Long-Term Survival After Carpentier-Edwards Perimount Aortic Valve Replacement in Denmark: A Multi-Centre Observational Study


 Background: This study describes the long-term survival, risk of reoperation and clinical outcomes for patients undergoing solitary surgical aortic valve replacement (SAVR) with a Carpentier-Edwards Perimount (CE-P) bioprosthetic in Denmark. The renewed interest in SAVR is based on the questioning regarding the long-term survival since new aortic replacement technique such as transcatheter aortic-valve replacement (TAVR) probably have shorter durability, why assessment of long-term survival could be a key issue for patients.Methods: From November 1999 to November 2015 a cohort of a total of 1604 patients aged 20-91 undergoing solitary SAVR with CE-P in Western Denmark was obtained November 2018 from the Western Danish Heart Registry (WDHR). The primary endpoint was long-term survival from all-cause mortality. Secondary endpoints were survival free from major adverse cardiovascular and cerebral events (MACCE), risk of reoperation, cause of late death, patient-prothesis mismatch, risk of AMI, stroke, pacemaker or ICD implantation and postoperative atrial fibrillation (POAF). Time-to event analysis was performed with Kaplan-Meier curve, cumulative incidence function was performed with Nelson-Aalen cumulative hazard estimates. Cox regression was applied to detect risk factors for death and reoperation.Results: In-hospital mortality was 2.7% and 30-day mortality at 3.4%. The 5-, 10- and 15-year survival from all-cause mortality was 77%, 52% and 24%, respectively. Survival without MACCE was 80% after 10 years. Significant risk factors of mortality were small valves, smoking and EuroSCORE II ≥4%. The risk of reoperation was <5% after 7.5 years and significant risk factors were valve prosthesis-patient mismatch and EuroSCORE II ≥4%.Conclusions: Patients operated with for aortic valve replacement with a Carpentier-Edwards Perimount valve shows a very satisfying long-term survival. Future research should aim to investigate biological valves long-term durability for comparison of different SAVR to different TAVR in long perspective.

The future application of SAVR is however being questioned, due to the technological advancement of transcatheter aortic-valve replacement (TAVR) (20). The primary objective of this registry-based retrospective cohort study is to investigate the long-term survival of all patients who underwent a solitary SAVR with CE-P valve bioprosthesis and secondary to explore the adverse clinical outcomes.

Methods
This registry-based study was approved by the Region Southern Denmark Data Protection Agency, Odense, Denmark, and the study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.
We conducted a population-based retrospective cohort study analysis including all patients who underwent solitary SAVR with CE-P valve in Western Denmark based on data from November 1999 to November 2015. The primary endpoint of this study was long-term survival from all-cause mortality with valve size 19 to 29 mm in comparison with the Danish background population. Secondary endpoints were survival from major adverse cardiovascular and cerebral events (MACCE), risk of reoperation, cause of late death, valve patient-prothesis mismatch (VP-PM), PAOF, risk of AMI, stroke and pacemaker. We excluded patients operated with other valve types of aortic valve replacement (AVR) or had concomitant surgery.
The data was obtained November 2018 from the Western Danish Heart Registry (WDHR), The National Danish Patient Registry and the Program of clinical quality development of the Danish Regions. WDHR is a multi-centre prospective registry and is the most comprehensive registry regarding AVR in Denmark. The background population was obtained from Statistics Denmark and matched according to our cohort with a mean age of 73 years and a follow-up of 15 years. MACCE is de ned as all-time cardiovascular events and early (≤30 days) cerebrovascular disease. Low-risk patients was de ned according to guidelines, EuroSCORE II <4%(1). VP-PM was evaluated as effective ori ce area index (EOAI) <0.85 cm 2 /m 2 estimated with manufactural effective ori ce area (EOA) measurements indexed with perioperative body surface area (BSA) knowing that the measurements reliability to predict EOAI are questioned. A total of 1613 people were registered with solitary SAVR in WDHR ( gure 1). Six patients were duplicates, so the rst surgery where kept, and the late will be included as reoperation. Three patients were removed due to invalid or inactive social security number. That leaves a population of 1604 patients whom all had an e cient follow-up.
Baseline characteristics were described using means, range and standard deviations for continuous variables and proportions for categorical variables. Time-to-death was calculated as the time in years from the date of operation to the time of death from all-cause or MACCE-cause. Survival was performed with the use of Kaplan-Meier estimates. The overall survival curve was compared to the background population graphicly by evaluating overlap of curves and con dence interval. Log-rank test was performed to compare equality of survivor function of subgroups. Cumulative incidence function of reoperation was performed with Nelson-Aalen cumulative hazard estimates. Only the rst re-event for each patient during the study was used for analysis. Cox regression was used to detect the risk factors for death and reoperation of any cause reporting hazard ratio (HR) and 95% con dence interval (CI). The age between 65 to 70 was set as reference for age related cox analysis. The same applies to prosthesis size 25 in respect to valve size related cox analysis. A P-value of <0.05 was considered signi cant. All statistical analyses were performed with the use of STATA software, version 15.

