Prognostic relevance of mitral and tricuspid regurgitation in patients with severe aortic stenosis

Prognostic relevance of mitral and tricuspid regurgitation in patients with severe aortic stenosis Abstract Aims Although concomitant mitral regurgitation (MR) and tricuspid regurgitation (TR) are frequently present in patients with aortic stenosis (AS), outcome data are scarce and treatment strategies are controversial. The aim of the present study was to assess the presentation and outcome of patients with AS and coexisting MR and TR. Methods and results Eighty-nine consecutive patients with severe AS and at least moderate MR (72 functional and 17 degenerative) were included and followed. Seventy-five patients were symptomatic at presentation. Sixty of these had severe symptoms (New York Heart Association class ≥3). Nine additional patients had an indication for valve procedures during follow-up. However, 35 patients were managed conservatively. Isolated aortic valve intervention was performed in 29 patients (22 valve replacement and 7 transcatheter aortic valve replacement) and concomitant mitral valve surgery in 20 patients. For the assessment of outcome, overall survival (i.e. time from study entry to death from any cause) was assessed: adjusted survival was significantly higher for patients undergoing any valve procedure as compared with patients managed conservatively (P = 0.032). Surgical treatment of severe concomitant MR was associated with improved survival in an unadjusted population but did not reach statistical significance after propensity adjustment. 14 of 36 patients who had concomittant moderate-to-severe tricuspid regurgitation (TR) underwent surgery of which 7 (50 %) died within 3 months postoperatively. On the other hand, only 1 of 35 (3%) with no or mild TR undergoing surgery died within 3 months post-operatively (P < 0.001). Conclusion Presence of MR in patients with severe AS characterizes a high-risk population. Timely aortic valve intervention confers a survival benefit and concomitant mitral valve surgery should be considered according to operative risk. The additional presence of significant TR is associated with dismal outcomes, regardless of the treatment strategy. aortic stenosis , mitral regurgitation , tricuspid regurgitation Introduction Multiple valve disease is increasingly prevalent and choosing the appropriate treatment strategy may pose challenges to the clinician. Moderate-to-severe mitral regurgitation (MR) is present in about 20% of elderly patients with severe aortic stenosis (AS),1 with a reported prevalence varying from 3 to 74% among different studies,2 and is associated with higher mortality after both surgical aortic valve replacement (SAVR)3 and transcatheter aortic valve replacement (TAVR) in particular when MR persists post-interventionally.4 In addition, some patients may present with concomitant tricuspid regurgitation (TR),5 which is a sign of advanced disease and a predictor of increased mortality after SAVR6 and TAVR.7 Whilst double valve surgery corrects both lesions, operative mortality is twice that of isolated AVR.8,9 Due to the associated afterload reduction, regression of MR severity may be observed in 50–70% of patients undergoing isolated SAVR and 50% of patients undergoing isolated TAVR.1 However, persisting or even worsening degrees of MR may occur in the remaining patients. A pragmatic therapeutic approach for concomitant MR in severe AS has been suggested, taking into account MR severity, aetiology as well as the procedural risk.10 However, both the European Society of Cardiology/European Association for Cardio-Thoracic Surgery and the American College of Cardiology/American Heart Association guidelines on valve disease conclude that there is paucity of data on the natural history on mixed and multiple valve disease which does not allow for evidence-based recommendations.11,12 The aim of the present study was therefore to assess the outcome of patients with severe AS and concomitant MR and TR with particular consideration of the impact of the respective treatment approaches so as to optimize the management of these patients. Methods Patient population The process of patient enrolment and the study flow is illustrated in Figure 1. All consecutive patients who were studied in our outpatient heart valve clinic (HVC) between 1999 and 2012 and who were found to have a combination of severe AS with at least moderate MR were included into the study. Exclusion criteria were previous cardiac surgery or additional hemodynamically significant valve lesions (moderate or severe) except for TR. Figure 1 View largeDownload slide Patient enrolment and study flow. Figure 1 View largeDownload slide Patient enrolment and study flow. According to these criteria, 89 consecutive patients (66 female) were identified. According to the purely observational study design, written informed consent was not demanded. The study protocol was approved by the ethics committee of the Medical University of Vienna. Clinical data At study entry, a comprehensive baseline assessment was performed that included medical history, assessment of current medication, physical examination, electrocardiogram, blood tests, and transthoracic echocardiography. The following data were collected: age, sex, body mass index, and body surface area; the patient’s symptomatic status; presence of comorbidities: coronary artery disease (history of myocardial infarction, angioplasty, coronary artery bypass graft (CABG), or angiographically documented coronary artery stenosis) chronic obstructive pulmonary disease (long-term use of bronchodilators or use of steroids for lung disease), arterial hypertension (blood pressure ≥140/90 mmHg at repeated measurements; or use of antihypertensive agents), atrial fibrillation (AF) (present on the electrocardiogram at baseline or verified episode of AF within the last 6 months), hypercholesterolemia (total serum cholesterol ≥240 mg/dL or cholesterol-lowering medication), and diabetes (fasting blood glucose level >126 mg/dL or use of antidiabetic medication). Echocardiographic data Echocardiography was performed using commercially available ultrasound systems. All patients underwent a comprehensive examination including M-Mode, 2D echocardiography, conventional, and colour Doppler by an experienced echocardiographer. Apical four-chamber and two-chamber views were used for calculation of ventricular volumes and ejection fraction by Simpson’s biplane formula. A left ventricular ejection fraction (LVEF) ≥60% was considered normal, a LVEF of 40–60% was considered mildly depressed, a LVEF of 30–40% moderately depressed, and a LVEF of <30% severely depressed. Right ventricular function was assessed both visually and based on tricuspid annular plane systolic excursion and Doppler tissue imaging as recommended13 and graded as normal, mildly, or severely depressed. Multiple transducer positions were used to record peak aortic jet velocities and aortic valve area was calculated using the continuity equation.14 Severe AS was defined by an aortic valve area ≤1 cm2 and an aortic velocity ≥ 4 m/s in the presence of normal flow. In patients with low flow gradient AS, the severity of AS was confirmed by dobutamine echocardiography15 and by the presence of extensive aortic valve calcification.16,17 In the quantification of lesion severity, potential interactions of coexisting lesions on the respective parameters were considered.10 An integrated approach including qualitative, quantitative, and semiquantitative parameters was used for the quantification of MR as proposed by current recommendations.18,19 The assessment included valve morphology, LV volume load, proximal regurgitant jet width, proximal flow convergence, and pulmonary venous flow pattern. LV diameters and ejection fraction, as well as systolic pulmonary artery pressure (using tricuspid regurgitant velocity), were measured as recommended.20 TR was quantified by an integrated approach.18 Echocardiographic parameters used for grading included TV morphology, vena contracta width; proximal flow convergence radius and hepatic venous flow pattern. RV, right atrial, and inferior vena cava diameters were also considered. Post-procedural evaluation of prosthetic valves was performed as recommended.21 Follow-up Patients were followed prospectively after their initial visit at the HVC. Asymptomatic patients were scheduled to undergo follow-up exams every 6 months based on a watchful waiting approach, and were referred to surgery once they had reached an indication for surgery.11,12 Patients who underwent valve procedures had a post-procedural follow-up visit 6–12 months after the intervention in the HVC to assess the surgical outcome. Further post-operative follow-up exams in the HVC were scheduled at extended intervals, depending on surgical and clinical outcomes. Follow-up information was obtained from interviews with the patients, their relatives and their physicians. Information regarding the development of cardiac symptoms, valve intervention, and death was obtained. Exercise testing was performed at clinical discretion in apparently asymptomatic patients. For the assessment of outcome, overall survival (i.e. time from study entry to death from any cause) was assessed. Choice of procedure In the presence of an indication for intervention, a comprehensive work-up (including coronary angiography, carotid ultrasound, spirometry, and aortic CT-angiography in selected patients) was performed, and cases were discussed in a heart team consisting of cardiac surgeons as well as invasive and non-invasive cardiologists. Treatment decisions were individualized considering the patient’s risk profile, comorbidities, age and preferences as well as the severity and aetiology of MR and the severity of TR.22 Statistical analysis Categorical baseline variables are described as counts and percentages and compared between groups using χ2 tests. Continuous baseline variables are described as medians and quartiles and compared between groups using Wilcoxon rank-sum tests and Kruskal–Wallis tests due to skewed distributions. Median follow-up is calculated using the inverse Kaplan–Meier method.23 Survival rates [with 95% confidence intervals (CIs)] at clinically relevant time points and median survival (with quartiles) are deduced from the Kaplan–Meier estimates. For graphically comparing patients undergoing valve procedures with those managed conservatively, Kaplan–Meier survival estimates are displayed for a landmark of 4 months after inclusion into the study in order to account for the time-dependence of the factor ‘valve procedure’. Patients censored or died before 4 months are excluded in Figure 2. A Cox regression model with time-dependent valve procedure factor is used to calculate a hazard ratio (HR) with 95% CI adjusted for EuroSCORE II. Post-interventional survival is compared between groups defined at or before surgery using Kaplan–Meier estimates and a log-rank test. In a Cox regression model an adjustment for baseline EuroSCORE II is accomplished by inverse probability weighting using a propensity score based on EuroSCORE II. The propensity score of a patient is defined as the probability to receive the treatment under investigation conditional on pre-treatment covariates.24 Each patient’s contribution is weighted by the inverse of this probability if treated with this treatment under investigation and by the inverse of one minus this probability otherwise. The potential influence of baseline TR is investigated in a Cox regression model adjusting for EuroSCORE II and time-dependent effects of surgery and (nested) tricuspid valve surgery. The reported P-values are the results of two-sided tests. P-values ≤0.05 are considered to be statistically significant. All computations were carried out using SAS software Version 9.4 (SAS Institute Inc., Cary, NC, USA, 2012). Results Baseline patient characteristics are given in Table 1. Patients addressed for severe AS and concomitant MR were relatively old (median 80 years, quartiles 75–84), had relevant comorbidities and consequently a high operative risk as reflected in the median EuroSCORE II of 7.1% (quartiles 4.5–10.9). At baseline, 36 patients presented with moderate MR and 53 patients with severe MR. LVEF was abnormal in 36 patients: 15 patients had mildly reduced LVEF and 21 had at least moderately reduced LVEF (<40%). Severe low-flow low-gradient AS confirmed by dobutamine stress-echocardiography was present in five patients while the other patients had high transaortic gradients despite a reduced LVEF. In addition, 36 patients had concomitant moderate-to-severe TR. Table 1 Baseline patient characteristics Variables Total population (n = 89) Patients without significant TR (n = 53) Patients with significant TR (n = 36) P-value Female gender 66 (74) 42 (79) 24 (66) 0.18 Age (years) 80 (75–84) 80 (74–83) 83 (75–85) 0.20 Aortic jet velocity (m/s) 4.6 (4.2–5.2) 4.6 (4.3–5.3) 4.4 (4.2–4.9) 0.16 Aortic mean gradient (mmHg) 53 (43–69) 56 (44–73) 52 (40–65) 0.14 Aortic valve area (cm2) 0.6 (0.4–0.7) 0.6 (0.5–0.8) 0.6 (0.5–0.7) 0.84 Coronary artery disease 40 (45) 24 (45) 16 (44) 0.94 Hypertension 62 (70) 37 (70) 25 (69) 0.97 Diabetes mellitus 21 (24) 13 (25) 8 (22) 0.80 Hypercholesterolemia 37 (42) 24 (45) 13 (36) 0.39 Systolic pulmonary artery pressure (mmHg) 54 (48–68) 51 (43–62) 60 (53–74) 0.002 Mildly depressed right ventricular function 9 (10) 3 (6) 6 (17) 0.15a Preserved right ventricular function 80 (90) 50 (94) 30 (83) 0.15a Baseline EuroSCORE II 7.1 (4.5–10.9) 7.1 (4.0–11.1) 6.8 (4.9–10.2) 0.86 Moderate-to severely depressed LV function 21 (24) 10 (19) 11 (31) 0.21 Moderate-to-severe TR 36 (40) 0 (0) 36 (100) <0.001 Variables Total population (n = 89) Patients without significant TR (n = 53) Patients with significant TR (n = 36) P-value Female gender 66 (74) 42 (79) 24 (66) 0.18 Age (years) 80 (75–84) 80 (74–83) 83 (75–85) 0.20 Aortic jet velocity (m/s) 4.6 (4.2–5.2) 4.6 (4.3–5.3) 4.4 (4.2–4.9) 0.16 Aortic mean gradient (mmHg) 53 (43–69) 56 (44–73) 52 (40–65) 0.14 Aortic valve area (cm2) 0.6 (0.4–0.7) 0.6 (0.5–0.8) 0.6 (0.5–0.7) 0.84 Coronary artery disease 40 (45) 24 (45) 16 (44) 0.94 Hypertension 62 (70) 37 (70) 25 (69) 0.97 Diabetes mellitus 21 (24) 13 (25) 8 (22) 0.80 Hypercholesterolemia 37 (42) 24 (45) 13 (36) 0.39 Systolic pulmonary artery pressure (mmHg) 54 (48–68) 51 (43–62) 60 (53–74) 0.002 Mildly depressed right ventricular function 9 (10) 3 (6) 6 (17) 0.15a Preserved right ventricular function 80 (90) 50 (94) 30 (83) 0.15a Baseline EuroSCORE II 7.1 (4.5–10.9) 7.1 (4.0–11.1) 6.8 (4.9–10.2) 0.86 Moderate-to severely depressed LV function 21 (24) 10 (19) 11 (31) 0.21 Moderate-to-severe TR 36 (40) 0 (0) 36 (100) <0.001 Data are given as median (quartiles) and count (%). a Fisher’s exact test instead of χ2 test due to small expected cell counts. Table 1 Baseline patient characteristics Variables Total population (n = 89) Patients without significant TR (n = 53) Patients with significant TR (n = 36) P-value Female gender 66 (74) 42 (79) 24 (66) 0.18 Age (years) 80 (75–84) 80 (74–83) 83 (75–85) 0.20 Aortic jet velocity (m/s) 4.6 (4.2–5.2) 4.6 (4.3–5.3) 4.4 (4.2–4.9) 0.16 Aortic mean gradient (mmHg) 53 (43–69) 56 (44–73) 52 (40–65) 0.14 Aortic valve area (cm2) 0.6 (0.4–0.7) 0.6 (0.5–0.8) 0.6 (0.5–0.7) 0.84 Coronary artery disease 40 (45) 24 (45) 16 (44) 0.94 Hypertension 62 (70) 37 (70) 25 (69) 0.97 Diabetes mellitus 21 (24) 13 (25) 8 (22) 0.80 Hypercholesterolemia 37 (42) 24 (45) 13 (36) 0.39 Systolic pulmonary artery pressure (mmHg) 54 (48–68) 51 (43–62) 60 (53–74) 0.002 Mildly depressed right ventricular function 9 (10) 3 (6) 6 (17) 0.15a Preserved right ventricular function 80 (90) 50 (94) 30 (83) 0.15a Baseline EuroSCORE II 7.1 (4.5–10.9) 7.1 (4.0–11.1) 6.8 (4.9–10.2) 0.86 Moderate-to severely depressed LV function 21 (24) 10 (19) 11 (31) 0.21 Moderate-to-severe TR 36 (40) 0 (0) 36 (100) <0.001 Variables Total population (n = 89) Patients without significant TR (n = 53) Patients with significant TR (n = 36) P-value Female gender 66 (74) 42 (79) 24 (66) 0.18 Age (years) 80 (75–84) 80 (74–83) 83 (75–85) 0.20 Aortic jet velocity (m/s) 4.6 (4.2–5.2) 4.6 (4.3–5.3) 4.4 (4.2–4.9) 0.16 Aortic mean gradient (mmHg) 53 (43–69) 56 (44–73) 52 (40–65) 0.14 Aortic valve area (cm2) 0.6 (0.4–0.7) 0.6 (0.5–0.8) 0.6 (0.5–0.7) 0.84 Coronary artery disease 40 (45) 24 (45) 16 (44) 0.94 Hypertension 62 (70) 37 (70) 25 (69) 0.97 Diabetes mellitus 21 (24) 13 (25) 8 (22) 0.80 Hypercholesterolemia 37 (42) 24 (45) 13 (36) 0.39 Systolic pulmonary artery pressure (mmHg) 54 (48–68) 51 (43–62) 60 (53–74) 0.002 Mildly depressed right ventricular function 9 (10) 3 (6) 6 (17) 0.15a Preserved right ventricular function 80 (90) 50 (94) 30 (83) 0.15a Baseline EuroSCORE II 7.1 (4.5–10.9) 7.1 (4.0–11.1) 6.8 (4.9–10.2) 0.86 Moderate-to severely depressed LV function 21 (24) 10 (19) 11 (31) 0.21 Moderate-to-severe TR 36 (40) 0 (0) 36 (100) <0.001 Data are given as median (quartiles) and count (%). a Fisher’s exact test instead of χ2 test due to small expected cell counts. Mechanisms of MR Seventy-two (81%) patients had secondary MR and 17 (19%) patients had primary MR. Of the latter, 10 had mitral valve prolapse, six had a flail leaflet and one patient had rheumatic mitral valve disease with severe MR and mild mitral stenosis. Some extent of age-related valve degeneration including thickening of the leaflet tips was present in the majority of patients with secondary MR. Presentation of patients At baseline, 14 (16%) patients were asymptomatic and 75 (84%) were symptomatic (exertional dyspnoea or angina), of which 10 (11%) had an additional history of syncope. Of the symptomatic patients, 80% (n = 60) were severely symptomatic (New York Heart Association/CCS class ≥ 3) and 33% (n = 25) had a history of decompensated heart failure that required urgent inpatient care. Event-free survival of the asymptomatic patients During a median follow-up of 47.2 (quartiles 27.2–114.4) months, nine of the 14 patients who were asymptomatic at presentation, developed an indication for surgery and 3 patients died (heart failure n = 1, trauma n = 1, and stroke n = 1), respectively. Indications for valve intervention During follow-up, 84 patients had indications for surgery for the following reasons: symptoms (n = 60); symptoms and left ventricular dysfunction (n = 21); and asymptomatic left ventricular dysfunction (n = 3). Valve interventions Valve procedures were performed in 49 patients: isolated aortic valve intervention in 28 patients (22 SAVR and 7 TAVR), SAVR and tricuspid repair in one patient, SAVR and mitral valve surgery in 9 of 10 (90%) patients with primary MR and in 11 of 39 (28%) patients with secondary MR. Eighteen (90%) of the patients that underwent concomitant mitral surgery had severe MR. Mitral valve repair was performed in 10 of the 20 patients undergoing mitral valve surgery. Post-operatively, MR had improved by 0.7 (0.4–1.0) degrees in patients undergoing isolated AVR and by 2.3 (1.8–2.7) degrees in patients undergoing combined surgery (P < 0.001). No significant change in TR severity was observed whether concomitant mitral valve surgery was performed or not. Concomitant tricuspid repair was performed in seven patients that underwent SAVR and mitral valve surgery. In 13 patients, concomitant CABG was performed. Valve interventions were not performed in 35 patients due to the following reasons: patient refusal (n = 16), denial because of high surgical risk (n = 12), death on the waiting list (n = 6), and surgery aborted due to porcelain aorta (n = 1). Patients who were denied surgery were older [83 (quartiles 81–88) vs. 80 (quartiles 75–79.2) years; P = 0.02] but had otherwise comparable clinical characteristics. Survival Fifty-three patients died during follow-up and all but four [trauma (two); stroke (one); unknown (one)] of these deaths were of cardiac origin. Overall survival rates for the entire patient population were 73% (95% CI 63–81), 58% (95% CI 46–68), and 34% (95% CI 22–46) at 1, 2, and 5 years, respectively. Three patients that were previously asymptomatic died 162, 189, and 706 days after their index examination due to acute heart failure (n = 1), trauma (n = 1), and stroke (n = 1). Of all patients with an indication for AVR who did not refuse surgery six patients died while waiting for valve intervention. These patients presented with one or more of the following characteristics: five presented with severe symptoms, four had a previous episode of cardiac decompensation, four had significant TR and two had a severely depressed systolic LV function. Reasons of death included acute heart failure (n = 5) and sepsis due to a superinfected femoral pseudoaneurysm after pre-operative coronary angiography (n = 1). 15 of 16 patients who had an indication for AVR due to symptoms but refused to undergo valve interventions died due to acute heart failure (n = 12), myocardial infarction (n = 1), sudden death (n = 1), and unknown (n = 1). Median survival for this subgroup of patients was 658 days (quartiles 399–1536). 