696 mm Hg.27–29 To design the ideal mesh for intraperitoneal placement, the paradoxical requirements of tissue separation on the visceral surface and tissue integration on the parietal surface need to be addressed.30 Physiomesh is a composite mesh consisting of a macroporous, warp-knitted polypropylene sandwiched between 2 tissue-separating layers of a bioabsorbable coating (poliglecaprone 25). Polydioxanone is used as glue to keep all layers together.30 The poliglecaprone-25 layers are comprised of a copolymer of eta-caprolactone and glycolide which degrade through hydrolysis and are expected to be fully absorbed within approximately 240 days.31
In a preclinical porcine model, Deeken and Matthews32 found for Ventralight ST/SorbaFix more favorable strength of tissue ingrowth and histologic response, and similar mesh contracture and adhesion characteristics compared with Physiomesh/Securestrap over a short-term 14-day implantation period. Vogels et al33 also reported in an experimental study in rats after 90 days significantly lower incorporation strengths for Physiomesh compared with all other mesh groups. They hypothesized that the reason for this delay of tissue integration was the application of an anti-adhesive coating on both sides of the mesh.33
Another important risk factor for recurrence after Physiomesh implantation could be the significant loss of cranio-caudal mesh size up to 30% after 90 days.33
In yet another experimental study, seroma was often observed with Physiomesh, whereby seromas were found trapped between the 2 poliglecaprone films.34
In a preclinical study conducted by Ethicon using rabbits as experimental models, Physiomesh was found to be superior to other composite meshes in preventing adhesions.35 The tissue integration, migration, and contraction characteristics of Physiomesh were also evaluated in another preclinical porcine study.36 At 28, 56, and 91 days postimplantation, Physiomesh had adequate tissue fixation and excellent tissue integration.
In 2017, the Medical Device Regulation (MDR) will replace the EU's current Medical Device Directive. Under the MDR, surgical meshes will, in future, be classified as risk class III medical devices. This means that clinical data will have to be gathered and evaluated before new meshes are placed on the market. The most appropriate means of doing so is likely to be RCTs. Through patient selection on the basis of exclusion and inclusion criteria, the quality of a medical device can be evaluated relatively quickly in not too large patient groups. This has been demonstrated in the RCT by Pawlak et al.16 Furthermore, once new surgical meshes have been placed on the market, manufacturers must submit, on a yearly basis, clinical data on the safety of their products. Registries can play a crucial role during this postmarketing surveillance process for surgical meshes. Since in a registry all patients are enrolled, registries need a correspondingly larger sample size to determine through multivariable analyses how the various influence factors affect the outcome. Accordingly, registries need more time than randomized studies to generate reliable statements. The new regulations for placement of medical devices on the market will, no doubt, be welcomed by surgeons as they help to reinforce their confidence in the medical devices placed on the market. Fostering awareness of these inter-relationships should be an important component of surgical training.
The lack of follow-up for 3105 out of 8319 patients (37.3%), and hence their exclusion from analysis, represents the main limitation of the present study. In a best-case worse-case scenario, we assumed that the recurrence rate was halved for the patients with no follow-up in the Physiomesh group, that is, 6% instead of 12%, and that this was doubled for the non-Physiomesh group, that is, 10% instead of 5%. Even given that assumption, there was still a highly significant difference in the recurrence rate to the disadvantage of Physiomesh (9.9% vs 6.9%; P < 0.001). Apart from data completeness, another principal concern with registries is that of making inferences without regard to the quality of the data. The best safeguard is to match the data against another registry, if possible, and literature data.37 In the present case of Physiomesh, the data from the Herniamed and Danish Hernia Registries and a RCT showed comparable results and led to the voluntary recall by the manufacturer.
In summary, the present multivariable analysis of data from the Herniamed Registry in laparoscopic IPOM revealed a significantly higher recurrence and pain rate when using Physiomesh compared with the other composite meshes recommended in the guidelines. The different findings obtained from animal experimental and clinical studies suggest that the Physiomesh product characteristics, and also patient and procedure-related factors, may have had a potential effect. Since, to date, the reasons have not been fully ascertained, the manufacturer initiated voluntary recall of Physiomesh from the market because the Danish Hernia Database had also revealed similar clinical findings. The importance of real-world data (registry-based, population-based) for postmarketing surveillance of surgical meshes has been demonstrated in this registry-based study, with similar findings in the Danish Hernia Database. Together, this has led to the decision taken by the manufacturer of Physiomesh. The experiences gathered over the years since the placement of Physiomesh on the market and the amount of validated data now collected in registries for evaluation of the quality of this mesh demonstrate that registries tend to be more suitable for long-term evaluation of surgical meshes for all patients operated on with this medical device. This is due to the fact that no patient with other factors that could impact the outcome is excluded from registries. Therefore, large sample sizes are needed for multivariable analysis. The sample size can be smaller in prospective randomized trials since several potential influence factors can be controlled on the basis of inclusion and exclusion criteria. Therefore, based on the new marketing authorization procedures, before surgical meshes are first placed on the market in the future, it is likely that RCTs will be carried out, whereas registry studies will be used to collect clinical data for postmarketing surveillance of surgical meshes.
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Keywords:Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
hernia mesh; hernia registries; incisional hernia; laparoscopic IPOM; postmarketing surveillance