Results
We included 1604 patients who received a solitary SAVR with CE-P bioprosthesis between November 1999 and November 2015, with a total follow-up of 11.386 patient-years (median follow-up: 7.1 years).
Baseline and operative characteristics

Discussion
This 15-year multi-centre observational follow-up study evaluated the long-term survival after SAVR with CE-P valve in terms of mortality and clinical outcomes in 1604 Danish patients having a solitary SAVR.
This study's observation of all-cause mortality was consistent with the Danish matched population after early risk and until year 10, were the mortality takes another discrete yet noticeable hit until the end of the follow-up ( gure 2). The early mortality was higher than predicted in comparison to mean ES2 of the population (meanES2: 1.45%, predicted number of deaths: 23). After patients surpass the general risk of the operation the rst 30 days, the survival rate matches to the Danish population for 10 years. We may assume that the CE-P valves durability is being challenged by this point, which can also be supported by literature describing the development of SVD in CE-P at 9.24% after 10 years (10), and 18% after 15 years (7 . This may suggest that ether the durability of the CE-P valve is not the primary cause of death in this age group, or and more likely that they're not suitable for reoperation because of development and progress of comorbidities. Furthermore, that the increased risk in mortality in small vales is presumable explained by the demographics rather than SVD development. Nevertheless, our ndings could indicate that patients undergoing SAVR with CE-P can expect a survival matching the background population the next 10 years after overcoming early risks. A Danish study described the 10-year survival from all-cause mortality of CE-P at 36% resulting, which is signi cantly worse than our ndings of 52% for roughly the same period (19). Canadian study (78%, 55% and 34% (21)) and others (23). We also investigated the survival from MACCEcause mortality in order to more comprehensive describe the valve durability in combination with all causes of late death ( gure 3). The cause of late death was 55.6% due to other than valve or MACCErelated causes, why one might argue that CE-P surpasses the general patient's life expectancy and therefore making it a reliable choice for SAVR and that future randomized studies could take MACCE into account when evaluating the durability in order to give a more widespread evaluation of the valves. VP-PM (HR: 2.19) and high-risk patients (HR: 6.62) had a signi cant impact on the risk of reoperation, while valve size was not an independent risk factor. VP-PM's impact on reoperation contradicts earlier report of CE-P using calculated EOA reference values to predict VP-PM, which were substantially higher than the values provided by the manufacture (24). The prediction of VP-PM is controversial because of various calculations, but one study comparing 4 methods argued that the best calculations are made by EOA measured in vivo by Doppler echocardiography (25). The latest meta-analysis supported the association of VP-PM have higher risk for perioperative, 1-, 5-and 10-year mortality rates in comparison to those with non-signi cant or no VP-PM. In our study, 12.7% had EOAI <0.85 why this could contribute to MACCEcause mortality, though our estimates are based on manufactural EOA measurements indexed with BSA. ES2 ≥4% were found as an independent risk factor for reoperation, which correlates with the selectionbias in this group. Patients with ES2 ≥4% have more comorbidities such as renal failure, previous AMI, COPD, poor lung capacity, endocarditis or the need of acute need of operation. This could also explain the prolonged hospital stay in high risk compared with low risk. The small valve sizes were not associated with reoperation, which may be explained by unsuitability for surgery or the small sample size. The operative risk of reoperation due to SVD in CE-P was