Discussion
To the best of our knowledge, this is the first RWD study in Japan to evaluate the long-term outcomes of AAA repair using an insurance claims database with anonymous data linkage. Although the 5-year mortality rates of EVAR and OAR were comparable, the higher reintervention rate of EVAR in rAAA suggests that regular follow-up with imaging is critical. International collaborations to create real-world surveillance systems are warranted to overcome minor differences in device use and patient selection with a common goal of improving the quality of care.
The relevance of JMDC, as one of the new sources of RWD, was studied from three different aspects: payment system, anonymous data linkage, and validity of signals. Japanese universal health insurance payment system consists of FFS and DPC.22 While DRG in the USA is a pay-per-case system, the Japanese DPC is a pay-per-day system with a blanket portion for basic hospital fees and an FFS portion. Therefore, missing data are rare for expensive imaging, surgeries, and devices.13 The anonymous data linkage system of JMDC enables the evaluation of risk factors and long-term outcomes across hospitals,19 increasing the sensitivity for reinterventions and CT scans. The validation of signals from the Japanese claims database has been extensively studied. For example, the specificity of codes for procedures, prescriptions, and devices are high, while code combination is needed to compensate for the ‘tentative diagnosis’ for billing purpose.23 Therefore, we have used our algorithm21 for code combination in JMDC to maximize specificity. We have compared our study design, including patient selection and device use (online supplemental table 2) and the short-term and long-term outcomes (online supplemental table 3) with existing registries in Japan.26–29 Accordingly, JMDC may have fit-for-purpose quality and relevance to efficiently monitor patients who underwent EVAR, at least for follow-up imaging and reintervention.
Reinterventions to address device or treatment failures are estimated to occur in 20%–30% of EVAR patients.3 16 We have adopted the definitions of reintervention from claims-based studies in the USA14–17 and mapped them to fit with the JMDC code (online supplemental table 1). Since existing registries in Japan (online supplemental table 2) did not cover the long-term outcomes of EVAR for rAAA, our report is the first to show that the reintervention rate of EVAR (15.4%) is significantly higher than OAR (8.2%) in rAAA (log-rank p=0.284 (figure 3B)). In addition, the Kaplan-Meier curve indicated that a steady increase canceled the early postoperative advantage of EVAR without a plateau in iAAA (7.8% vs 11.0%, log-rank p=0.284 (figure 3A)). Although EVAR may have a lower perioperative adverse event than OAR, the early advantage may not be maintained long-term. In fact, both sac expansion and no reduction in sac size post-EVAR are associated with endoleaks, which are the most common reason for aortic reinterventions.30 Therefore, we suggest guidelines recommending lifelong annual follow-up for patients who underwent EVAR starting 30 days post-procedure are relevant, at least for those ≤75 years of age, in Japan.
Follow-up imaging to identify and correct device-related or procedure-related complications after EVAR is recommended by multiple guidelines.1–5 However, imaging follow-up compliance is reported to be only about 40% despite these important recommendations.9 Previous reports from Japanese registries did not include information on this critical compliance.26–29 Because Japanese hospitals have more CT scanners per capita than other countries,31 patients may get scanned at a nearby clinic rather than at the tertiary hospital where vascular surgeons belong. The patient-centric nature of JMDC to link procedure codes of follow-up imaging across hospitals has enabled to detection of impressive numbers of CT follow-ups per year (table 2). Therefore, a claims-based database with anonymous linkage can be an example of a relevant and efficient long-term real-world surveillance system to improve care for patients who underwent EVAR.