10 out of 12 patients in whom the heart team recommended a conservative strategy died due to acute heart failure (n = 5), myocardial infarction (n = 2), pneumonia (n = 1), trauma (n = 1), and unknown (n = 1). Median survival for this subgroup was 241 days (quartiles 87–843). In addition, one patient in whom surgery was aborted due to porcelain aorta in the pre-TAVR era died from acute heart failure. Survival according to management strategy Survival rates comparing patients undergoing valve intervention with those managed conservatively are displayed for a landmark of 4 months after inclusion into the study (Figure 2): of all 74 patients still under study at 4 months those already having had valve intervention (23 patients) show higher survival rates when compared with those who had not yet undergone valve intervention (51 patients). The effect of valve interventions also persisted after adjusting for the pre-operative EuroSCORE II (HR = 0.50; P = 0.032). Figure 2 View largeDownload slide Kaplan–Meier overall survival estimates for patients still under study at 4 months who underwent valve interventions within 4 months (red line) vs. patients who had not (yet) undergone valve intervention up to 4 months (blue line). Figure 2 View largeDownload slide Kaplan–Meier overall survival estimates for patients still under study at 4 months who underwent valve interventions within 4 months (red line) vs. patients who had not (yet) undergone valve intervention up to 4 months (blue line). Post-interventional survival Eighteen deaths occurred among the 49 patients that had undergone valve interventions. Overall post-procedural survival rates were 81% (95% CI 66–90), 75% (95% CI 59–85), and 57% (95% CI 36–73) at 1, 2, and 5 years, respectively. There were three periprocedural (within 30 days) and five early post-procedural (1–3 months after the valve procedure) deaths: myocardial infarction (n = 2), haemorrhagic shock (n = 1), sepsis (n = 1), and acute heart failure (n = 1). Ten patients died during late follow-up (n = 10) due to acute heart failure (n = 8), mitral valve endocarditis (n = 1), and myocardial infarction (n = 1). Post-interventional survival according to interventional strategy For the graphic presentation of post-interventional survival, patients were subdivided into three groups: patients receiving combined aortic and mitral valve surgery (Group 1), patients with moderate MR at baseline receiving an isolated aortic intervention (Group 2), and patients with severe MR who underwent isolated aortic intervention (Group 3). The baseline characteristics of these groups are given in Table 2. Table 2 Baseline patient characteristics based on treatment strategy Variables Combined aortic and mitral surgery (n = 20) Moderate MR − isolated aortic intervention (n = 19) Severe MR − isolated aortic intervention (n = 10) P-value Gender (female) 12 15 8 0.339 Age (years) 70 (63.3–78.3) 78 (75–81) 86 (83–88.3) 0.0002a Aortic jet velocity (m/s) 4.7 (4.4–5) 4.8 (4.4–5.6) 4.3 (3.9–4.9) 0.16 Aortic mean gradient (mmHg) 55 (45–70) 60 (51–81) 51 (37–58) 0.08 Aortic valve area (cm2) 0.6 (0.4–0.8) 0.5 (0.4–0.6) 0.7 (0.4–0.8) 0.46 Coronary artery disease 9 (45) 8 (42) 8 (80) 0.10 Hypertension 13 (65) 13 (68) 5 (50) 0.61 Diabetes mellitus 3 (15) 5 (26) 2 (20) 0.68 Hypercholesterolemia 6 (30) 11 (58) 2 (20) 0.08 Baseline logistic EuroSCORE 4.6 (2.4–6.9) 6.1 (4.2–8.7) 11.8 (9.1–16.3) <0.001a Moderate-to severely depressed LV function 2 (10) 4 (21) 6 (60) 0.011a Moderate-to-severe TR 7 (35) 2 (11) 5 (50) 0.058 Variables Combined aortic and mitral surgery (n = 20) Moderate MR − isolated aortic intervention (n = 19) Severe MR − isolated aortic intervention (n = 10) P-value Gender (female) 12 15 8 0.339 Age (years) 70 (63.3–78.3) 78 (75–81) 86 (83–88.3) 0.0002a Aortic jet velocity (m/s) 4.7 (4.4–5) 4.8 (4.4–5.6) 4.3 (3.9–4.9) 0.16 Aortic mean gradient (mmHg) 55 (45–70) 60 (51–81) 51 (37–58) 0.08 Aortic valve area (cm2) 0.6 (0.4–0.8) 0.5 (0.4–0.6) 0.7 (0.4–0.8) 0.46 Coronary artery disease 9 (45) 8 (42) 8 (80) 0.10 Hypertension 13 (65) 13 (68) 5 (50) 0.61 Diabetes mellitus 3 (15) 5 (26) 2 (20) 0.68 Hypercholesterolemia 6 (30) 11 (58) 2 (20) 0.08 Baseline logistic EuroSCORE 4.6 (2.4–6.9) 6.1 (4.2–8.7) 11.8 (9.1–16.3) <0.001a Moderate-to severely depressed LV function 2 (10) 4 (21) 6 (60) 0.011a Moderate-to-severe TR 7 (35) 2 (11) 5 (50) 0.058 Data are given as median (quartiles) and count (%). a Significant (without multiplicity correction). Table 2 Baseline patient characteristics based on treatment strategy Variables Combined aortic and mitral surgery (n = 20) Moderate MR − isolated aortic intervention (n = 19) Severe MR − isolated aortic intervention (n = 10) P-value Gender (female) 12 15 8 0.339 Age (years) 70 (63.3–78.3) 78 (75–81) 86 (83–88.3) 0.0002a Aortic jet velocity (m/s) 4.7 (4.4–5) 4.8 (4.4–5.6) 4.3 (3.9–4.9) 0.16 Aortic mean gradient (mmHg) 55 (45–70) 60 (51–81) 51 (37–58) 0.08 Aortic valve area (cm2) 0.6 (0.4–0.8) 0.5 (0.4–0.6) 0.7 (0.4–0.8) 0.46 Coronary artery disease 9 (45) 8 (42) 8 (80) 0.10 Hypertension 13 (65) 13 (68) 5 (50) 0.61 Diabetes mellitus 3 (15) 5 (26) 2 (20) 0.68 Hypercholesterolemia 6 (30) 11 (58) 2 (20) 0.08 Baseline logistic EuroSCORE 4.6 (2.4–6.9) 6.1 (4.2–8.7) 11.8 (9.1–16.3) <0.001a Moderate-to severely depressed LV function 2 (10) 4 (21) 6 (60) 0.011a Moderate-to-severe TR 7 (35) 2 (11) 5 (50) 0.058 Variables Combined aortic and mitral surgery (n = 20) Moderate MR − isolated aortic intervention (n = 19) Severe MR − isolated aortic intervention (n = 10) P-value Gender (female) 12 15 8 0.339 Age (years) 70 (63.3–78.3) 78 (75–81) 86 (83–88.3) 0.0002a Aortic jet velocity (m/s) 4.7 (4.4–5) 4.8 (4.4–5.6) 4.3 (3.9–4.9) 0.16 Aortic mean gradient (mmHg) 55 (45–70) 60 (51–81) 51 (37–58) 0.08 Aortic valve area (cm2) 0.6 (0.4–0.8) 0.5 (0.4–0.6) 0.7 (0.4–0.8) 0.46 Coronary artery disease 9 (45) 8 (42) 8 (80) 0.10 Hypertension 13 (65) 13 (68) 5 (50) 0.61 Diabetes mellitus 3 (15) 5 (26) 2 (20) 0.68 Hypercholesterolemia 6 (30) 11 (58) 2 (20) 0.08 Baseline logistic EuroSCORE 4.6 (2.4–6.9) 6.1 (4.2–8.7) 11.8 (9.1–16.3) <0.001a Moderate-to severely depressed LV function 2 (10) 4 (21) 6 (60) 0.011a Moderate-to-severe TR 7 (35) 2 (11) 5 (50) 0.058 Data are given as median (quartiles) and count (%). a Significant (without multiplicity correction). Unadjusted post-procedural survival rates at 1, 2, and 5 years, were, 85% (95% CI 60–95), 78% (95% CI 52–91), and 59% (95% CI 18–85), respectively for Group 1; 94% (95% CI 65–99), 85% (95% CI 50–96), and 75% (95% CI 40–92) for Group 2; and 50% (95% CI 18–75), 50% (95% CI 18–75), and 25% (95% CI 4–55) for Group 3 (P = 0.031; Figure 3). Figure 3 View largeDownload slide Kaplan–Meier post-interventional survival estimates for patients with moderate MR left untreated (green line), severe MR that was treated (red line), and severe MR left untreated (blue line). MR, mitral regurgitation. Figure 3 View largeDownload slide Kaplan–Meier post-interventional survival estimates for patients with moderate MR left untreated (green line), severe MR that was treated (red line), and severe MR left untreated (blue line). MR, mitral regurgitation. Using propensity score adjustment for the pre-operative EuroSCORE II, the survival benefit for patients that had undergone concomitant mitral surgery was no longer statistically significant [HR (Group 1 vs. 2 and 3) = 0.80 (95% CI 0.28–2.29; P = 0.673)] Concomitant TR in patients with AS and MR The presence of moderate-to-severe TR was associated with lower overall survival rates: 45% (95% CI 28–61), 32% (95% CI 17–48), and 12% (95% CI 2–29) at 1, 2, and 5 years, respectively as compared with 92% (95% CI 80–97), 76% (95% CI 60–86), and 49% (95% CI 31–65) at 1, 2, and 5 years, respectively for patients with no or mild TR (adjusted HR = 3.06; 95% CI 1.63–5.75; P < 0.001; Figure 4). Apart from more pronounced pulmonary hypertension, patients with significant TR had a similar risk profile (Table 1). Figure 4 View largeDownload slide Kaplan–Meier overall survival estimates for patients with moderate to severe TR (blue line) and for patients with no or mild TR (red line). TR, tricuspid regurgitation. Figure 4 View largeDownload slide Kaplan–Meier overall survival estimates for patients with moderate to severe TR (blue line) and for patients with no or mild TR (red line). TR, tricuspid regurgitation. The presence of significant TR was also associated with early post-operative mortality (moderate-to-severe TR was present in 14 patients undergoing valve interventions and tricuspid surgery was performed in seven of these): the 3-month mortality rate after surgery for the 35 patients being operated with no or mild TR was 3.0% as compared with 51.0% for the 14 patients with moderate-to-severe TR (P < 0.001). Of the latter, three had undergone combined aortic, mitral, and tricuspid surgery, while four had undergone isolated aortic intervention (two of them TAVR). Discussion A high-risk population Concomitant significant MR in patients with severe AS characterizes a high-risk population, as reflected by the following findings: The patients included in this series were mostly high-risk patients (EuroSCORE II: 7.1%) that were old (median age 80 years) and had important comorbidities. It is thus a population at significant operative risk. Most of these patients already presented with symptoms at their index examination, with the majority being severely symptomatic. Furthermore, one-third of the symptomatic patients already had a history of previous cardiac decompensation that required inpatient care and six symptomatic patients rapidly died before any intervention could be scheduled. Overall survival rates for the entire patient population were 73% (95% CI 63–81), 58% (95% CI 46–68), and 34% (95% CI 22–46) at 1, 2, and 5 years, respectively. In comparison, patients with isolated severe symptomatic AS from an earlier series25 had significantly better overall survival with rates of 90% (95% CI 86–93%), 85% (95% CI 80–89%), and 70% (95% CI 63–76%) at 1, 2, and 5 years, respectively (P < 0.001). Twenty-four percent of the patients already had a moderate-to severely depressed LVEF. Thirty percent of the patients had very severe AS, as defined by a peak aortic-jet velocity of greater than 5 m/s,26 despite the presence of MR. The 15 asymptomatic patients had an event-rate of 69% at 2 years. Role and timing of valve procedures Many of the patients did not undergo any valve procedure at all due to patient refusal in 16 patients and denial by the heart team in 12 patients. Patients being denied valve procedures were older but had an otherwise comparable risk profile. Intervention however, when performed, was associated with a survival benefit. The high risk of mortality during workup/on the waiting list for valve procedures [six of 84 (7%) patients with an indication for AVR died while waiting for intervention], further emphasizes the importance of urgent treatment without any delays in this high-risk population. It can be expected that with the advent of transcatheter treatment options, fewer patients may be denied treatment. At the same time, the potential futility of these interventions will need to be considered. Impact of different treatment strategies Concomitant mitral surgery was performed in 18 of 28 (64%) patients with severe MR and in 2 of 21 (10%) patients with moderate MR. In the present series, secondary MR was the predominant aetiology (81%). The decisions were taken by the Heart Team based on an individualized approach, considering interventional risks and the expected disease course. In an unadjusted analysis, post-interventional outcomes after AVR were comparable for patients who underwent concomitant mitral valve surgery for severe MR and for patients with concomitant moderate MR that was left untreated, while patients with severe MR who underwent isolated AVR had a high mortality. Importantly, this finding supports the careful integrated approach used to quantify MR in the present study, as emphasized by current guidelines.27,28 With propensity score adjustment for the baseline EuroSCORE II, the benefit of concomitant mitral surgery in the presence of severe MR (HR 0.52) did not reach statistical significance but nevertheless, a significant reduction in MR was achieved when compared with patients with isolated aortic intervention. It has been demonstrated previously that moderate or severe MR at baseline was associated with increased 2-year mortality after SAVR but not after TAVR.29 Nevertheless, in a recent meta-analysis of 8 studies comprising 8927 patients, significant residual MR after TAVR was associated with an increased 1-year mortality after TAVR.30 Therefore, concomitant mitral valve surgery should be considered, when the incremental surgical risk is acceptable. In the presence of a high surgical risk, isolated aortic valve intervention may nevertheless be associated with a survival benefit. Careful patient assessment, procedural risk stratification and an individualized decision is thus essential. Novel percutaneous treatment approaches might be beneficial for high-risk patients requiring multivalve procedures.31 Prognostic value of TR It is accepted that in patients with severe primary MR, the surgical correction of concomitant significant TR can be performed without significantly increased surgical risk and is associated with good post-operative outcomes.32 In contrast, the presence of moderate-to-severe TR in patients with AS and MR is a strong independent predictor of increased mortality (HR 3.06) even when adjusting for the baseline EuroSCORE II. Furthermore, in the present series, it was associated with a periprocedural mortality close to 50% as compared with 3% (P < 0.001) for patients without significant TR. Accordingly, a subgroup analysis of the PARTNER II trial7 demonstrated that moderate or severe TR and right heart enlargement are independently associated with increased 1-year mortality in inoperable patients treated with TAVR. The presence of TR thus indicates more advanced disease stages.33 In this regard, the present findings suggest that performing valve procedures in patients with severe AS, concomitant MR and significant TR should be carefully balanced against the poor outcome that these patients may experience. It is thus important to recognize severe concomitant TR in the pre-interventional workup and risk assessment. Study limitations The proportion of patients with severe AS presenting with concomitant MR is in the lower range of the reported prevalence and might be explained by different referral patterns in the pre-transcatheter treatment era. Higher referral can be expected in the current era. The present study is a purely observational series of consecutive patients and has the inherent limitation of not being a randomized trial regarding treatment choices. Nevertheless, this limitation is compensated for by propensity score matching. Only a limited number of the patients in the present study were treated with TAVR (either because it was decided to perform a surgical multivalvular procedure or due to inclusion in the pre-TAVR era). While this made it possible to more accurately document the natural course of the disease, the precise role of TAVR in the treatment of these patients remains to be established. Serum biomarkers were not routinely assessed in this patient population. The patients included in the present study, however, were mostly severely symptomatic and many of them already had had an episode of decompensated congestive heart failure. Therefore, we believe that assessment of serum biomarkers such as N-terminal pro-B-type natriuretic peptide (NT-proBNP) would not have changed the decision-making process. While a predictive value of neurohormones in AS has been reported,34 future studies should assess its potential role in the specific population of patients with multivalvular disease. The patient’s frailty or immobility was not systematically assessed by a geriatrician and thus might be subject to bias of the attending physician in the valve clinic. Conclusion Presence of MR in patients with severe AS characterizes a high-risk population of elderly and mostly severely symptomatic patients. Timely aortic valve intervention confers a survival benefit and concomitant mitral valve surgery should be considered according to operative risk. The additional presence of significant TR is associated with dismal outcomes, regardless of the treatment strategy. Conflict of interest: None declared. References 1 Nombela-Franco L , Ribeiro HB , Urena M , Allende R , Amat-Santos I , DeLarochelliere R et al. Significant mitral regurgitation left untreated at the time of aortic valve replacement: a comprehensive review of a frequent entity in the transcatheter aortic valve replacement era . J Am Coll Cardiol 2014 ; 63 : 2643 – 58 . Google Scholar CrossRef Search ADS PubMed 2 Unger P , Dedobbeleer C , Van Camp G , Plein D , Cosyns B , Lancellotti P. Republished review: mitral regurgitation in patients with aortic stenosis undergoing valve replacement . Postgrad Med J 2011 ; 87 : 150 – 5 . Google Scholar CrossRef Search ADS PubMed 3 Barreiro CJ , Patel ND , Fitton TP , Williams JA , Bonde PN , Chan V et al. Aortic valve replacement and concomitant mitral valve regurgitation in the elderly: impact on survival and functional outcome . Circulation 2005 ; 112 : I443 – 7 . Google Scholar PubMed 4 Khawaja MZ , Williams R , Hung J , Arri S , Asrress KN , Bolter K et al. Impact of preprocedural mitral regurgitation upon mortality after transcatheter aortic valve implantation (TAVI) for severe aortic stenosis . Heart 2014 ; 100 : 1799 – 803 . Google Scholar CrossRef Search ADS PubMed 5 Barbanti M , Binder RK , Dvir D , Tan J , Freeman M , Thompson CR et al. Prevalence and impact of preoperative moderate/severe tricuspid regurgitation on patients undergoing transcatheter aortic valve replacement . Catheter Cardiovasc Interv 2015 ; 85 : 677 – 84 . Google Scholar CrossRef Search ADS PubMed 6 Mascherbauer J , Kammerlander AA , Marzluf BA , Graf A , Kocher A , Bonderman D. Prognostic impact of tricuspid regurgitation in patients undergoing aortic valve surgery for aortic stenosis . PLoS One 2015 ; 10 : e0136024 . Google Scholar CrossRef Search ADS PubMed 7 Lindman BR , Maniar HS , Jaber WA , Lerakis S , Mack MJ , Suri RM et al. Effect of tricuspid regurgitation and the right heart on survival after transcatheter aortic valve replacement: insights from the Placement of Aortic Transcatheter Valves II inoperable cohort . Circ Cardiovasc Interv 2015 ; 8 : e002073 . Google Scholar CrossRef Search ADS PubMed 8 Mueller XM , Tevaearai HT , Stumpe F , Fischer AP , Hurni M , Ruchat P et al. Long-term results of mitral-aortic valve operations . J Thorac Cardiovasc Surg 1998 ; 115 : 1298 – 309 . Google Scholar CrossRef Search ADS PubMed 9 Arom KV , Nicoloff DM , Kersten TE , Northrup WF 3rd , Lindsay WG , Emery RW. Ten-year follow-up study of patients who had double valve replacement with the St. Jude Medical prosthesis . J Thorac Cardiovasc Surg 1989 ; 98 : 1008 – 15 ; discussion 15–6. Google Scholar PubMed 10 Unger P , Rosenhek R , Dedobbeleer C , Berrebi A , Lancellotti P. Management of multiple valve disease . Heart 2011 ; 97 : 272 – 7 . Google Scholar CrossRef Search ADS PubMed 11 Joint Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology (ESC); European Association for Cardio-Thoracic Surgery (EACTS) , Vahanian A , Alfieri O , Andreotti F , Antunes MJ et al. Guidelines on the management of valvular heart disease (version 2012) . Eur Heart J 2012 ; 33 : 2451 – 96 . Google Scholar CrossRef Search ADS PubMed 12 Nishimura RA , Otto CM , Bonow RO , Carabello BA , Erwin JP 3rd , Guyton RA et al. 2014 AHA/ACC guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines . J Am Coll Cardiol 2014 ; 63 : e57 – 185 . Google Scholar CrossRef Search ADS PubMed 13 Rudski LG , Lai WW , Afilalo J , Hua L , Handschumacher MD , Chandrasekaran K et al. Guidelines for the echocardiographic assessment of the right heart in adults: a report from the American Society of Echocardiography endorsed by the European Association of Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of Echocardiography . J Am Soc Echocardiogr 2010 ; 23 : 685 – 713; quiz 86–8. Google Scholar CrossRef Search ADS PubMed 14 Otto CM , Pearlman AS , Comess KA , Reamer RP , Janko CL , Huntsman LL. Determination of the stenotic aortic valve area in adults using Doppler echocardiography . J Am Coll Cardiol 1986 ; 7 : 509 – 17 . Google Scholar CrossRef Search ADS PubMed 15 Monin JL , Quere JP , Monchi M , Petit H , Baleynaud S , Chauvel C et al. Low-gradient aortic stenosis: operative risk stratification and predictors for long-term outcome: a multicenter study using dobutamine stress hemodynamics . Circulation 2003 ; 108 : 319 – 24 . Google Scholar CrossRef Search ADS PubMed 16 Cueff C , Serfaty JM , Cimadevilla C , Laissy JP , Himbert D , Tubach F et al. Measurement of aortic valve calcification using multislice computed tomography: correlation with haemodynamic severity of aortic stenosis and clinical implication for patients with low ejection fraction . Heart 2011 ; 97 : 721 – 6 . Google Scholar CrossRef Search ADS PubMed 17 Rosenhek R , Binder T , Porenta G , Lang I , Christ G , Schemper M et al. Predictors of outcome in severe, asymptomatic aortic stenosis . N Engl J Med 2000 ; 343 : 611 – 7 . Google Scholar CrossRef Search ADS PubMed 18 Lancellotti P , Moura L , Pierard LA , Agricola E , Popescu BA , Tribouilloy C et al. European Association of Echocardiography recommendations for the assessment of valvular regurgitation. Part 2: mitral and tricuspid regurgitation (native valve disease) . Eur J Echocardiogr 2010 ; 11 : 307 – 32 . Google Scholar CrossRef Search ADS PubMed 19 Zoghbi WA , Enriquez-Sarano M , Foster E , Grayburn PA , Kraft CD , Levine RA et al. Recommendations for evaluation of the severity of native valvular regurgitation with two-dimensional and Doppler echocardiography . J Am Soc Echocardiogr 2003 ; 16 : 777 – 802 . Google Scholar CrossRef Search ADS PubMed 20 Gottdiener JS , Bednarz J , Devereux R , Gardin J , Klein