earlier described at 0% for size 19 and 21 and 0.1% for all valve sizes (19), which may support our non-correlation of small valves with reoperation. However, the only way to nally evaluate whether a correlation between small valves and the development of SVD is present, is by performing a prospective study with close echocardiographic follow-up, so no patient would experience SVD without notice. The cumulative incidence function of reoperation due to any cause was < 5% after 7.5 years ( gure 5), which is higher than previous studies reporting freedom of reoperation at 96%-99.5% after 10 years (19,21,26). This could be due to our broad range of age (20-91 years) (21). Forcillo et al. divided their population into 3 different age-categories illustrating that younger patients had a higher risk of reoperation with a 10-year risk of 90% in <60 years of age with no mention of the subgroup size (21), and Langanay et al. had an age range of 80-96 years (26). The small sample size after 7.5 years inhibits further associations to be made. Other clinical implications such as stroke, AMI, permanent pacemaker or ICD and POAF is at focus, especially in the comparison to TAVR. We observed a 30-days stroke rate at 1.3% (21 patients; HR:1.35; CI:0.74-2.45; P = 0.32) being lower than the SAVR ndings in the PARTNER 3 trail which was 2.4% (meanES2: 1.5%) (20). The 30-day incidence of AMI was also lower in our study (0.4%) compared to literature (1.3-1.6%) (20,27). Lower incidence was also found regarding pacemaker or ICD implantation (3.9%), as SAVR-reports once again reports higher incidences (4.1-7.4% -only pacemaker only) (20,27,28). Interestingly, our data matches in general the ndings found in another CE-P valves cohort study (stroke 1%, AMI 1%, atrioventricular-block 4% (21)). The incidence of POAF (36.4%) is however higher than some reports (11%) (27), which might be due to the de nition of POAF in regards to duration and the overall awareness in the ward, since it is comparable to other ndings (32%-39.5%) (20,29).
This research was limited by its retrospective design and the absence of continuance echocardiographic evaluation of SVD (6,30). Long-term SVD and its relations to long-term survival therefore still remains in question. Furthermore, of the 1604 patients, 754 died before this study was conducted, and postoperative evaluation of SVD would not have been possible and 8.2% of cause of death remains uncertain. Additionally, the cohort was database-dependent and therefore relays on correct SKS codes, though earlier studies of the WDHD have shown very good quality evaluation with errors lower than 3% (31). Selection bias in this study was minimized by the universal health care system based on the Beveridge model.

Conclusion
We cautiously conclude that our ndings match previous literature, and that CE-P is a well-tested valve with satisfying long-term durability, which do not affect the long-term survival seriously for patients undergoing aortic valve replacement. This support the idea for future comparative research of TAVRvalves may be randomized solely against Carpentier-Edwards Perimount, and not pooled with other inferior bioprosthetic valves (3). Availability of data and materials The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests
The authors declare no con ict of interest.

Funding
This research received no grants from any funding agency in commercial, the public, or not-for-pro t sectors.
Authors' contributions LK and LR initiated and led the study, organized data collection and carried out the statistical analyses as well as drafting of the manuscript. MK wrote parts of the manuscript, and contributed to the study design. All authors revised the manuscript critically and and approved the content of the nal manuscript.  VP-PM: Valve prosthesis-patient mismatch. *P < 0.05. **Age groups for reoperation are sorted by the age of the primary CE-P procedure. *** Reoperation after primary AVR with another CE-P or TAVR ****Cox regression of the rst 10 years.