Mortality is the most critical outcome in long-term follow-up studies. Data from the registry of the JSVS indicated that the 30-day mortality in rAAA (15.7% in OAR and 15.3% in EVAR) was lower than that in Europe (31.6%) and the USA (30.0%).5 26 Our 30-day and 5-year mortality data after EVAR or OAR were comparable (online supplemental table 3A, 3B). However, while the external validity of claims-based analyses is high for procedures including reintervention and imaging, the patient selection and device use may affect the mortality when using JMDC as a source for RWD. For patient selection in iAAA, guidelines recommend AAA repair for aneurysm sizes larger than 55 mm in males and 50 mm in females.3–5 However, significant variation exists in the management of AAA,32 33 and some Japanese hospitals set indications of OAR and EVAR to 50 mm in males and 45 mm in females.5 Since there is no clinical information available from the JMDC claims database, we have searched the literature and found a detailed analysis from the Japanese Committee for Stent-graft Management (JACSM).27 The mean diameter was 51 mm (47–57 mm). Of the 37,224 patients who underwent EVAR for iAAA in the JACSM registry, 13,682 (36.8%) were smaller than 50 mm, 10,567 (28.4%) were between 50 and 55 mm, 5256 (14.1%) were between 55 and 60 mm, and 7719 (20.7%) were larger than 60 mm. Therefore, the indication of EVAR for iAAA in the JMDC may also be smaller than in other countries. Regarding the device used for rAAA, the proportion of EVAR (%EVAR) tended to be lower in younger cohorts (online supplemental table 3B), reflecting concerns about the impact of EVAR longevity on long-term outcomes. However, the JACSM registry, collected under the Pharmaceuticals and Medical Devices Act, excluded rAAA cases because of the off-label use. In other words, most of the resource for a post-marketing surveillance system with the highest sensitivity is not aimed at the highest risk patient population. Therefore, regulators, manufacturers, and academia need to optimize the allocation of resources to create a real-world surveillance system9 to collect long-term follow-up data for quality improvement.34–36
There are opportunities for international collaborations to improve the quality of care.37 Codes and algorithms from previous claims-based studies helped identify an unmet medical need in Japan, that is, the need to create a real-world surveillance system for the long-term follow-up of EVAR in rAAA. Historically, highly coordinated cooperative efforts of vascular surgeons, such as the VASCUNET and the VQI, have helped develop evidence-based guidelines to improve the outcomes of patients with AAA.38 In addition, the Medical Device Epidemiology Network (MDEpiNet), a public-private partnership supported by the US FDA, has established the ICVR.39–41 Japanese surgeons also contributed to internationally coordinated registry networks.42 One important lesson from the experiences of international collaborations is to have governing structures for data sharing. In addition to direct data sharing from multiple sources, distributed systems enable more inclusive collaboration for research and surveillance. Global efforts have focused on high priority questions related to device use and patient selection variation. From regulatory and industry perspectives, RWE from RWD can be used for pre-market and post-market purposes.37 However, various factors, including financial incentives, disincentives, varying skillsets, or access to devices, need to be optimized to maximize patient outcomes. Especially, the long-term follow-up linking multiple sources of RWD becomes more challenging when facing data protection laws in different countries. Therefore, further studies on international collaborations to explore feasible and efficient sources of RWD are warranted.
Limitations
This study has some limitations.
First, we could not fully adjust for unmeasured confounding factors in an observational study. Therefore, randomized controlled trials are the gold standard for the appraisal of causalities.
Second, JMDC, like other receipt databases, does not contain medical information such as laboratory data and images. Therefore, known risk factors for AAA, including aortic diameter, may have been confounded. Further studies are needed to clinically validate the sensitivity and specificity of comorbidities and outcomes.
Third, because codes such as UDI, used to uniquely identify devices, are not implemented in the Japanese insurance system, it was impossible to determine the causal relationship between adverse events and specific devices, procedures, or diseases.
Fourth, we studied only those cases that could undergo intervention with EVAR or OAR. However, many cases of rAAA die before surgery or even before arriving at the hospital. Yamaguchi et al reported that in octogenarians emergency repair was less likely (42.8% vs 68.0%) but in-hospital death regardless of repair was higher (61.8% vs 37.6%) than in younger patients.29 Therefore, future studies including older patients are warranted to optimally allocate medical resources and improve the population-based outcomes of rAAA.
Fifth, JMDC is known to have a ‘healthy-workers bias’.21 While the prevalence of AAA is higher in older people, beneficiaries of this claims database JMDC consist of corporate employees and their families aged ≤75 years. Accordingly, age and socioeconomic status may be contributing to lower mortality rates.
Finally, JMDC also has a ‘survivorship bias’ since the system captures in-hospital deaths directly but out-of-hospital deaths only indirectly. For example, Sakai et al reported that although the sensitivity and specificity of procedures, prescriptions, and in-hospital deaths were high, the sensitivity of outpatient death was limited to about 50%.43 Therefore, although systematic bias between groups is unlikely, our data regarding long-term mortality need to be interpreted with this in mind.
In conclusion, our analysis of the long-term outcomes using a Japanese insurance claims database with anonymous data linkage revealed a high compliance with the regular annual follow-up imaging and comparable 5-year mortality between EVAR and OAR in patients who underwent AAA repair. However, EVAR had a significantly higher reintervention rate in ruptured AAA (rAAA), and a long-term upward trend offset the initial benefit in intact cases (iAAA). Therefore, patients who underwent EVAR should receive lifelong annual follow-up imaging starting at 30 days post-procedure. Furthermore, international collaborations to create real-world surveillance systems are warranted.
