Original Article. Relationship Between Valve Calcification and Long-Term Results of Percutaneous Mitral Commissurotomy for Rheumatic Mitral Stenosis

Transcription

1 Original Article Relationship Between Valve Calcification and Long-Term Results of Percutaneous Mitral Commissurotomy for Rheumatic Mitral Stenosis Claire Bouleti, MD, PhD; Bernard Iung, MD; Dominique Himbert, MD; David Messika-Zeitoun, MD, PhD; Eric Brochet, MD; Eric Garbarz, MD; Bertrand Cormier, MD; Alec Vahanian, MD Downloaded from by guest on June 8, 208 Background Indications of percutaneous mitral commissurotomy (PMC) remain debated in calcific mitral stenosis. We analyzed long-term results of PMC for calcific mitral stenosis and the factors associated with late functional results. Methods and Results We compared the characteristics and outcome of 34 patients undergoing PMC for calcific mitral stenosis with 70 patients with noncalcified valves followed up to 20 years. Calcification was defined by fluoroscopy, and its extent was graded from to 4. Good immediate results (valve area.5 cm 2 with mitral regurgitation 2/4) were obtained in 25 patients (80%) with calcified valves and 66 (93%) with noncalcified valves (P<0.00). The hazard ratio for good functional results (survival without cardiovascular death, without mitral reintervention, and in New York Heart Association class I or II) was 2.5 (95% confidence interval [2. 2.9]; P<0.000) in patients with calcified valves (2±3% at 20 years) relative to the noncalcified group (38±2% at 20 years). In the 25 patients with calcified valves who had good immediate results, 5-year rates of good functional results were 35±4% for minor (grade ) calcification, 24±6% for grade 2, and 0±6% for severe (grades 3 4) calcification. Factors associated with poor late functional results on multivariable analysis were calcification extent, older age, higher New York Heart Association class, atrial fibrillation, and higher mean gradient after PMC. Conclusions Although late results of PMC are less satisfying in calcific mitral stenosis, long-term functional outcome depends on calcification extent, patient characteristics, and immediate results of PMC. These findings support the use of PMC as first-line treatment in selected patients with calcific mitral stenosis. (Circ Cardiovasc Interv. 204;7:00-00.) Percutaneous mitral commissurotomy (PMC) is the reference treatment for mitral stenosis (MS) in patients with favorable valvular anatomy.,2 Valve calcification is a known predictor of poor results after PMC in both the immediate and long term. 3 8 Specific series have shown the feasibility of PMC in patients with calcified valves, but follow-up was most often limited to midterm. 9 The only study reporting >0-year follow-up analyzed only commissural calcification. 2 Whether patients with calcified valves should be candidates for PMC or be referred for surgery as first-line treatment is still a debated issue. This is of particular importance in Western countries where valve calcification is frequently encountered in rheumatic MS. 3 5 The aim of this study is, therefore, to analyze clinical results of PMC according to the presence and extent of valve calcification, with a particular emphasis on long-term results. Key Words: balloon valvuloplasty mitral valve stenosis Methods Study Population The population consisted of 024 consecutive patients, residing in France, who underwent PMC for rheumatic MS between 986 and 995 in our institution. Patients presenting with degenerative calcific MS because of annular and leaflet calcification without commissural fusion were not considered for PMC. To assess the relationship between the presence of valve calcification, as defined by fluoroscopy, and outcome, the overall population was split into calcified and noncalcified groups. Of this cohort, 34 (3%) had valve calcification, whereas 70 patients (69%) had noncalcified valves. Previous cerebral or peripheral embolic event occurred in 9 patients (9%), a mean of 3 years before PMC. The study was approved by the local review committee. Patients gave written informed consent before PMC. Measurements Echocardiographic examination was performed on the day preceding PMC and 24 to 48 hours after the procedure by the same experienced Received September 3, 203; accepted April 8, 204. From the Department of Cardiology, Assistance Publique Hôpitaux de Paris, Bichat Hospital, Paris-Diderot University, Paris, France. The Data Supplement is available at Correspondence to Bernard Iung, MD, Department of Cardiology, Bichat Hospital, Paris-Diderot University, 46 rue Henri Huchard, 7508 Paris, France. bernard.iung@bch.aphp.fr 204 American Heart Association, Inc. Circ Cardiovasc Interv is available at DOI: 0.6/CIRCINTERVENTIONS

2 2 Circ Cardiovasc Interv June 204 Downloaded from by guest on June 8, 208 WHAT IS KNOWN Percutaneous mitral commissurotomy is feasible in patients with calcific rheumatic mitral stenosis, but immediate and midterm results are less satisfying than in patients with noncalcified valves. The respective indications for percutaneous mitral commissurotomy and surgery are, therefore, debated in patients with calcific mitral stenosis. WHAT THE STUDY ADDS Twenty-year follow-up showed that several factors were associated with the worse outcome of patients with calcific mitral stenosis after percutaneous mitral commissurotomy. More severe valve calcification, as assessed by fluoroscopy, was associated with worse long-term functional results. Percutaneous mitral commissurotomy should be widely considered in patients with grade and 2 calcification, and the assessment of immediate results should pay particular attention to mitral gradient. echocardiographers. The reference measurement for valve area was planimetry by 2-dimensional echocardiography. In cases of missing data, Doppler was used as a substitution measurement. 