A , Manning WJ et al. American Society of Echocardiography recommendations for use of echocardiography in clinical trials . J Am Soc Echocardiogr 2004 ; 17 : 1086 – 119 . Google Scholar PubMed 21 Zoghbi WA , Chambers JB , Dumesnil JG , Foster E , Gottdiener JS , Grayburn PA et al. Recommendations for evaluation of prosthetic valves with echocardiography and doppler ultrasound: a report From the American Society of Echocardiography’s Guidelines and Standards Committee and the Task Force on Prosthetic Valves, developed in conjunction with the American College of Cardiology Cardiovascular Imaging Committee, Cardiac Imaging Committee of the American Heart Association, the European Association of Echocardiography, a registered branch of the European Society of Cardiology, the Japanese Society of Echocardiography and the Canadian Society of Echocardiography, endorsed by the American College of Cardiology Foundation, American Heart Association, European Association of Echocardiography, a registered branch of the European Society of Cardiology, the Japanese Society of Echocardiography, and Canadian Society of Echocardiography . J Am Soc Echocardiogr 2009 ; 22 : 975 – 1014 ; quiz 82–4. Google Scholar CrossRef Search ADS PubMed 22 Rosenhek R , Iung B , Tornos P , Antunes MJ , Prendergast BD , Otto CM et al. ESC working group on valvular heart disease position paper: assessing the risk of interventions in patients with valvular heart disease . Eur Heart J 2012 ; 33 :822–8, 8a, 8b. 23 Schemper M , Smith TL. A note on quantifying follow-up in studies of failure time . Control Clin Trials 1996 ; 17 : 343 – 6 . Google Scholar CrossRef Search ADS PubMed 24 Heinze G , Juni P. An overview of the objectives of and the approaches to propensity score analyses . Eur Heart J 2011 ; 32 : 1704 – 8 . Google Scholar CrossRef Search ADS PubMed 25 Zilberszac R , Lancellotti P , Gilon D , Gabriel H , Schemper M , Maurer G et al. Role of a heart valve clinic programme in the management of patients with aortic stenosis . Eur Heart J Cardiovasc Imaging 2017 ; 18 : 138 – 44 . Google Scholar CrossRef Search ADS PubMed 26 Rosenhek R , Zilberszac R , Schemper M , Czerny M , Mundigler G , Graf S et al. Natural history of very severe aortic stenosis . Circulation 2010 ; 121 : 151 – 6 . Google Scholar CrossRef Search ADS PubMed 27 Lancellotti P , Tribouilloy C , Hagendorff A , Popescu BA , Edvardsen T , Pierard LA et al. Recommendations for the echocardiographic assessment of native valvular regurgitation: an executive summary from the European Association of Cardiovascular Imaging . Eur Heart J Cardiovasc Imaging 2013 ; 14 : 611 – 44 . Google Scholar CrossRef Search ADS PubMed 28 Zoghbi WA , Adams D , Bonow RO , Enriquez-Sarano M , Foster E , Grayburn PA et al. Recommendations for noninvasive evaluation of native valvular regurgitation: a report from the American Society of Echocardiography Developed in Collaboration with the Society for Cardiovascular Magnetic Resonance . J Am Soc Echocardiogr 2017 ; 30 : 303 – 71 . Google Scholar CrossRef Search ADS PubMed 29 Barbanti M , Webb JG , Hahn RT , Feldman T , Boone RH , Smith CR et al. Impact of preoperative moderate/severe mitral regurgitation on 2-year outcome after transcatheter and surgical aortic valve replacement: insight from the Placement of Aortic Transcatheter Valve (PARTNER) Trial Cohort A . Circulation 2013 ; 128 : 2776 – 84 . Google Scholar CrossRef Search ADS PubMed 30 Chakravarty T , Van Belle E , Jilaihawi H , Noheria A , Testa L , Bedogni F et al. Meta-analysis of the impact of mitral regurgitation on outcomes after transcatheter aortic valve implantation . Am J Cardiol 2015 ; 115 : 942 – 9 . Google Scholar CrossRef Search ADS PubMed 31 Rudolph V , Schirmer J , Franzen O , Schluter M , Seiffert M , Treede H et al. Bivalvular transcatheter treatment of high-surgical-risk patients with coexisting severe aortic stenosis and significant mitral regurgitation . Int J Cardiol 2013 ; 167 : 716 – 20 . Google Scholar CrossRef Search ADS PubMed 32 De Meester P , De Cock D , Van De Bruaene A , Gabriels C , Buys R , Helsen F et al. Additional tricuspid annuloplasty in mitral valve surgery results in better clinical outcome . Heart 2015 ; 101 : 720 – 6 . Google Scholar CrossRef Search ADS PubMed 33 Taramasso M , Vanermen H , Maisano F , Guidotti A , La Canna G , Alfieri O. The growing clinical importance of secondary tricuspid regurgitation . J Am Coll Cardiol 2012 ; 59 : 703 – 10 . Google Scholar CrossRef Search ADS PubMed 34 Bergler-Klein J , Klaar U , Heger M , Rosenhek R , Mundigler G , Gabriel H et al. Natriuretic peptides predict symptom-free survival and postoperative outcome in severe aortic stenosis . Circulation 2004 ; 109 : 2302 – 8 . Google Scholar CrossRef Search ADS PubMed Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Heart Journal – Cardiovascular Imaging Oxford University Press

Prognostic relevance of mitral and tricuspid regurgitation in patients with severe aortic stenosis

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Oxford University Press
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com.
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2047-2404
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10.1093/ehjci/jey027
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Abstract

Abstract Aims Although concomitant mitral regurgitation (MR) and tricuspid regurgitation (TR) are frequently present in patients with aortic stenosis (AS), outcome data are scarce and treatment strategies are controversial. The aim of the present study was to assess the presentation and outcome of patients with AS and coexisting MR and TR. Methods and results Eighty-nine consecutive patients with severe AS and at least moderate MR (72 functional and 17 degenerative) were included and followed. Seventy-five patients were symptomatic at presentation. Sixty of these had severe symptoms (New York Heart Association class ≥3). Nine additional patients had an indication for valve procedures during follow-up. However, 35 patients were managed conservatively. Isolated aortic valve intervention was performed in 29 patients (22 valve replacement and 7 transcatheter aortic valve replacement) and concomitant mitral valve surgery in 20 patients. For the assessment of outcome, overall survival (i.e. time from study entry to death from any cause) was assessed: adjusted survival was significantly higher for patients undergoing any valve procedure as compared with patients managed conservatively (P = 0.032). Surgical treatment of severe concomitant MR was associated with improved survival in an unadjusted population but did not reach statistical significance after propensity adjustment. 14 of 36 patients who had concomittant moderate-to-severe tricuspid regurgitation (TR) underwent surgery of which 7 (50 %) died within 3 months postoperatively. On the other hand, only 1 of 35 (3%) with no or mild TR undergoing surgery died within 3 months post-operatively (P < 0.001). Conclusion Presence of MR in patients with severe AS characterizes a high-risk population. Timely aortic valve intervention confers a survival benefit and concomitant mitral valve surgery should be considered according to operative risk. The additional presence of significant TR is associated with dismal outcomes, regardless of the treatment strategy. aortic stenosis , mitral regurgitation , tricuspid regurgitation Introduction Multiple valve disease is increasingly prevalent and choosing the appropriate treatment strategy may pose challenges to the clinician. Moderate-to-severe mitral regurgitation (MR) is present in about 20% of elderly patients with severe aortic stenosis (AS),1 with a reported prevalence varying from 3 to 74% among different studies,2 and is associated with higher mortality after both surgical aortic valve replacement (SAVR)3 and transcatheter aortic valve replacement (TAVR) in particular when MR persists post-interventionally.4 In addition, some patients may present with concomitant tricuspid regurgitation (TR),5 which is a sign of advanced disease and a predictor of increased mortality after SAVR6 and TAVR.7 Whilst double valve surgery corrects both lesions, operative mortality is twice that of isolated AVR.8,9 Due to the associated afterload reduction, regression of MR severity may be observed in 50–70% of patients undergoing isolated SAVR and 50% of patients undergoing isolated TAVR.1 However, persisting or even worsening degrees of MR may occur in the remaining patients. A pragmatic therapeutic approach for concomitant MR in severe AS has been suggested, taking into account MR severity, aetiology as well as the procedural risk.10 However, both the European Society of Cardiology/European Association for Cardio-Thoracic Surgery and the American College of Cardiology/American Heart Association guidelines on valve disease conclude that there is paucity of data on the natural history on mixed and multiple valve disease which does not allow for evidence-based recommendations.11,12 The aim of the present study was therefore to assess the outcome of patients with severe AS and concomitant MR and TR with particular consideration of the impact of the respective treatment approaches so as to optimize the management of these patients. Methods Patient population The process of patient enrolment and the study flow is illustrated in Figure 1. All consecutive patients who were studied in our outpatient heart valve clinic (HVC) between 1999 and 2012 and who were found to have a combination of severe AS with at least moderate MR were included into the study. Exclusion criteria were previous cardiac surgery or additional hemodynamically significant valve lesions (moderate or severe) except for TR. Figure 1 View largeDownload slide Patient enrolment and study flow. Figure 1 View largeDownload slide Patient enrolment and study flow. According to these criteria, 89 consecutive patients (66 female) were identified. According to the purely observational study design, written informed consent was not demanded. The study protocol was approved by the ethics committee of the Medical University of Vienna. Clinical data At study entry, a comprehensive baseline assessment was performed that included medical history, assessment of current medication, physical examination, electrocardiogram, blood tests, and transthoracic echocardiography. The following data were collected: age, sex, body mass index, and body surface area; the patient’s symptomatic status; presence of comorbidities: coronary artery disease (history of myocardial infarction, angioplasty, coronary artery bypass graft (CABG), or angiographically documented coronary artery stenosis) chronic obstructive pulmonary disease (long-term use of bronchodilators or use of steroids for lung disease), arterial hypertension (blood pressure ≥140/90 mmHg at repeated measurements; or use of antihypertensive agents), atrial fibrillation (AF) (present on the electrocardiogram at baseline or verified episode of AF within the last 6 months), hypercholesterolemia (total serum cholesterol ≥240 mg/dL or cholesterol-lowering medication), and diabetes (fasting blood glucose level >126 mg/dL or use of antidiabetic medication). Echocardiographic data Echocardiography was performed using commercially available ultrasound systems. All patients underwent a comprehensive examination including M-Mode, 2D echocardiography, conventional, and colour Doppler by an experienced echocardiographer. Apical four-chamber and two-chamber views were used for calculation of ventricular volumes and ejection fraction by Simpson’s biplane formula. A left ventricular ejection fraction (LVEF) ≥60% was considered normal, a LVEF of 40–60% was considered mildly depressed, a LVEF of 30–40% moderately depressed, and a LVEF of <30% severely depressed. Right ventricular function was assessed both visually and based on tricuspid annular plane systolic excursion and Doppler tissue imaging as recommended13 and graded as normal, mildly, or severely depressed. Multiple transducer positions were used to record peak aortic jet velocities and aortic valve area was calculated using the continuity equation.14 Severe AS was defined by an aortic valve area ≤1 cm2 and an aortic velocity ≥ 4 m/s in the presence of normal flow. In patients with low flow gradient AS, the severity of AS was confirmed by dobutamine echocardiography15 and by the presence of extensive aortic valve calcification.16,17 In the quantification of lesion severity, potential interactions of coexisting lesions on the respective parameters were considered.10 An integrated approach including qualitative, quantitative, and semiquantitative parameters was used for the quantification of MR as proposed by current recommendations.18,19 The assessment included valve morphology, LV volume load, proximal regurgitant jet width, proximal flow convergence, and pulmonary venous flow pattern. LV diameters and ejection fraction, as well as systolic pulmonary artery pressure (using tricuspid regurgitant velocity), were measured as recommended.20 TR was quantified by an integrated approach.18 Echocardiographic parameters used for grading included TV morphology, vena contracta width; proximal flow convergence radius and hepatic venous flow pattern. RV, right atrial, and inferior vena cava diameters were also considered. Post-procedural evaluation of prosthetic valves was performed as recommended.21 Follow-up Patients were followed prospectively after their initial visit at the HVC. Asymptomatic patients were scheduled to undergo follow-up exams every 6 months based on a watchful waiting approach, and were referred to surgery once they had reached an indication for surgery.11,12 Patients who underwent valve procedures had a post-procedural follow-up visit 6–12 months after the intervention in the HVC to assess the surgical outcome. Further post-operative follow-up exams in the HVC were scheduled at extended intervals, depending on surgical and clinical outcomes. Follow-up information was obtained from interviews with the patients, their relatives and their physicians. Information regarding the development of cardiac symptoms, valve intervention, and death was obtained. Exercise testing was performed at clinical discretion in apparently asymptomatic patients. For the assessment of outcome, overall survival (i.e. time from study entry to death from any cause) was assessed. Choice of procedure In the presence of an indication for intervention, a comprehensive work-up (including coronary angiography, carotid ultrasound, spirometry, and aortic CT-angiography in selected patients) was performed, and cases were discussed in a heart team consisting of cardiac surgeons as well as invasive and non-invasive cardiologists. Treatment decisions were individualized considering the patient’s risk profile, comorbidities, age and preferences as well as the severity and aetiology of MR and the severity of TR.22 Statistical analysis Categorical baseline variables are described as counts and percentages and compared between groups using χ2 tests. Continuous baseline variables are described as medians and quartiles and compared between groups using Wilcoxon rank-sum tests and Kruskal–Wallis tests due to skewed distributions. Median follow-up is calculated using the inverse Kaplan–Meier method.23 Survival rates [with 95% confidence intervals (CIs)] at clinically relevant time points and median survival (with quartiles) are deduced from the Kaplan–Meier estimates. For graphically comparing patients undergoing valve procedures with those managed conservatively, Kaplan–Meier survival estimates are displayed for a landmark of 4 months after inclusion into the study in order to account for the time-dependence of the factor ‘valve procedure’. Patients censored or died before 4 months are excluded in Figure 2. A Cox regression model with time-dependent valve procedure factor is used to calculate a hazard ratio (HR) with 95% CI adjusted for EuroSCORE II. Post-interventional survival is compared between groups defined at or before surgery using Kaplan–Meier estimates and a log-rank test. In a Cox regression model an adjustment for baseline EuroSCORE II is accomplished by inverse probability weighting using a propensity score based on EuroSCORE II. The propensity score of a patient is defined as the probability to receive the treatment under investigation conditional on pre-treatment covariates.24 Each patient’s contribution is weighted by the inverse of this probability if treated with this treatment under investigation and by the inverse of one minus this probability otherwise. The potential influence of baseline TR is investigated in a Cox regression model adjusting for EuroSCORE II and time-dependent effects of surgery and (nested) tricuspid valve surgery. The reported P-values are the results of two-sided tests. P-values ≤0.05 are considered to be statistically significant. All computations were carried out using SAS software Version 9.4 (SAS Institute Inc., Cary, NC, USA, 2012). Results Baseline patient characteristics are given in Table 1. Patients addressed for severe AS and concomitant MR were relatively old (median 80 years, quartiles 75–84), had relevant comorbidities and consequently a high operative risk as reflected in the median EuroSCORE II of 7.1% (quartiles 4.5–10.9). At baseline, 36 patients presented with moderate MR and 53 patients with severe MR. LVEF was abnormal in 36 patients: 15 patients had mildly reduced LVEF and 21 had at least moderately reduced LVEF (<40%). Severe low-flow low-gradient AS confirmed by dobutamine stress-echocardiography was present in five patients while the other patients had high transaortic gradients despite a reduced LVEF. In addition, 36 patients had concomitant moderate-to-severe TR. Table 1 Baseline patient characteristics Variables Total population (n = 89) Patients without significant TR (n = 53) Patients with significant TR (n = 36) P-value Female gender 66 (74) 42 (79) 24 (66) 0.18 Age (years) 80 (75–84) 80 (74–83) 83 (75–85) 0.20 Aortic jet velocity (m/s) 4.6 (4.2–5.2) 4.6 (4.3–5.3) 4.4 (4.2–4.9) 0.16 Aortic mean gradient (mmHg) 53 (43–69) 56 (44–73) 52 (40–65) 0.14 Aortic valve area (cm2) 0.6 (0.4–0.7) 0.6 (0.5–0.8) 0.6 (0.5–0.7) 0.84 Coronary artery disease 40 (45) 24 (45) 16 (44) 0.94 Hypertension 62 (70) 37 (70) 25 (69) 0.97 Diabetes mellitus 21 (24) 13 (25) 8 (22) 0.80 Hypercholesterolemia 37 (42) 24 (45) 13 (36) 0.39 Systolic pulmonary artery pressure (mmHg) 54 (48–68) 51 (43–62) 60 (53–74) 0.002 Mildly depressed right ventricular function 9 (10) 3 (6) 6 (17) 0.15a Preserved right ventricular function 80 (90) 50 (94) 30 (83) 0.15a Baseline EuroSCORE II 7.1 (4.5–10.9) 7.1 (4.0–11.1) 6.8 (4.9–10.2) 0.86 Moderate-to severely depressed LV function 21 (24) 10 (19) 11 (31) 0.21 Moderate-to-severe TR 36 (40) 0 (0) 36 (100) <0.001 Variables Total population (n = 89) Patients without significant TR (n = 53) Patients with significant TR (n = 36) P-value Female gender 66 (74) 42 (79) 24 (66) 0.18 Age (years) 80 (75–84) 80 (74–83) 83 (75–85) 0.20 Aortic jet velocity (m/s) 4.6 (4.2–5.2) 4.6 (4.3–5.3) 4.4 (4.2–4.9) 0.16 Aortic mean gradient (mmHg) 53 (43–69) 56 (44–73) 52 (40–65) 0.14 Aortic valve area (cm2) 0.6 (0.4–0.7) 0.6 (0.5–0.8) 0.6 (0.5–0.7) 0.84 Coronary artery disease 40 (45) 24 (45) 16 (44) 0.94 Hypertension 62 (70) 37 (70) 25 (69) 0.97 Diabetes mellitus 21 (24) 13 (25) 8 (22) 0.80 Hypercholesterolemia 37 (42) 24 (45) 13 (36) 0.39 Systolic pulmonary artery pressure (mmHg) 54 (48–68) 51 (43–62) 60 (53–74) 0.002 Mildly depressed right ventricular function 9 (10) 3 (6) 6 (17) 0.15a Preserved right ventricular function 80 (90) 50 (94) 30 (83) 0.15a Baseline EuroSCORE II 7.1 (4.5–10.9) 7.1 (4.0–11.1) 6.8 (4.9–10.2) 0.86 Moderate-to severely depressed LV function 21 (24) 10 (19) 11 (31) 0.21 Moderate-to-severe TR 36 (40) 0 (0) 36 (100) <0.001 Data are given as median (quartiles) and count (%). a Fisher’s exact test instead of χ2 test due to small expected cell counts. Table 1 Baseline patient characteristics Variables Total population (n = 89) Patients without significant TR (n = 53) Patients with significant TR (n = 36) P-value Female gender 66 (74) 42 (79) 24 (66) 0.18 Age (years) 80 (75–84) 80 (74–83) 83 (75–85) 0.20 Aortic jet velocity (m/s) 4.6 (4.2–5.2) 4.6 (4.3–5.3) 4.4 (4.2–4.9) 0.16 Aortic mean gradient (mmHg) 53 (43–69) 56 (44–73) 52 (40–65) 0.14 Aortic valve area (cm2) 0.6 (0.4–0.7) 0.6 (0.5–0.8) 0.6 (0.5–0.7) 0.84 Coronary artery disease 40 (45) 24 (45) 16 (44) 0.94 Hypertension 62 (70) 37 (70) 25 (69) 0.97 Diabetes mellitus 21 (24) 13 (25) 8 (22) 0.80 Hypercholesterolemia 37 (42) 24 (45) 13 (36) 0.39 Systolic pulmonary artery pressure (mmHg) 54 (48–68) 51 (43–62) 60 (53–74) 0.002 Mildly depressed right ventricular function 9 (10) 3 (6) 6 (17) 0.15a Preserved right ventricular function 80 (90) 50 (94) 30 (83) 0.15a Baseline EuroSCORE II 7.1 (4.5–10.9) 7.1 (4.0–11.1) 6.8 (4.9–10.2) 0.86 Moderate-to severely depressed LV function 21 (24) 10 (19) 11 (31) 0.21 Moderate-to-severe TR 36 (40) 0 (0) 36 (100) <0.001 Variables Total population (n = 89) Patients without significant TR (n = 53) Patients with significant TR (n = 36) P-value Female gender 66 (74) 42 (79) 24 (66) 0.18 Age (years) 80 (75–84) 80 (74–83) 83 (75–85) 0.20 Aortic jet velocity (m/s) 4.6 (4.2–5.2) 4.6 (4.3–5.3) 4.4 (4.2–4.9) 0.16 Aortic mean gradient (mmHg) 53 (43–69) 56 (44–73) 52 (40–65) 0.14 Aortic valve area (cm2) 0.6 (0.4–0.7) 0.6 (0.5–0.8) 0.6 (0.5–0.7) 0.84 Coronary artery disease 40 (45) 24 (45) 16 (44) 0.94 Hypertension 62 (70) 37 (70) 25 (69) 0.97 Diabetes mellitus 21 (24) 13 (25) 8 (22) 0.80 