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Abstract
Background Rheumatic heart disease (RHD) accounts for the highest number of deaths from valvular heart disease globally. Yet, rheumatic aortic stenosis (AS) was excluded from landmark studies investigating the safety and efficacy of transcatheter aortic valve implantation (TAVI). We aimed to describe the clinical and anatomical characteristics of patients with rheumatic AS undergoing TAVI, and to compare procedural and clinical outcomes with patients undergoing TAVI for degenerative AS.
Methods In a prospective TAVI registry, patients with rheumatic AS were identified based on International Classification of Diseases version 10 codes and/or a documented history of acute rheumatic fever and/or the World Heart Federation criteria for echocardiographic diagnosis of RHD, and were propensity score-matched in a 1:4 ratio to patients with degenerative AS.
Results Among 2329 patients undergoing TAVI, 105 (4.5%) had rheumatic AS. Compared with patients with degenerative AS, patients with rheumatic AS were more commonly female, older, had higher surgical risk and more commonly suffered from multivalvular heart disease. In the unmatched cohort, both technical success (85.7% vs 85.9%, p=0.887) and 1-year cardiovascular mortality (10.0% vs 8.6%; HR 1.16, 95% CI 0.61 to 2.18, p=0.656) were comparable between patients with rheumatic and degenerative AS. In contrast, patients with rheumatic AS had lower rates of 30-day and 1-year cardiovascular mortality compared with matched patients with degenerative AS (1.9% vs 8.9%, adjusted HR (HRadj) 0.18, 95% CI 0.04 to 0.80, p=0.024; and 10.0% vs 20.3%, HRadj 0.44, 95% CI 0.24 to 0.84, p=0.012, respectively).
Conclusion TAVI may be a safe and effective treatment strategy for selected elderly patients with rheumatic AS.
Trial registration number NCT01368250.
- aortic stenosis
- transcatheter aortic valve replacement
Data availability statement
Data are available upon reasonable request. The data underlying this article were provided by CTU, University of Bern, by permission. Data will be shared on request to the corresponding author with permission from CTU, University of Bern.
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Introduction
Rheumatic heart disease (RHD) results from a chronic inflammatory response to repeated episodes of untreated streptococcal pharyngitis and accounts for two out of three deaths from valvular heart disease worldwide.1 2 A steady decline in the prevalence of RHD in high-income countries over recent decades contrasts with a continuously high burden of disease in low-income and middle-income countries.
Mitral regurgitation (MR), mitral stenosis (MS) and aortic regurgitation (AR) are the typical manifestations of RHD, while rheumatic aortic stenosis (AS) is comparably less common and frequently combined with other valvular lesions.3–5 Transcatheter aortic valve implantation (TAVI) has revolutionised the treatment of patients with symptomatic severe AS. Patients with rheumatic AS were, however, excluded from landmark trials, and the available evidence is limited to small case series and data from insurance claims without granularity on imaging features and concomitant valvular disease.6–10 Primary concerns to expand TAVI to patients with rheumatic AS relate to the typical morphological features of RHD with fibrinous thickening of the leaflets, commissural fusion, limited calcification and the frequent combination of AS with other valvular lesions less amenable to transcatheter interventions.3–5 7 8 11 12
The aim of the present analysis was to describe the clinical and anatomical characteristics of patients with rheumatic AS undergoing TAVI, and to compare procedural and clinical outcomes with patients undergoing TAVI for degenerative AS.
Methods
Study design and population
The study cohort for this retrospective analysis comprised consecutive patients undergoing TAVI at Bern University Hospital from August 2007 to December 2019 who were prospectively enrolled into the Bern TAVI registry, which forms part of the nationwide Swiss TAVI registry. For the purpose of the present study, patients who underwent TAVI for a degenerated surgical or transcatheter aortic bioprosthesis, patients who underwent TAVI for pure native aortic valve regurgitation and those without comprehensive data for the diagnosis of RHD were excluded. All participants provided written informed consent prior to inclusion.