4 The degree of mitral regurgitation (MR) was assessed using left ventriculography according to Sellers classification or a semiquantitative evaluation by color Doppler in cases of missing data. 6 Calcified valves were defined using fluoroscopy and corresponded to group 3 of the Cormier classification. 4 The extent of calcification was graded into 4 groups by 2 observers, from small nodule (grade ) to extensive calcification (grade 4), according to their extent on fluoroscopic examination, as previously described. 7 The 34 patients of the calcified group were split into grade (77 patients, 56%), grade 2 (89 patients, 28%), grade 3 (35 patients, %), and grade 4 (3 patients, 4%). Noncalcified valves corresponded to group or 2 of the Cormier classification. Commissural opening after PMC was assessed as previously described and classified into 3 groups: group (no or partial splitting of both commissures), group 2 (complete splitting of one commissure), and group 3 (complete splitting of both commissures). 8 Procedure All procedures were performed using the antegrade transvenous approach. A single balloon was used in patients from the calcified group and 5 patients from the noncalcified group, and then a double balloon was used in 26 patients from the calcified group and 264 patients from the noncalcified group. Finally, beginning in October 990, we systematically used the Inoue balloon in the remaining 77 patients from the calcified group and 43 patients from the noncalcified group, according to the stepwise technique under echocardiographic monitoring. Follow-Up Follow-up was prospectively performed in the 024 patients. Data were collected either during patient s visits to the department or by a standardized questionnaire sent to the patient s cardiologist. Data collection was blinded to the results of the PMC. Follow-up was concluded in December Patients were considered lost to follow-up if their last follow-up examination was before January Follow-up was complete in 290 patients (92%) of the calcified group and 633 patients (89%) of the noncalcified group. Median follow-up was 22 months (interquartile range, months). End Points Good immediate results were defined by a composite criterion combining a final valve area.5 cm 2 and MR 2/4. 4,9 2 For the assessment of late results of PMC, the events taken into account were death, need for valvular surgery or repeat balloon commisurotomy, and poor functional status with New York Heart Association (NYHA) III or IV at last follow-up. These clinical events were combined into the following composite end points:. Overall survival 2. Good functional results defined as cardiovascular survival without reintervention on the mitral valve and in NYHA class II Survival status was censored at the time of surgery or repeat dilatation. Statistical Analysis All data were entered prospectively in a computerized database starting from 986. Continuous variables were expressed as mean value±sd. Cumulative survival curves were determined for the 2 end points of late results according to the Kaplan Meier method. A landmark analysis was also performed including the patients who still had good functional results at month after PMC. Comparisons between subgroups used the unpaired Student t test or ANOVA for quantitative variables and the χ 2 test for qualitative variables. Univariable analysis of the factors associated with poor immediate results was performed using a t test or a χ 2 test as appropriate. Variables with P<0.20 were entered in a multivariable logistic model and selected by a backward procedure with a threshold of P=0.05. The analysis of the factors associated with the predefined end point of late functional results in patients with valve calcification was studied in the 25 patients who experienced good immediate results of PMC (mitral valve area.5 cm 2 and MR 2/4). Univariable analysis of the factors associated with late results was performed with a Cox model for the 0 preprocedure variables listed in Table, the extent of calcification, the type of balloon, and the 4 postprocedure variables (ie, mitral valve area, mean mitral gradient, commissural opening, and MR). Variables with P<0.20 were entered in a multivariable Cox model and selected by a backward procedure with a threshold of P=0.05. Two-way interactions were tested between selected variables. We used a Cox univariable model to study hazard ratios between age and the risk of death, and age and poor functional results. We performed a propensity analysis to account for the imbalance of covariates between patients with and without valve calcification. A propensity score was fitted using a nonparsimonious multivariable logistic model including the 0 variables listed in Table and the type of balloon as covariates. The presence of valve calcification was the dependent variable. We then matched the 34 patients with valve calcification with the 760 patients without valve calcification according to the closest propensity score, using a caliper width of 0.02, to create 2 subgroups of 96 matched pairs. 22 We assessed the degree of imbalance within the pairs using the standardized difference. 22,23 Rates of survival and good functional results were estimated in the 2 matched subgroups using the Kaplan Meier method and compared using a Cox model stratified on the propensity score. 22 Analysis was performed with SAS statistical software (release 9.2, SAS Institute Inc, Cary, NC). Results Population Baseline characteristics of patients with and without valve calcification are reported in Table. All characteristics were less favorable in patients in the calcified group compared with