Hypercholesterolemia 37 (42) 24 (45) 13 (36) 0.39 Systolic pulmonary artery pressure (mmHg) 54 (48–68) 51 (43–62) 60 (53–74) 0.002 Mildly depressed right ventricular function 9 (10) 3 (6) 6 (17) 0.15a Preserved right ventricular function 80 (90) 50 (94) 30 (83) 0.15a Baseline EuroSCORE II 7.1 (4.5–10.9) 7.1 (4.0–11.1) 6.8 (4.9–10.2) 0.86 Moderate-to severely depressed LV function 21 (24) 10 (19) 11 (31) 0.21 Moderate-to-severe TR 36 (40) 0 (0) 36 (100) <0.001 Data are given as median (quartiles) and count (%). a Fisher’s exact test instead of χ2 test due to small expected cell counts. Mechanisms of MR Seventy-two (81%) patients had secondary MR and 17 (19%) patients had primary MR. Of the latter, 10 had mitral valve prolapse, six had a flail leaflet and one patient had rheumatic mitral valve disease with severe MR and mild mitral stenosis. Some extent of age-related valve degeneration including thickening of the leaflet tips was present in the majority of patients with secondary MR. Presentation of patients At baseline, 14 (16%) patients were asymptomatic and 75 (84%) were symptomatic (exertional dyspnoea or angina), of which 10 (11%) had an additional history of syncope. Of the symptomatic patients, 80% (n = 60) were severely symptomatic (New York Heart Association/CCS class ≥ 3) and 33% (n = 25) had a history of decompensated heart failure that required urgent inpatient care. Event-free survival of the asymptomatic patients During a median follow-up of 47.2 (quartiles 27.2–114.4) months, nine of the 14 patients who were asymptomatic at presentation, developed an indication for surgery and 3 patients died (heart failure n = 1, trauma n = 1, and stroke n = 1), respectively. Indications for valve intervention During follow-up, 84 patients had indications for surgery for the following reasons: symptoms (n = 60); symptoms and left ventricular dysfunction (n = 21); and asymptomatic left ventricular dysfunction (n = 3). Valve interventions Valve procedures were performed in 49 patients: isolated aortic valve intervention in 28 patients (22 SAVR and 7 TAVR), SAVR and tricuspid repair in one patient, SAVR and mitral valve surgery in 9 of 10 (90%) patients with primary MR and in 11 of 39 (28%) patients with secondary MR. Eighteen (90%) of the patients that underwent concomitant mitral surgery had severe MR. Mitral valve repair was performed in 10 of the 20 patients undergoing mitral valve surgery. Post-operatively, MR had improved by 0.7 (0.4–1.0) degrees in patients undergoing isolated AVR and by 2.3 (1.8–2.7) degrees in patients undergoing combined surgery (P < 0.001). No significant change in TR severity was observed whether concomitant mitral valve surgery was performed or not. Concomitant tricuspid repair was performed in seven patients that underwent SAVR and mitral valve surgery. In 13 patients, concomitant CABG was performed. Valve interventions were not performed in 35 patients due to the following reasons: patient refusal (n = 16), denial because of high surgical risk (n = 12), death on the waiting list (n = 6), and surgery aborted due to porcelain aorta (n = 1). Patients who were denied surgery were older [83 (quartiles 81–88) vs. 80 (quartiles 75–79.2) years; P = 0.02] but had otherwise comparable clinical characteristics. Survival Fifty-three patients died during follow-up and all but four [trauma (two); stroke (one); unknown (one)] of these deaths were of cardiac origin. Overall survival rates for the entire patient population were 73% (95% CI 63–81), 58% (95% CI 46–68), and 34% (95% CI 22–46) at 1, 2, and 5 years, respectively. Three patients that were previously asymptomatic died 162, 189, and 706 days after their index examination due to acute heart failure (n = 1), trauma (n = 1), and stroke (n = 1). Of all patients with an indication for AVR who did not refuse surgery six patients died while waiting for valve intervention. These patients presented with one or more of the following characteristics: five presented with severe symptoms, four had a previous episode of cardiac decompensation, four had significant TR and two had a severely depressed systolic LV function. Reasons of death included acute heart failure (n = 5) and sepsis due to a superinfected femoral pseudoaneurysm after pre-operative coronary angiography (n = 1). 15 of 16 patients who had an indication for AVR due to symptoms but refused to undergo valve interventions died due to acute heart failure (n = 12), myocardial infarction (n = 1), sudden death (n = 1), and unknown (n = 1). Median survival for this subgroup of patients was 658 days (quartiles 399–1536). 10 out of 12 patients in whom the heart team recommended a conservative strategy died due to acute heart failure (n = 5), myocardial infarction (n = 2), pneumonia (n = 1), trauma (n = 1), and unknown (n = 1). Median survival for this subgroup was 241 days (quartiles 87–843). In addition, one patient in whom surgery was aborted due to porcelain aorta in the pre-TAVR era died from acute heart failure. Survival according to management strategy Survival rates comparing patients undergoing valve intervention with those managed conservatively are displayed for a landmark of 4 months after inclusion into the study (Figure 2): of all 74 patients still under study at 4 months those already having had valve intervention (23 patients) show higher survival rates when compared with those who had not yet undergone valve intervention (51 patients). The effect of valve interventions also persisted after adjusting for the pre-operative EuroSCORE II (HR = 0.50; P = 0.032). Figure 2 View largeDownload slide Kaplan–Meier overall survival estimates for patients still under study at 4 months who underwent valve interventions within 4 months (red line) vs. patients who had not (yet) undergone valve intervention up to 4 months (blue line). Figure 2 View largeDownload slide Kaplan–Meier overall survival estimates for patients still under study at 4 months who underwent valve interventions within 4 months (red line) vs. patients who had not (yet) undergone valve intervention up to 4 months (blue line). Post-interventional survival Eighteen deaths occurred among the 49 patients that had undergone valve interventions. Overall post-procedural survival rates were 81% (95% CI 66–90), 75% (95% CI 59–85), and 57% (95% CI 36–73) at 1, 2, and 5 years, respectively. There were three periprocedural (within 30 days) and five early post-procedural (1–3 months after the valve procedure) deaths: myocardial infarction (n = 2), haemorrhagic shock (n = 1), sepsis (n = 1), and acute heart failure (n = 1). Ten patients died during late follow-up (n = 10) due to acute heart failure (n = 8), mitral valve endocarditis (n = 1), and myocardial infarction (n = 1). Post-interventional survival according to interventional strategy For the graphic presentation of post-interventional survival, patients were subdivided into three groups: patients receiving combined aortic and mitral valve surgery (Group 1), patients with moderate MR at baseline receiving an isolated aortic intervention (Group 2), and patients with severe MR who underwent isolated aortic intervention (Group 3). The baseline characteristics of these groups are given in Table 2. Table 2 Baseline patient characteristics based on treatment strategy Variables Combined aortic and mitral surgery (n = 20) Moderate MR − isolated aortic intervention (n = 19) Severe MR − isolated aortic intervention (n = 10) P-value Gender (female) 12 15 8 0.339 Age (years) 70 (63.3–78.3) 78 (75–81) 86 (83–88.3) 0.0002a Aortic jet velocity (m/s) 4.7 (4.4–5) 4.8 (4.4–5.6) 4.3 (3.9–4.9) 0.16 Aortic mean gradient (mmHg) 55 (45–70) 60 (51–81) 51 (37–58) 0.08 Aortic valve area (cm2) 0.6 (0.4–0.8) 0.5 (0.4–0.6) 0.7 (0.4–0.8) 0.46 Coronary artery disease 9 (45) 8 (42) 8 (80) 0.10 Hypertension 13 (65) 13 (68) 5 (50) 0.61 Diabetes mellitus 3 (15) 5 (26) 2 (20) 0.68 Hypercholesterolemia 6 (30) 11 (58) 2 (20) 0.08 Baseline logistic EuroSCORE 4.6 (2.4–6.9) 6.1 (4.2–8.7) 11.8 (9.1–16.3) <0.001a Moderate-to severely depressed LV function 2 (10) 4 (21) 6 (60) 0.011a Moderate-to-severe TR 7 (35) 2 (11) 5 (50) 0.058 Variables Combined aortic and mitral surgery (n = 20) Moderate MR − isolated aortic intervention (n = 19) Severe MR − isolated aortic intervention (n = 10) P-value Gender (female) 12 15 8 0.339 Age (years) 70 (63.3–78.3) 78 (75–81) 86 (83–88.3) 0.0002a Aortic jet velocity (m/s) 4.7 (4.4–5) 4.8 (4.4–5.6) 4.3 (3.9–4.9) 0.16 Aortic mean gradient (mmHg) 55 (45–70) 60 (51–81) 51 (37–58) 0.08 Aortic valve area (cm2) 0.6 (0.4–0.8) 0.5 (0.4–0.6) 0.7 (0.4–0.8) 0.46 Coronary artery disease 9 (45) 8 (42) 8 (80) 0.10 Hypertension 13 (65) 13 (68) 5 (50) 0.61 Diabetes mellitus 3 (15) 5 (26) 2 (20) 0.68 Hypercholesterolemia 6 (30) 11 (58) 2 (20) 0.08 Baseline logistic EuroSCORE 4.6 (2.4–6.9) 6.1 (4.2–8.7) 11.8 (9.1–16.3) <0.001a Moderate-to severely depressed LV function 2 (10) 4 (21) 6 (60) 0.011a Moderate-to-severe TR 7 (35) 2 (11) 5 (50) 0.058 Data are given as median (quartiles) and count (%). a Significant (without multiplicity correction). Table 2 Baseline patient characteristics based on treatment strategy Variables Combined aortic and mitral surgery (n = 20) Moderate MR − isolated aortic intervention (n = 19) Severe MR − isolated aortic intervention (n = 10) P-value Gender (female) 12 15 8 0.339 Age (years) 70 (63.3–78.3) 78 (75–81) 86 (83–88.3) 0.0002a Aortic jet velocity (m/s) 4.7 (4.4–5) 4.8 (4.4–5.6) 4.3 (3.9–4.9) 0.16 Aortic mean gradient (mmHg) 55 (45–70) 60 (51–81) 51 (37–58) 0.08 Aortic valve area (cm2) 0.6 (0.4–0.8) 0.5 (0.4–0.6) 0.7 (0.4–0.8) 0.46 Coronary artery disease 9 (45) 8 (42) 8 (80) 0.10 Hypertension 13 (65) 13 (68) 5 (50) 0.61 Diabetes mellitus 3 (15) 5 (26) 2 (20) 0.68 Hypercholesterolemia 6 (30) 11 (58) 2 (20) 0.08 Baseline logistic EuroSCORE 4.6 (2.4–6.9) 6.1 (4.2–8.7) 11.8 (9.1–16.3) <0.001a Moderate-to severely depressed LV function 2 (10) 4 (21) 6 (60) 0.011a Moderate-to-severe TR 7 (35) 2 (11) 5 (50) 0.058 Variables Combined aortic and mitral surgery (n = 20) Moderate MR − isolated aortic intervention (n = 19) Severe MR − isolated aortic intervention (n = 10) P-value Gender (female) 12 15 8 0.339 Age (years) 70 (63.3–78.3) 78 (75–81) 86 (83–88.3) 0.0002a Aortic jet velocity (m/s) 4.7 (4.4–5) 4.8 (4.4–5.6) 4.3 (3.9–4.9) 0.16 Aortic mean gradient (mmHg) 55 (45–70) 60 (51–81) 51 (37–58) 0.08 Aortic valve area (cm2) 0.6 (0.4–0.8) 0.5 (0.4–0.6) 0.7 (0.4–0.8) 0.46 Coronary artery disease 9 (45) 8 (42) 8 (80) 0.10 Hypertension 13 (65) 13 (68) 5 (50) 0.61 Diabetes mellitus 3 (15) 5 (26) 2 (20) 0.68 Hypercholesterolemia 6 (30) 11 (58) 2 (20) 0.08 Baseline logistic EuroSCORE 4.6 (2.4–6.9) 6.1 (4.2–8.7) 11.8 (9.1–16.3) <0.001a Moderate-to severely depressed LV function 2 (10) 4 (21) 6 (60) 0.011a Moderate-to-severe TR 7 (35) 2 (11) 5 (50) 0.058 Data are given