Diagnosis of RHD
Diagnoses of RHD were based on a clinical diagnosis of RHD according to International Classification of Diseases version 10 (ICD-10) codes (I05, I06, I07, I08 and I09) and/or a documented history of acute rheumatic fever, and/or functional and morphological features of RHD as defined by the criteria of the World Heart Federation (WHF) for echocardiographic diagnosis of RHD in individuals >40 years.13 Patients with (1) moderate or greater MR, (2) mean mitral gradient ≥4 mm Hg, or (3) moderate or greater AR were retrieved for further analysis of morphological features consistent with RHD. A diagnosis of RHD was made in the presence of at least two of the following morphological features of RHD of the mitral valve: (1) anterior mitral valve leaflet thickening ≥5 mm, (2) chordal thickening and (3) restricted leaflet motion (figure 1, online supplemental files 1; 2). There is no definition of morphological features of the aortic valve for individuals ≥35 years. A clinical diagnosis of RHD according to ICD-10 codes was further confirmed by the presence of a documented history of acute rheumatic fever or the presence of echocardiographic features of RHD.
Supplemental material
Supplementary video
Echocardiographic assessment of morphological features of RHD. (Left) Parasternal long-axis views showing thickening of the AMVL (upper) compared with a normal anterior mitral leaflet (lower). (Middle) Parasternal long-axis views showing restricted leaflet motion with classic dog-leg deformity of the anterior mitral leaflet (arrowhead, upper) and non-restricted leaflet motion (arrowhead, lower). (Right) Apical views with chordal thickening (arrowhead, upper) and normal chordal morphology (arrowhead, lower). A video of the echocardiography of an RHD case is provided in online supplemental files 1, 2. AMVL, anterior mitral valve leaflet; RHD, rheumatic heart disease.
Assessment of the morphological criteria of RHD was individually performed by two assessors (TO and DT). In case of discrepant diagnosis between the two investigators, the diagnosis was determined by a third investigator (EB). Interobserver agreement was excellent between the two primary investigators (kappa=0.85, p<0.001).
Data collection and clinical endpoints
A web-based database with standardised case report forms is used for prospective data collection. Baseline echocardiographic and CT imaging data were independently re-evaluated by dedicated imaging specialists and integrated into the database. Valve dysfunction (regurgitation and stenosis) was graded according to integrative criteria described by current guidelines.14 15 Aortic valvular complex calcium volume (mm3) was quantified as previously validated.16 Clinical follow-up data at 30 days, 1 year and 5 years were obtained using standardised interviews, documentation from referring physicians and hospital discharge summaries. Adverse events were reviewed by a dedicated clinical event committee and adjudicated according to the standardised endpoint definitions proposed by the Valve Academic Research Consortium (VARC).17 An independent Clinical Trials Unit is responsible for central data monitoring to verify completeness and accuracy of data and independent statistical analysis.
Statistical analysis
Categorical variables are reported as frequencies and percentages and compared using χ2 test or two-tailed Fisher’s exact test. Continuous variables are presented as mean±SD and compared between groups using two-sample t-test. Time-to-event curves were depicted using the Kaplan-Meier method. Conditional Poisson regression analysis for binary outcome and conditional Cox regression with Breslow method for time-to-event outcome were used to calculate rate ratio (RR) and hazard ratios (HR), respectively, and 95% confidence intervals (CI). In all time-to-event analyses, data for a patient were censored at the time of the first event that occurred in that patient. All p values were two-sided and p<0.05 was considered significant for all tests.
It was anticipated that patients with rheumatic AS and degenerative AS would have significantly different patient baseline demographics. To adjust confounding due to these differences, 1:4 propensity score matching was used (online supplemental file 1). Absolute standardised differences (ASD) were estimated to assess the balance in baseline demographics. ASD <0.10 was considered to indicate good balance. Multivariable adjustment was further performed with Society of Thoracic Surgeons Predicted Risk of Mortality (STS-PROM), chronic kidney disease (CKD), body mass index (BMI), chronic obstructive pulmonary disease (COPD) and history of coronary artery bypass graft (CABG) in view of residual imbalances between groups. All statistical analyses were performed using Stata V.15.1.
Patient and public involvement
Patients were not involved in the research process of this study.
Results
Baseline clinical characteristics
Among 2329 patients undergoing TAVI between August 2007 and December 2019, 105 (4.5%) were identified to have rheumatic AS (figure 2). Out of 85 patients with a diagnosis of RHD according to ICD-10 codes, 59 did not fulfil the WHF criteria and had no documented history of acute rheumatic fever; thus, they were not included in the rheumatic AS cohort.
A flow chart of patients included in the present analysis. AMVL, anterior mitral valve leaflet; AR, aortic regurgitation; ARF, acute rheumatic fever; ICD-10, International Classification of Diseases version 10; MR, mitral regurgitation; MV, mitral valve; RHD, rheumatic heart disease; TAVI, transcatheter aortic valve implantation.