3 Bouleti et al Balloon Commissurotomy in Calcific Mitral Stenosis 3 Downloaded from by guest on June 8, 208 Table. Baseline Characteristics of Patients With and Without Valve Calcification Calcified Valves (n=34) Mean±SD or n (%) Noncalcified Valves (n=70) Mean±SD or n (%) P Value Age, y 58±3 46±2 <0.000 Female 236 (75) 62 (86) <0.000 NYHA functional class <0.000 I 2 () 3 (0.5) II 50 (6) 82 (26) III 237 (75) 507 (7) IV 25 (8) 8 (2.5) Previous commissurotomy 62 (20) 0 (4) 0.03 Previous embolism 54 (7) 65 (9) Atrial fibrillation 79 (57) 229 (32) <0.000 Left atrial diameter, mm 53±9 49±7 <0.000 Mitral valve area, cm 2.0±0.2.±0.2 <0.000 Mean mitral gradient, mm Hg 0.3±4.5 0.± Mitral regurgitation <0.000 Grade 0 47 (47) 494 (70) Grade 63 (52) 20 (29) Grade 2 4 () 6 () NYHA indicates New York Heart Association. the noncalcified group, except for the mean transmitral gradient: patients were significantly older, more symptomatic, less frequently in sinus rhythm, with more severe MR, and they displayed a smaller mitral valve area. Baseline characteristics of the patients with calcified valves according to the extent of valve calcification are reported in Table 2. Patients with calcification grades 3 and 4 were studied as group. The comparison between the 3 grades of calcification showed that most characteristics were worse as the severity of valve calcification increased. Procedure We used the 3 available techniques at the time of this study, that is, single balloon, double balloon, or the Inoue balloon, in patients with and without valve calcification. There was no difference in device used according to the calcification status (P=0.9). Immediate Results After PMC, 4 patients died in the calcified group (.3%), whereas no in-hospital death occurred in the noncalcified group (P=0.009). The most frequent complication was severe traumatic MR ( 3/4) in 2 patients (3.8%) in the calcified group and 23 patients (3.2%) in the noncalcified group (P=0.26). Embolism leaving sequelae occurred in patient in the calcified group (0.3%) and 2 patients in the noncalcified group (0.3%; P=0.68). Good immediate results were obtained in 25 patients (80%) in the calcified group and 66 patients (93%) in the noncalcified group (P<0.00). The factors associated with poor immediate results in univariable analysis are shown in Table I in the Data Supplement. Variables included in the multivariable analysis were age, NYHA class, previous embolism, atrial fibrillation, extent of calcification, left atrial diameter, mitral valve area before PMC, MR before PMC, and the type of balloon. The results of multivariable analysis are detailed in Table 3. After balloon commissurotomy, mean valve area reached.8±0.3 cm 2 for the calcified group and.9±0.3 cm 2 for the noncalcified group (P<0.000). Mean gradient decreased to 5.2±2.3 mm Hg for the calcified group and 4.6±2.0 mm Hg for the noncalcified group (P<0.000). Late Results The first events that occurred during follow-up are detailed in Table 4 according to whether patients had calcified valves or not. The most frequent events were interventions on the mitral valve with 57 procedures (50%) in the calcified group and 274 procedures (39%) in the noncalcified group. Patients in the calcified group had more frequent intervention on the mitral valve, and they also had few repeat PMC or conservative surgery. Isolated mitral valve replacement was by far the most frequent treatment in this subgroup (76% of the procedures). Finally, 4% of patients in each group were in NYHA class III or IV, either waiting for surgery or under medical treatment alone. There was a significant increase in the risk of death and of poor late functional results after the age of 50 years (Figure I in the Data Supplement). Therefore, we specifically assessed late outcome of patients aged 50 and >50 years at the time of PMC. The curves corresponding to the 2 end points (overall survival and good functional results) are represented in Figures and 2 for the 2 groups of calcified and noncalcified patients. Consistently with patient characteristics, patients with valve calcification displayed a lower survival rate than patients without valve calcification. Overall survival was 50±6% in patients with valve calcification and 8±2% in patients without valve calcification at 20 years (P<0.000; Figure A). Because age and the presence of calcification are linked, we also analyzed survival in patients aged 50 years (Figure B) and in those aged >50 years (Figure C) Good functional results, defined as survival without cardiovascular death, without reintervention on the mitral valve, and in NYHA class I or II, were observed in 2±3% of patients with valve calcification and 38±2% of patients without valve calcification at 20 years (P<0.000). The landmark analysis using a -month landmark time point also showed significant differences in rates of good functional results according to the presence or absence of valve calcification (Figure II in the Data Supplement). Factors Associated With Late Results of PMC for Calcific MS Factors associated with late functional results were analyzed in the 25 patients of the calcified group who had good immediate results of PMC. Results of the univariable analysis and age-adjusted analysis are presented in Table II in the Data Supplement. Variables included in the multivariable Cox analyis were age, sex, NYHA class, atrial fibrillation, extent of calcification, left atrial diameter, mitral valve area before