as median (quartiles) and count (%). a Significant (without multiplicity correction). Unadjusted post-procedural survival rates at 1, 2, and 5 years, were, 85% (95% CI 60–95), 78% (95% CI 52–91), and 59% (95% CI 18–85), respectively for Group 1; 94% (95% CI 65–99), 85% (95% CI 50–96), and 75% (95% CI 40–92) for Group 2; and 50% (95% CI 18–75), 50% (95% CI 18–75), and 25% (95% CI 4–55) for Group 3 (P = 0.031; Figure 3). Figure 3 View largeDownload slide Kaplan–Meier post-interventional survival estimates for patients with moderate MR left untreated (green line), severe MR that was treated (red line), and severe MR left untreated (blue line). MR, mitral regurgitation. Figure 3 View largeDownload slide Kaplan–Meier post-interventional survival estimates for patients with moderate MR left untreated (green line), severe MR that was treated (red line), and severe MR left untreated (blue line). MR, mitral regurgitation. Using propensity score adjustment for the pre-operative EuroSCORE II, the survival benefit for patients that had undergone concomitant mitral surgery was no longer statistically significant [HR (Group 1 vs. 2 and 3) = 0.80 (95% CI 0.28–2.29; P = 0.673)] Concomitant TR in patients with AS and MR The presence of moderate-to-severe TR was associated with lower overall survival rates: 45% (95% CI 28–61), 32% (95% CI 17–48), and 12% (95% CI 2–29) at 1, 2, and 5 years, respectively as compared with 92% (95% CI 80–97), 76% (95% CI 60–86), and 49% (95% CI 31–65) at 1, 2, and 5 years, respectively for patients with no or mild TR (adjusted HR = 3.06; 95% CI 1.63–5.75; P < 0.001; Figure 4). Apart from more pronounced pulmonary hypertension, patients with significant TR had a similar risk profile (Table 1). Figure 4 View largeDownload slide Kaplan–Meier overall survival estimates for patients with moderate to severe TR (blue line) and for patients with no or mild TR (red line). TR, tricuspid regurgitation. Figure 4 View largeDownload slide Kaplan–Meier overall survival estimates for patients with moderate to severe TR (blue line) and for patients with no or mild TR (red line). TR, tricuspid regurgitation. The presence of significant TR was also associated with early post-operative mortality (moderate-to-severe TR was present in 14 patients undergoing valve interventions and tricuspid surgery was performed in seven of these): the 3-month mortality rate after surgery for the 35 patients being operated with no or mild TR was 3.0% as compared with 51.0% for the 14 patients with moderate-to-severe TR (P < 0.001). Of the latter, three had undergone combined aortic, mitral, and tricuspid surgery, while four had undergone isolated aortic intervention (two of them TAVR). Discussion A high-risk population Concomitant significant MR in patients with severe AS characterizes a high-risk population, as reflected by the following findings: The patients included in this series were mostly high-risk patients (EuroSCORE II: 7.1%) that were old (median age 80 years) and had important comorbidities. It is thus a population at significant operative risk. Most of these patients already presented with symptoms at their index examination, with the majority being severely symptomatic. Furthermore, one-third of the symptomatic patients already had a history of previous cardiac decompensation that required inpatient care and six symptomatic patients rapidly died before any intervention could be scheduled. Overall survival rates for the entire patient population were 73% (95% CI 63–81), 58% (95% CI 46–68), and 34% (95% CI 22–46) at 1, 2, and 5 years, respectively. In comparison, patients with isolated severe symptomatic AS from an earlier series25 had significantly better overall survival with rates of 90% (95% CI 86–93%), 85% (95% CI 80–89%), and 70% (95% CI 63–76%) at 1, 2, and 5 years, respectively (P < 0.001). Twenty-four percent of the patients already had a moderate-to severely depressed LVEF. Thirty percent of the patients had very severe AS, as defined by a peak aortic-jet velocity of greater than 5 m/s,26 despite the presence of MR. The 15 asymptomatic patients had an event-rate of 69% at 2 years. Role and timing of valve procedures Many of the patients did not undergo any valve procedure at all due to patient refusal in 16 patients and denial by the heart team in 12 patients. Patients being denied valve procedures were older but had an otherwise comparable risk profile. Intervention however, when performed, was associated with a survival benefit. The high risk of mortality during workup/on the waiting list for valve procedures [six of 84 (7%) patients with an indication for AVR died while waiting for intervention], further emphasizes the importance of urgent treatment without any delays in this high-risk population. It can be expected that with the advent of transcatheter treatment options, fewer patients may be denied treatment. At the same time, the potential futility of these interventions will need to be considered. Impact of different treatment strategies Concomitant mitral surgery was performed in 18 of 28 (64%) patients with severe MR and in 2 of 21 (10%) patients with moderate MR. In the present series, secondary MR was the predominant aetiology (81%). The decisions were taken by the Heart Team based on an individualized approach, considering interventional risks and the expected disease course. In an unadjusted analysis, post-interventional outcomes after AVR were comparable for patients who underwent concomitant mitral valve surgery for severe MR and for patients with concomitant moderate MR that was left untreated, while patients with severe MR who underwent isolated AVR had a high mortality. Importantly, this finding supports the careful integrated approach used to quantify MR in the present study, as emphasized by current guidelines.27,28 With propensity score adjustment for the baseline EuroSCORE II, the benefit of concomitant mitral surgery in the presence of severe MR (HR 0.52) did not reach statistical significance but nevertheless, a significant reduction in MR was achieved when compared with patients with isolated aortic intervention. It has been demonstrated previously that moderate or severe MR at baseline was associated with increased 2-year mortality after SAVR but not after TAVR.29 Nevertheless, in a recent meta-analysis of 8 studies comprising 8927 patients, significant residual MR after TAVR was associated with an increased 1-year mortality after TAVR.30 Therefore, concomitant mitral valve surgery should be considered, when the incremental surgical risk is acceptable. In the presence of a high surgical risk, isolated aortic valve intervention may nevertheless be associated with a survival benefit. Careful patient assessment, procedural risk stratification and an individualized decision is thus essential. Novel percutaneous treatment approaches might be beneficial for high-risk patients requiring multivalve procedures.31 Prognostic value of TR It is accepted that in patients with severe primary MR, the surgical correction of concomitant significant TR can be performed without significantly increased surgical risk and is associated with good post-operative outcomes.32 In contrast, the presence of moderate-to-severe TR in patients with AS and MR is a strong independent predictor of increased mortality (HR 3.06) even when adjusting for the baseline EuroSCORE II. Furthermore, in the present series, it was associated with a periprocedural mortality close to 50% as compared with 3% (P < 0.001) for patients without significant TR. Accordingly, a subgroup analysis of the PARTNER II trial7 demonstrated that moderate or severe TR and right heart enlargement are independently associated with increased 1-year mortality in inoperable patients treated with TAVR. The presence of TR thus indicates more advanced disease stages.33 In this regard, the present findings suggest that performing valve procedures in patients with severe AS, concomitant MR and significant TR should be carefully balanced against the poor outcome that these patients may experience. It is thus important to recognize severe concomitant TR in the pre-interventional workup and risk assessment. Study limitations The proportion of patients with severe AS presenting with concomitant MR is in the lower range of the reported prevalence and might be explained by different referral patterns in the pre-transcatheter treatment era. Higher referral can be expected in the current era. The present study is a purely observational series of consecutive patients and has the inherent limitation of not being a randomized trial regarding treatment choices. Nevertheless, this limitation is compensated for by propensity score matching. Only a limited number of the patients in the present study were treated with TAVR (either because it was decided to perform a surgical multivalvular procedure or due to inclusion in the pre-TAVR era). While this made it possible to more accurately document the natural course of the disease, the precise role of TAVR in the treatment of these patients remains to be established. Serum biomarkers were not routinely assessed in this patient population. The patients included in the present study, however, were mostly severely symptomatic and many of them already had had an episode of decompensated congestive heart failure. Therefore, we believe that assessment of serum biomarkers such as N-terminal pro-B-type natriuretic peptide (NT-proBNP) would not have changed the decision-making process. While a predictive value of neurohormones in AS has been reported,34 future studies should assess its potential role in the specific population of patients with multivalvular disease. The patient’s frailty or immobility was not systematically assessed by a geriatrician and thus might be subject to bias of the attending physician in the valve clinic. Conclusion Presence of MR in patients with severe AS characterizes a high-risk population of elderly and mostly severely symptomatic patients. Timely aortic valve intervention confers a survival benefit and concomitant mitral valve surgery should be considered according to operative risk. The additional presence of significant TR is associated with dismal outcomes, regardless of the treatment strategy. Conflict of interest: None declared. References 1 Nombela-Franco L , Ribeiro HB , Urena M , Allende R , Amat-Santos I , DeLarochelliere R et al. Significant mitral regurgitation left untreated at the time of aortic valve replacement: a comprehensive review of a frequent entity in the transcatheter aortic valve replacement era . J Am Coll Cardiol 2014 ; 63 : 2643 – 58 . 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European Heart Journal – Cardiovascular ImagingOxford University Press

Published: Sep 1, 2018

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