Baseline characteristics of the unmatched and the matched populations are shown in table 1. Before propensity score matching, patients with rheumatic AS were more commonly female (74.3% vs 50.5%, p<0.001), older (84.2±6.1 years vs 82.1±6.1 years, p<0.001), had lower BMI (24.4±5.50 kg/m2 vs 26.7±5.22 kg/m2, p<0.001), had an increased surgical risk (STS-PROM: 7.1±4.5 vs 5.3±4.0, p<0.001) and had more advanced heart failure symptoms (New York Heart Association III/IV: 81.0% vs 68.1%, p=0.005) than patients with degenerative AS. While dyslipidaemia (50.5% vs 66.3%, p=0.001) and coronary artery disease (48.6% vs 61.9%, p=0.007) were less frequent in patients with rheumatic AS compared with degenerative AS, atrial fibrillation (50.5% vs 33.4%, p<0.001), CKD (83.8% vs 67.6%, p<0.001) and history of mitral valve surgery (4.8% vs 1.2%, p=0.013) were recorded more frequently among patients with rheumatic AS. Patients with rheumatic AS were more likely to be treated with oral anticoagulation, particularly with vitamin K antagonists (VKA), than those with degenerative AS (aspirin: 47.6% vs 59.9%, p=0.014; VKA: 30.5% vs 17.2%, p=0.001).
Baseline characteristics of the unmatched and matched population
Imaging characteristics
Imaging characteristics of the unmatched and matched population are shown in table 2. Multivalvular heart disease was more common among patients with rheumatic AS than patients with degenerative AS. Patients with rheumatic AS had higher prevalence of moderate or greater AR (19.0% vs 8.5%, p=0.001), MR (59.4% vs 21.7%, p<0.001), MS (21.9% vs 1.9%, p<0.001) and tricuspid regurgitation (37.4% vs 15.8%, p<0.001) than patients with degenerative AS.
Imaging characteristics of the unmatched and matched population
On echocardiographic assessment, patients with rheumatic AS had a smaller aortic valve area (0.58±0.22 cm2 vs 0.67±0.24 cm2, p<0.001) and higher pulmonary artery systolic pressure (53.1±15.5 mm Hg vs 47.6±16.0 mm Hg, p=0.001) compared with patients with degenerative AS. Aortic valvular complex calcium volume was not different between the groups (312.6±337.1 mm2 vs 333.9±342.6 mm2, p=0.556).
Propensity score matching
After propensity score matching, patients with rheumatic and degenerative AS were well balanced with ASD <0.10 across all measured baseline characteristics, except for a larger BMI (ASD=0.135), lower rates of CKD (ASD=0.123) and prior CABG (ASD=0.100), and more frequent COPD (ASD=0.136) in patients with rheumatic AS than in patients with degenerative AS.
Procedural characteristics and technical success
Procedural characteristics and outcomes in the unmatched and matched cohorts are shown in table 3. There were no differences in the primary access site, type of valve implanted and use of predilation/postdilation between the groups before and after propensity score matching. Procedural complications were rare, with no differences between the groups with regard to valve dislocation/embolisation, conversion to surgical aortic valve replacement, annular rupture/aortic dissection, cardiac tamponade/rupture and coronary artery obstruction in both the unmatched and matched population. VARC-3 technical success was achieved in more than 85% of patients, without significant differences between groups both in the unmatched (p=0.887) and matched (p=0.505) cohort. At discharge, there were no significant differences in valve haemodynamics and rates of paravalvular regurgitation between the groups.
Procedural characteristics and complications of the unmatched and matched population
Clinical outcomes
Clinical follow-up at 1 year was complete in 2300 patients (99.0%). Clinical outcomes at 30 days and at 1 year in the unmatched and matched cohort are shown in table 4. In the unmatched population, there were no significant differences in 30-day cardiovascular mortality (1.9% vs 2.7%; HR 0.71, 95% CI 0.17 to 2.91, p=0.637) and 30-day stroke rates (2.9% vs 3.6%; HR 0.80, 95% CI 0.25 to 2.52, p=0.699). After propensity score matching, cardiovascular mortality at 30 days was significantly lower in patients with rheumatic AS compared with patients with degenerative AS (1.9% vs 8.6%; adjusted HR (HRadj) 0.18, 95% CI 0.04 to 0.80, p=0.024), while numerically lower rates of stroke did not reach conventional levels of statistical significance (2.9% vs 6.3%; HRadj 0.45, 95% CI 0.11 to 1.89, p=0.180).