4 4 Circ Cardiovasc Interv June 204 Table 2. Baseline and Periprocedural Characteristics of Patients With Calcific Mitral Stenosis According to the Extent of Calcification Downloaded from by guest on June 8, 208 Grade (n=77) Mean±SD or n (%) Extent of Valve Calcification Grade 2 (n=89) Mean±SD or n (%) Grades 3 4 (n=48) Mean±SD or n (%) P Value Preprocedure Age, y 55±3 60±3 64± Female 43 (8) 65 (73) 28 (58) NYHA functional class I () () 0 (0) 0.03 II 37 (2) 7 (8) 6 (2) III 3 (74) 70 (79) 36 (75) IV 8 (4) (2) 6 (3) Previous commissurotomy 34 (9) 8 (20) 0 (2) 0.96 Previous embolism 29 (6) 3 (5) 2 (25) 0.28 Atrial fibrillation 96 (54) 53 (60) 30 (63) 0.50 Left atrial diameter, mm 52±8 55±8 54± Mitral valve area, cm 2.0±0.2.0± ± Mean mitral gradient, mm Hg 0.± ±3.9.7± Mitral regurgitation Grade 0 95 (54) 40 (45) 2 (25) Grade 8 (45) 48 (54) 34 (7) Grade 2 () () 2 (4) Procedure Balloon 0.39 Inoue 94 (53) 53 (60) 30 (63) Single or double balloon 83 (47) 36 (40) 8 (37) Postprocedure Final mitral valve area, cm 2.8±0.3.7±0.3.6± Final mean mitral gradient, mm Hg 4.7± ± ± Commissural opening* 0.06 Group 5 (30) 32 (4) 5 (40) Group 2 79 (47) 40 (5) 6 (42) Group 3 38 (23) 6 (8) 7 (8) Final mitral regurgitation 0.52 Grade 0 47 (27) 9 (22) 6 (3) Grade 75 (43) 38 (44) 24 (52) Grade 2 46 (26) 27 (3) 5 (33) Grades (4) 3 (3) (2) NYHA indicates New York Heart Association. *Data available in 284 of the 34 patients. PMC, the type of balloon, final mitral valve area, final mitral gradient, and commissural opening. Multivariable Cox analysis identified 5 variables associated with poor late functional results after good immediate results of PMC in patients with valve calcification (Table 5). Four were preprocedural variables (ie, severe valve calcification [grade 3 or 4; P<0.0], older age [P<0.0], higher NYHA functional class [P<0.0], and atrial fibrillation [P<0.0007]). The fifth and only postprocedural variable was a higher mean mitral gradient after PMC (P<0.000). We then showed the relationship between the extent of calcification and late functional results after good immediate results of PMC (Figure 3). At 5 years, good functional results were obtained in 35±4% of patients with grade calcification, in 24±6% of patients with grade 2 calcification, and in 0±6% of patients with more severe calcification. Good functional results of PMC in patients with grade 2 calcification are detailed in Figure 4 according to their final mitral gradient. Propensity Analysis Propensity score matching achieved an appropriate balance of covariates, as shown by all standardized differences <0% (Table III in the Data Supplement). 23 The mean propensity

5 Bouleti et al Balloon Commissurotomy in Calcific Mitral Stenosis 5 Table 3. Multivariable Analysis of the Factors Associated With Poor Immediate Results of PMC in the 34 Patients With Calcific Mitral Stenosis Variables and Subgroups Adjusted Odds Ratio (95% CI) P Value Downloaded from by guest on June 8, 208 Extent of valve calcification Grade Grade (.2 4.8) 0.0 Grades ( ) 0.29 Age (per 0-y increase).5 (.2.9) 0.00 Valve area before PMC.3 (..5) (per 0. cm 2 decrease) Balloon Inoue Single or double balloon 3.0 (.6 5.6) CI indicates confidence interval; and PMC, percutaneous mitral commissurotomy. score was ±0.977 in the 96 patients with valve calcification and ± in the 96 patients without valve calcification (standardized difference, 0.027). Late outcome for the 2 propensity-matched subgroups is displayed in Figure 5. There was no difference in survival. The difference in good functional results was smaller than in the whole population but remained significant. Discussion In this series of 024 patients including 34 patients with calcified valves, we confirm the association between valve calcification and poor immediate results of PMC. More importantly, valve calcification was associated with worse late functional results. Besides the presence of valve calcification, the extent of calcification is an important factor to take into account. We report, indeed, that > in 3 patients with grade calcification who underwent PMC still have a good functional result 5 years after good immediate results. The prediction of longterm functional results in patients with valve calcification is multifactorial, including clinical and anatomic preprocedural characteristics and also the final mitral gradient. Table 4. Events Occurring During Follow-Up After PMC According to the Presence of Valve Calcification Calcified Valves (n=34) n (%) Noncalcified Valves (n=70) n (%) Death 82 (26) 76 () Cardiovascular related 64 (20) 34 (5) Noncardiovascular 8 (6) 42 (6) Procedure on the mitral valve 57 (50) 274 (39) Open-heart commissurotomy/repair 3 () 3 (4) Repeat PMC 2 (4) 73 (0) Isolated MVR 9 (38) 3 (9) MVR associated with other procedure 23 (7) 39 (6) Deterioration in NYHA class III or IV 3 (4) 3 (4) MVR indicates mitral valve replacement; NYHA, New York Heart Association; and PMC, percutaneous mitral commissurotomy. Figure. Kaplan Meier curves for survival according to the presence of valve calcification. A, Overall population (n=024). B, Patients aged 50 years (n=575). C, Patients aged >50 years (n=449). Immediate Results of PMC Valve calcification is associated with poor immediate results after mitral commissurotomy, whether percutaneous or surgical. 3,5,6,2,24,25 We confirm in this large series that valve function is less satisfying after PMC in patients with valve calcification, with a significantly lower final valve area and a higher final mitral gradient than in patients with noncalcified valves. Differences in valve area and gradient after PMC were also significant according to the extent of valve calcification. This is consistent with previous findings 9 and is likely to be because of the higher stiffness of severely calcified valves. The extent of valve calcification was also associated with poor immediate