Clinical outcomes of the unmatched and matched population
Cumulative incidence of cardiovascular mortality and stroke in the unmatched and matched cohort up to 1-year follow-up is depicted in figure 3. In the unmatched population, there were no significant differences in 1-year cardiovascular mortality (10.0% vs 8.6%; HR 1.16, 95% CI 0.61 to 2.18, p=0.656) and 1-year stroke between groups. In the matched cohort, patients with rheumatic AS had lower cardiovascular mortality at 1 year than patients with degenerative AS (10.0% vs 20.3%; HRadj 0.44, 95% CI 0.24 to 0.84, p=0.012), while there was no significant difference in the 1-year stroke rate between groups (6.2% vs 8.7%; HRadj 0.66, 95% CI 0.28 to 1.58, p=0.353). There were no significant differences in the other clinical outcomes between groups both in the unmatched and matched cohorts (table 4).
Kaplan-Meier curves for cardiovascular death and stroke in the entire cohort and propensity score-matched cohort. HR and p values were calculated using Cox proportional hazard models. RHD, rheumatic heart disease; TAVI, transcatheter aortic valve implantation.
Extended follow-up data until 5 years in the matched cohort are shown in figure 4. Consistent with the 1-year analysis, patients with rheumatic AS had lower cardiovascular mortality at 5 years than those with degenerative AS. There were no significant differences in the occurrence of structural valve deterioration and repeat aortic valve intervention between groups.
Kaplan-Meier curves for cardiovascular death, structural valve deterioration and unplanned repeat aortic valve intervention up to 5 years in the propensity score-matched cohort. Structural valve deterioration was defined according to the Valve Academic Research Consortium-2 criteria.17 Unplanned repeat aortic valve intervention was defined as a composite endpoint including valve-in-valve procedure, balloon valvuloplasty, surgical revision or paravalvular leak closure. HR and p values were calculated using Cox proportional hazard models. RHD, rheumatic heart disease; TAVI, transcatheter aortic valve implantation.
Discussion
In this registry-based study of patients undergoing TAVI for native severe AS, rheumatic AS was identified in nearly 5% of patients. Compared with patients with degenerative AS, patients with rheumatic AS were more commonly female, older, and had higher surgical risk and higher prevalence of multivalvular heart disease. Nevertheless, patients with rheumatic AS were found to have comparable rates of technical success as patients with degenerative AS. Furthermore, cardiovascular mortality was substantially lower in patients with rheumatic AS compared with propensity score-matched patients with degenerative AS.
The prevalence of rheumatic AS documented in our cohort is consistent with data from the Euro Heart Survey on valvular heart disease. Among 5001 patients from 92 centres in 25 European countries, RHD accounted for approximately 10% of patients with AS and peaked during the sixth decade of life.18 In contrast, Medicare data from the USA indicate that less than 1% of patients underwent TAVI for rheumatic AS.8 Several factors need to be considered in the interpretation of the reported prevalence of RHD. First, the methods used for the identification of patients with RHD were different across studies. While diagnosis was based on a combination of clinical context, echocardiographic findings and surgical presentation in the Euro Heart Survey,18 the study from the USA relied on ICD-10 codes.8 In the present study, ICD-10 codes were also considered; however, the final diagnosis was based on a documented history of acute rheumatic fever and/or the standardised WHF criteria for echocardiographic diagnosis of RHD.13 Second, RHD typically presents with MR, MS or AR in middle age. Manifestation of isolated rheumatic AS in octogenarians is comparably rare. Furthermore, rheumatic AS commonly presents with multivalvular heart disease qualifying for surgical valve replacement rather than transcatheter intervention.4 5 19 In the present study of selected patients undergoing TAVI, concomitant clinically relevant AR was documented in 20%, MR in 60%, MS in 20% and tricuspid regurgitation in 40% of patients with rheumatic AS. Third, although the prevalence of RHD in Switzerland was substantially higher in the first half of the 20th century when current TAVI candidates were children, RHD is now comparably rare in affluent regions of the world. However, RHD among TAVI candidates may increase in significance in the forthcoming years as a consequence of expansion of TAVI to younger patients and immigration from low-income and middle-income countries20; most importantly, however, RHD will come to the spotlight with dissemination of TAVI to middle-income countries.21 Affordable transcatheter heart valves (THV) developed in emerging countries22 23 may open the door to this technology for the rest of the world24 and catalyse the expansion of TAVI to patients with RHD.