6 6 Circ Cardiovasc Interv June 204 Table 5. Multivariable Cox Analysis of the Factors Associated With Poor Late Functional Results After Good Immediate Results of PMC for Calcific Mitral Stenosis Variables and Subgroups Adjusted Hazard Ratio (95% CI) P Value Downloaded from by guest on June 8, 208 Extent of valve calcification Grade Grade 2. (0.8.6) 0.56 Grades (.2 2.7) 0.0 Age (per 0-y increase).2 (.0.4) 0.0 NYHA functional class 0.0 I II III IV.7 (. 2.5) Rhythm Sinus Atrial fibrillation.8 (.3 2.5) Mean gradient after PMC <0.000 Per mm Hg increase.2 (..3) CI indicates confidence interval; NYHA, New York Heart Association; and PMC, percutaneous mitral commissurotomy. compared with patients free from calcification. 9,0 This is the consequence of worse immediate results of PMC in patients with calcified valves but also of a higher attrition rate during follow-up as shown by the landmark analysis. These results are not only related to the presence of calcification on its own but to less favorable clinical and anatomic characteristics. Patients with valve calcification were significantly older, more frequently in atrial fibrillation, and more symptomatic than those without calcification, which is consistent with other series. 9,0 It is likely that these unfavorable characteristics strongly contribute to the survival rate of 50% and the good functional result rate of 2% at 20 years. This is confirmed by the propensity analysis. When comparing the 2 matched subgroups of 96 patients differing only by valve calcification, there was finally no difference in survival. As for functional results, calcific MS remained a factor of poor prognosis. Figure 2. Kaplan Meier curves for good functional results according to the presence of valve calcification. A, Overall population (n=024). B, Patients aged 50 years (n=575). C, Patients aged >50 years (n=449). results of PMC in multivariable analysis in addition to age, initial valve area, and the type of balloon. However, despite the less satisfying results in this particular population, 80% of patients still experienced good immediate results after PMC, with a low rate of complications. The procedure remains safe in the calcified group with an in-hospital death rate of.3% in our series. Late Results of PMC As in other series with a shorter follow-up, valve calcification is strongly associated with poor late results after PMC with significantly lower rates of survival and event-free survival Figure 3. Kaplan Meier curves for good functional results after good immediate results according to the presence and extent of valve calcification.

7 Bouleti et al Balloon Commissurotomy in Calcific Mitral Stenosis 7 Downloaded from by guest on June 8, 208 Figure 4. Kaplan Meier curves for good functional results after good immediate results of patients with grade 2 calcification according to their mean mitral gradient after percutaneous mitral commissurotomy. Interventions during follow-up consisted in mitral valve replacement, either singly or in combination with another procedure, in 90% of patients with calcified valves and in 62% of those with noncalcified valves. Late deterioration of valve function after successful PMC is most often because of mitral restenosis. 26 Surgery for calcific MS is most often valve replacement, and this highlights the usefulness of PMC to defer prosthetic valve replacement with its inherent complications. 27 Certain patients with calcified valves can benefit from PMC if they present clinical characteristics associated with good late functional results. The identification of these factors is, therefore, crucial for the appropriate selection of patients with calcified valves. Factors Associated With Late Results of PMC for Calcific MS We chose to restrict the analysis to the 25 patients who had good immediate results of PMC to ensure homogeneity in the mechanism of deterioration, which is mitral restenosis, and therefore allow for reliable identification of the factors associated with late results. In the present series, a younger age, sinus rhythm, and a lower NYHA functional class were associated with good late functional results. These factors are not specific to patients with calcified valves and are commonly reported in other series on late results of PMC. 5,8,3,9,20,28 There was no relationship between the technique used for PMC and late functional results in this study. We found that extent of calcification was also associated with late results, the results being particularly poor in patients with severe calcification (grades 3 and 4), only 0% presenting good functional results at 20 years. Surgical management should thus be considered as first-line treatment. However, PMC can be used as a palliative procedure for these patients when they are contraindicated or at high risk for surgery, according to guidelines.,2 Patients with grade calcification, however, present good late results of PMC, with > in 3 patients still presenting good functional results at 5 years. PMC can thus be considered as first-line treatment in these patients, even more so when other characteristics are favorable, with resort to surgery in the event of a suboptimal initial result. The difficulty resides in patients with grade 2 calcification whose results are less satisfying, although in 4 patients still have good functional results at 5 years. The variable that had the lowest P value in multivariate analysis of late results in this study was the final mean mitral gradient. The importance of mean gradient has already been reported in other studies reporting late results of PMC. 5,6,8,9 However, most teams still focus on mitral valve area as illustrated by the recent proposition by Song et al 20 to improve the definition of good immediate results of PMC by using a mitral valve area cutoff of.8 cm 2. We think that it would be more valuable to consider the final mitral gradient, which has an incremental prognostic value in addition to mitral valve area, possibly by evaluating the stiffness of the mitral valve. Moreover, in this population of patients with calcified valves, the assessment of mitral valve area using planimetry is less reliable. In keeping with these findings, we split the patients with grade 2 calcification according to their final mitral gradient. Given the distribution of patients and according to the previously reported cutoff of 6 mm Hg for final mitral gradient, 8 we showed that 35±8% of patients with mean gradient <6 Figure 5. Kaplan Meier curves for event rates in the 2 propensity-matched subgroups. A, Survival. B, Good functional results.

8 8 Circ Cardiovasc Interv June 204 Downloaded from by guest on June 8, 208 mm Hg had good functional results at 5 years after good immediate results of PMC, whereas patients with a higher gradient only had 0±6%. This difference was mainly because of a separation between the curves occurring during the first 2 years after PMC. This highlights the need for a close follow-up during the first years after PMC in patients with calcified valves. Finally, these results confirm the usefulness of final mitral gradient for the evaluation of late results after PMC. Limitations The main limitation of this study is the absence of the location of mitral valve calcification in our prospective database. Calcification of both commissures is a contraindication for PMC, 2 but PMC can be attempted in selected patients with unicommissural calcification. Although fluoroscopic examination is more reliable than echocardiography for the diagnosis of valve calcification, it does not allow for precise location. Commissural calcification has been associated with poor results of PMC, but the experience and follow-up are limited Scoring systems specifically assessing commissural calcification have been proposed to improve the prediction of results of PMC, but they present some weaknesses. First, they rely only on echocardiographic examination that may overestimate the diagnosis of calcification. Second, no scoring system has been proven to be superior to another. Moreover, the largest series yet published on late results of PMC in patients with calcified valves used fluoroscopy to determine the presence of calcification. 9 Computed tomography can accurately assess the severity and location of valve calcification but was not routinely used when the present cohort was recruited. It now represents an appealing technique, but its incremental predictive value for late results of PMC for calcific MS has not been studied to date. Conclusions This study, reporting the longest follow-up after PMC in patients with calcified valves, shows that calcific MS is associated with pejorative clinical characteristics that account for lower late survival rates. Therapeutic indications should be individualized according to age, symptoms, and rhythm. More importantly, the present findings allow for further refinement of the management strategy. We show, indeed, that the negative prognostic association is primarily for patients with severe valve calcification (grade 3 or 4) in whom surgery is more appropriate, and PMC is only a palliative procedure. Conversely, PMC should be widely considered in patients with grade calcification because> in 3 of them still exhibit good functional results at 5 years. The decision is more difficult in patients with grade 2 calcification. PMC can be used as a first-line treatment because in 4 patients still derive a functional benefit after 5 years. Mean mitral gradient after PMC is important for prognostic assessment and the modalities of follow-up. Patients with grade 2 calcification and a final mean mitral gradient <6 mm Hg present late results as good as those of patients with grade calcification, whereas patients with a final gradient 6 mm Hg present late results comparable with patients with grade 3 or 4 calcification. Patients with a high final gradient should be carefully followed up to allow for timely surgery. Disclosures Dr Iung has received consultant fees from Abbott, Boehringer Ingelheim, and Valtech and speaker s fees from Edwards Lifesciences. Dr Himbert has received proctoring fees from Edwards Lifesciences and Medtronic. Dr Brochet has received proctoring fees from Edwards Lifesciences. Dr Messika-Zeitoun has received speaker s fees from Edwards Lifesciences. Dr Vahanian is member of Advisory Board for Medtronic, Abbott, Valtech, and Boehringer Ingelheim and has received speaker s fees from Edwards Lifesciences and Siemens. The other authors report no conflicts. References. Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin JP III, Guyton RA, O Gara PT, Ruiz CE, Skubas NJ, Sorajja P, Sundt TM III, Thomas JD. 204 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 [published online ahead of print March 3, 204]. Circulation. doi: 0.6/ CIR CIR Accessed March 25, Vahanian A, Alfieri O, Andreotti F, Antunes MJ, Baron-Esquivias G, Baumgartner H, Borger MA, Carrel TP, De Bonis M, Evangelista A, Falk V, Iung B, Lancellotti P, Pierard L, Price S, Schafers HJ, Schuler G, Stepinska J, Swedberg K, Takkenberg J, Von Oppell UO, Windecker S, Zamorano JL, Zembala M, Bax JJ, Ceconi C, Dean V, Deaton C, Fagard R, Funck-Brentano C, Hasdai D, Hoes A, Kirchhof P, Knuuti J, Kolh P, McDonagh T, Moulin C, Popescu BA, Reiner Z, Sechtem U, Sirnes PA, Tendera M, Torbicki A, Von Segesser L, Badano LP, Bunc M, Claeys MJ, Drinkovic N, Filippatos G, Habib G, Kappetein AP, Kassab R, Lip GY, Moat N, Nickenig G, Otto CM, Pepper J, Piazza N, Pieper PG, Rosenhek R, Shuka N, Schwammenthal E, Schwitter J, Mas PT, Trindade PT, Walther T. Guidelines on the management of valvular heart disease (version 202): The Joint Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J. 202;33: Palacios IF, Block PC, Wilkins GT, Weyman AE. Follow-up of patients undergoing percutaneous mitral balloon valvotomy. Analysis of factors determining restenosis. Circulation. 