In the present study, procedural outcomes, including technical success and valve performance, were similar in patients with rheumatic and degenerative AS. Postinflammatory commissural fusion and fibrinous thickening of the aortic valve with limited calcification12 25 raised concern about adequate anchoring of THVs, and was one of the reasons why this population has been excluded from major randomised trials.9 10 12 However, in the present study, patients with rheumatic AS had a similar amount of aortic valvular complex calcification compared with patients with degenerative AS. This observation is consistent with the results of a previous case series of rheumatic AS reporting a mean Agatston score of the aortic valvular complex of 2061±864,7 and is also corroborated by the findings of a histopathological study that found no significant differences in the severity and localisation of calcification between cases of rheumatic and degenerative AS.26 While patients identified to have RHD in our cohort were safely and effectively treated with conventional THV systems, it is important to note that they are not representative of the majority of young patients with RHD. Dedicated devices may need to address higher prevalence of AR in patients with RHD. A THV system with self-locating inflatable balloon trunks and antigen-depleted and antigen-masked bioprosthetic leaflets specifically designed for patients with RHD showed promising results in a preclinical study.27
In the unmatched cohort, the rates of cardiovascular mortality and disabling stroke were comparable in patients with rheumatic and degenerative AS despite higher surgical risk and higher prevalence of multivalvular disease in patients with RHD. Similarly, in an analysis from the Medicare health claims database, patients with rheumatic AS had comparable mortality at a median follow-up of 17 months as patients with degenerative AS despite higher prevalence of heart failure, prior ischaemic stroke, atrial fibrillation and lung disease. Of note, the latter study lacks detailed imaging data on multivalvular disease, which significantly affects patient outcomes following TAVI.11 In previous analyses, we demonstrated an increased risk of cardiovascular mortality in TAVI patients with concomitant primary MR as compared with patients with no or functional MR,28 in patients with degenerative or rheumatic MS as compared with patients with no MS,29 and in patients with valvular atrial fibrillation as compared with patients with non-valvular atrial fibrillation and no atrial fibrillation.30 Nevertheless, patients with rheumatic AS, who frequently presented with multivalvular disease, had comparable clinical outcomes as patients with degenerative AS. Furthermore, when propensity score-matched to patients with degenerative AS with similar prevalence of multivalvular heart disease, patients with rheumatic AS had significantly lower cardiovascular mortality. The reason for this finding resorts to speculation. A selection of patients with slower progression of RHD may explain both the late presentation in their 80s and the lower impact of multivalvular disease on overall prognosis compared with patients with degenerative aetiology.
Study limitations
The findings of our cohort study are exploratory and need to be interpreted in light of several limitations. First, the diagnosis of RHD was carefully verified based on established criteria; however, the criteria were not designed to differentiate between degenerative and rheumatic aetiology in this elderly population. The validity of using the criteria in TAVI populations needs to be further examined. Although commissural fusion, the most typical manifestation of rheumatic MS, was observed in all patients with RHD with assessable short-axis views (n=37), the assessment was frequently impossible due to unavailability or poor quality of images. The assessment of commissural fusion of the aortic valve is further compromised due to the presence of degenerative changes and severe stenosis (online supplemental files 1, 3). Although commissural fusion of the aortic valve was observed in all but one of assessable cases (n=48/49), a typical less-calcified triangular orifice with commissural fusion was observed in only one in five of the cases. Patients identified to have RHD in our TAVI registry are, thus, highly selected individuals and not representative of patients with RHD in other regions of the world. The findings of octogenarians with rheumatic AS undergoing TAVI are therefore not generalisable to younger patients with RHD with non-calcified fibrotic AS. Second, the number of patients with rheumatic AS in our cohort was modest. Conversely, our registry yields detailed imaging data and granularity in terms of procedural success and long-term clinical outcome. The robustness of the findings is furthermore underscored by the prospective data collection, completeness of 1-year follow-up in 99% of patients, independent event adjudication and rigorous statistical analysis by an independent statistical unit. Third, while we used propensity score matching, unmeasured confounding may have affected our findings and cannot be ruled out.