989;79: Iung B, Cormier B, Ducimetière P, Porte JM, Nallet O, Michel PL, Acar J, Vahanian A. Immediate results of percutaneous mitral commissurotomy. A predictive model on a series of 54 patients. Circulation. 996;94: Meneveau N, Schiele F, Seronde MF, Breton V, Gupta S, Bernard Y, Bassand JP. Predictors of event-free survival after percutaneous mitral commissurotomy. Heart. 998;80: Ben-Farhat M, Betbout F, Gamra H, Maatouk F, Ben-Hamda K, Abdellaoui M, Hammami S, Jarrar M, Addad F, Dridi Z. Predictors of long-term event-free survival and of freedom from restenosis after percutaneous balloon mitral commissurotomy. Am Heart J. 200;42: Shaw TR, Sutaria N, Prendergast B. Clinical and haemodynamic profiles of young, middle aged, and elderly patients with mitral stenosis undergoing mitral balloon valvotomy. Heart. 2003;89: Bouleti C, Iung B, Laouénan C, Himbert D, Brochet E, Messika-Zeitoun D, Détaint D, Garbarz E, Cormier B, Michel PL, Mentré F, Vahanian A. Late results of percutaneous mitral commissurotomy up to 20 years: development and validation of a risk score predicting late functional results from a series of 92 patients. Circulation. 202;25: Tuzcu EM, Block PC, Griffin B, Dinsmore R, Newell JB, Palacios IF. Percutaneous mitral balloon valvotomy in patients with calcific mitral stenosis: immediate and long-term outcome. J Am Coll Cardiol. 994;23: Zhang HP, Allen JW, Lau FY, Ruiz CE. Immediate and late outcome of percutaneous balloon mitral valvotomy in patients with significantly calcified valves. Am Heart J. 995;29: Abraham KA, Chandrasekar B, Rajagopal S, Somanath HS, Sudarsana G. Percutaneous transvenous mitral commissurotomy for significant calcific mitral stenosis: utility of the stepwise balloon dilatation technique and follow-up results. J Invasive Cardiol. 999;: Tanaka S, Watanabe S, Matsuo H, Segawa T, Iwama M, Hirose T, Takahashi H, Ono K, Warita S, Kojima T, Minatoguchi S, Fujiwara H.

9 Bouleti et al Balloon Commissurotomy in Calcific Mitral Stenosis 9 Downloaded from by guest on June 8, 208 Over 0 years clinical outcomes in patients with mitral stenosis with unilateral commissural calcification treated with catheter balloon commissurotomy: single-center experience. J Cardiol. 2008;5: Palacios IF, Sanchez PL, Harrell LC, Weyman AE, Block PC. Which patients benefit from percutaneous mitral balloon valvuloplasty? Prevalvuloplasty and postvalvuloplasty variables that predict long-term outcome. Circulation. 2002;05: Iung B, Nicoud-Houel A, Fondard O, Hafid Akoudad, Haghighat T, Brochet E, Garbarz E, Cormier B, Baron G, Luxereau P, Vahanian A. Temporal trends in percutaneous mitral commissurotomy over a 5-year period. Eur Heart J. 2004;25: Chandrashekhar Y, Westaby S, Narula J. Mitral stenosis. Lancet. 2009;374: Helmcke F, Nanda NC, Hsiung MC, Soto B, Adey CK, Goyal RG, Gatewood RP Jr. Color Doppler assessment of mitral regurgitation with orthogonal planes. Circulation. 987;75: Iung B, Garbarz E, Doutrelant L, Berdah P, Michaud P, Farah B, Mokhtari M, Makita Y, Michel PL, Luxereau P, Cormier B, Vahanian A. Late results of percutaneous mitral commissurotomy for calcific mitral stenosis. Am J Cardiol. 2000;85: Messika-Zeitoun D, Blanc J, Iung B, Brochet E, Cormier B, Himbert D, Vahanian A. Impact of degree of commissural opening after percutaneous mitral commissurotomy on long-term outcome. JACC Cardiovasc Imaging. 2009;2: Wang A, Krasuski RA, Warner JJ, Pieper K, Kisslo KB, Bashore TM, Harrison JK. Serial echocardiographic evaluation of restenosis after successful percutaneous mitral commissurotomy. J Am Coll Cardiol. 2002;39: Song JK, Song JM, Kang DH, Yun SC, Park DW, Lee SW, Kim YH, Lee CW, Hong MK, Kim JJ, Park SW, Park SJ. Restenosis and adverse clinical events after successful percutaneous mitral valvuloplasty: immediate postprocedural mitral valve area as an important prognosticator. Eur Heart J. 2009;30: Cruz-Gonzalez I, Sanchez-Ledesma M, Sanchez PL, Martin-Moreiras J, Jneid H, Rengifo-Moreno P, Inglessis-Azuaje I, Maree AO, Palacios IF. Predicting success and long-term outcomes of percutaneous mitral valvuloplasty: a multifactorial score. Am J Med. 2009;22:58.e e58.e Austin PC. Primer on statistical interpretation or methods report card on propensity-score matching in the cardiology literature from 2004 to 2006: a systematic review. Circ Cardiovasc Qual Outcomes. 2008;: D Agostino RB Jr. Propensity score methods for bias reduction in the comparison of a treatment to a non-randomized control group. Stat Med. 998;7: Ellis LB, Singh JB, Morales DD, Harken DE. Fifteen-to twenty-year study of one thousand patients undergoing closed mitral valvuloplasty. Circulation. 