Supplemental material
Conclusion
TAVI may be a safe and effective treatment strategy for selected elderly patients with rheumatic AS. Further studies are warranted to explore TAVI in regions of the world where an endemic pattern of RHD prevails.
Key messages
What is already known on this subject?
Patients with rheumatic aortic stenosis (AS) were excluded from landmark trials and available evidence is limited to small case series and administrative data without granularity on imaging features and concomitant valvular disease.
What might this study add?
In this registry-based study of patients undergoing transcatheter aortic valve implantation (TAVI) for native severe AS, patients with rheumatic AS had comparable procedural and 1-year and 5-year clinical outcomes with patients with degenerative AS despite higher surgical risk and higher prevalence of multivalvular heart disease.
Furthermore, cardiovascular mortality up to 1 year was substantially lower in patients with rheumatic AS compared with propensity score-matched patients with degenerative AS.
How might this impact on clinical practice?
TAVI may be offered as a safe and effective treatment strategy for elderly patients with rheumatic AS.
Further studies are warranted to explore TAVI in regions of the world where an endemic pattern of rheumatic heart disease prevails.
Data availability statement
Data are available upon reasonable request. The data underlying this article were provided by CTU, University of Bern, by permission. Data will be shared on request to the corresponding author with permission from CTU, University of Bern.
Ethics statements
Patient consent for publication
Ethics approval
This study involves human participants and was approved by Bern Cantonal Ethics Committee. The study was conducted in compliance with the Declaration of Helsinki. Participants gave informed consent to participate in the study before taking part.
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
TO and DT are joint first authors.
Twitter @taishiokuno, @DaijiroTomii, @CaglayanDmrl, @DanielHagemeyer, @FabienPraz, @StefanStortecky, @ThomPilgrim
TO and DT contributed equally.
Contributors TO, DT and TP conceived the study. TO and TP were responsible for the design of the study. TO, DT, TP, EB, JL, CR, CD, SH, DHa, AP, DHe, FP, SS and SW were responsible for the acquisition of data. DHe and TO did the analysis and interpreted the results in collaboration with TP, DT and all other authors. TO, DT and TP wrote the first draft of the report. TO and TP are guarantors for the manuscript. All authors critically revised the report for important intellectual content and approved the final version.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests SW reports research and educational grants to the institution from Abbott, Amgen, AstraZeneca, BMS, Bayer, Biotronik, Boston Scientific, Cardinal Health, CardioValve, CSL Behring, Daiichi Sankyo, Edwards Lifesciences, Guerbet, InfraRedx, Johnson & Johnson, Medicure, Medtronic, Novartis, Polares, OrPha Suisse, Pfizer, Regeneron, Sanofi-Aventis, Sinomed, Terumo and V-Wave. SW serves as unpaid advisory board member and/or unpaid member of the steering/executive group of trials funded by Abbott, Abiomed, Amgen, AstraZeneca, BMS, Boston Scientific, Biotronik, CardioValve, Edwards Lifesciences, MedAlliance, Medtronic, Novartis, Polares, Sinomed, V-Wave and Xeltis, but has not received personal payments by pharmaceutical companies or device manufacturers. He is also member of the steering/executive committee group of several investigator-initiated trials that receive funding by industry without impact on his personal remuneration. SW is an unpaid member of the Pfizer Research Award selection committee in Switzerland and of the Women as One Awards Committee. TP reports research grants to the institution from Edwards Lifesciences, Boston Scientific and Biotronik, personal fees from Biotronik and Boston Scientific, and other from HighLife SAS. FP reports travel expenses from Abbott, Edwards Lifesciences and Polares Medical. SS reports research grants to the institution from Edwards Lifesciences, Medtronic, Boston Scientific and Abbott, as well as personal fees from Boston Scientific, Teleflex and BTG. TO reports speaker fees from Abbott. DHe is with CTU Bern, University of Bern, which has a staff policy of not accepting honoraria or consultancy fees. However, CTU Bern is involved in design, conduct or analysis of clinical studies funded by not-for-profit and for-profit organisations. In particular, pharmaceutical and medical device companies provide direct funding to some of these studies. For an up-to-date list of CTU Bern’s conflicts of interest, see http://www.ctu.unibe.ch/research/declaration_of_interest/index_eng.html. All other authors have no relationships relevant to the content of this article to disclose.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research. Refer to the Methods section for further details.
Provenance and peer review Commissioned; externally peer reviewed.
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