973;48: Rihal CS, Schaff HV, Frye RL, Bailey KR, Hammes LN, Holmes DR Jr. Long-term follow-up of patients undergoing closed transventricular mitral commissurotomy: a useful surrogate for percutaneous balloon mitral valvuloplasty? J Am Coll Cardiol. 992;20: Iung B, Garbarz E, Michaud P, Helou S, Farah B, Berdah P, Michel PL, Cormier B, Vahanian A. Late results of percutaneous mitral commissurotomy in a series of 024 patients. Analysis of late clinical deterioration: frequency, anatomic findings, and predictive factors. Circulation. 999;99: Rahimtoola SH. Choice of prosthetic heart valve in adults an update. J Am Coll Cardiol. 200;55: Fawzy ME. Long-term results up to 9 years of mitral balloon valvuloplasty. Asian Cardiovasc Thorac Ann. 2009;7: Cannan CR, Nishimura RA, Reeder GS, Ilstrup DR, Larson DR, Holmes DR, Tajik AJ. Echocardiographic assessment of commissural calcium: a simple predictor of outcome after percutaneous mitral balloon valvotomy. J Am Coll Cardiol. 997;29: Sutaria N, Shaw TR, Prendergast B, Northridge D. Transoesophageal echocardiographic assessment of mitral valve commissural morphology predicts outcome after balloon mitral valvotomy. Heart. 2006;92: Padial LR, Freitas N, Sagie A, Newell JB, Weyman AE, Levine RA, Palacios IF. Echocardiography can predict which patients will develop severe mitral regurgitation after percutaneous mitral valvulotomy. J Am Coll Cardiol. 996;27:

10 Relationship Between Valve Calcification and Long-Term Results of Percutaneous Mitral Commissurotomy for Rheumatic Mitral Stenosis Claire Bouleti, Bernard Iung, Dominique Himbert, David Messika-Zeitoun, Eric Brochet, Eric Garbarz, Bertrand Cormier and Alec Vahanian Downloaded from by guest on June 8, 208 Circ Cardiovasc Interv. published online April 29, 204; Circulation: Cardiovascular Interventions is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 7523 Copyright 204 American Heart Association, Inc. All rights reserved. Print ISSN: Online ISSN: The online version of this article, along with updated information and services, is located on the World Wide Web at: Data Supplement (unedited) at: Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published in Circulation: Cardiovascular Interventions can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for which permission is being requested is located, click Request Permissions in the middle column of the Web page under Services. Further information about this process is available in the Permissions and Rights Question and Answer document. Reprints: Information about reprints can be found online at: Subscriptions: Information about subscribing to Circulation: Cardiovascular Interventions is online at:

11 SUPPLEMENTAL MATERIAL Supplemental Table : Univariable analysis of factors associated with immediate results of PMC in the 34 patients with calcific mitral stenosis. n= Good results (n=25) Mean ± SD or n (%) Poor results (n=63) Mean ± SD or n (%) Age (years) ± 3 63 ± Female gender (74) 5 (8) 0.23 NYHA functional class I II III IV () 46 (8) 86 (74) 7 (7) 0 (0) 4 (6) 5 (8) 8 (3) Previous commissurotomy (8) 6 (25) 0.2 Previous embolism (6) 5 (24) 0.2 Atrial fibrillation (55) 42 (67) 0.08 Extent of valve calcification Grade Grade 2 Grade (6) 63 (25) 35 (4) 24 (38) 26 (4) 3 (2) p Left atrial diameter (mm) ± 8 56 ± ± ± Mean mitral gradient (mmhg) ± ± Mitral regurgitation Grade 0 Grade Grade (50) 2 (48) 4 (2) 2 (33) 42 (67) 0 (0) 0.03 Balloon Inoue balloon Single or double-balloon (39) 52 (6) 38 (60) 25 (40) Commissural opening* Group Group 2 Group (26) 23 (53) 49 (2) 38 (73) 2 (23) 2 (4) <0.000 *: data available in 284 of the 34 patients NYHA: New York Heart Association.

12 Supplemental Table 2: Univariable and age-adjusted analyses of factors associated with poor late functional results after good immediate results of PMC for calcific mitral stenosis. n= Unadjusted hazard ratio [95% CI] p Age-adjusted hazard ratio [95% CI] PRE-PROCEDURE Age (per 0-year increase) 25.3 [.2-.5] < Sex Female Male NYHA functional class I-II III-IV Previous commissurotomy No Yes Previous embolism No Yes Rhythm Sinus Atrial fibrillation [.0-.9] [.0-2.2] [0.7-.5] [0.7-.5].0.8 [.3-2.4] p.7 [.2-2.4] [0.9-2.] [0.8-.8] [0.6-.4] [.-2.] 0.0 Extent of valve calcification Grade Grade 2 Grades 3-4 Left atrial diameter (per 0 mm increase) Mitral valve area (per 0. cm² decrease) Mean mitral gradient (per mm Hg increase) [0.9-.8] 2.2 [.5-3.4] [0.8-.6] ] [0.9-.4] 0.9. [0.9-.3] [0.9-.0] [0.9-.] [0.9-.0] [.0-.0] 0.76 Mitral regurgitation Grade 0 Grade -2 PROCEDURE Balloon Inoue Single or double-balloon [0.9-.7] [.-.9] [0.8-.5] [.3-2.3]

13 POST-PROCEDURE Final mitral valve area (per 0. cm² decrease) Final mean mitral gradient (per mmhg increase) 250. [.0-.2] [.0-.] [.-.3] < [.-.3] <0.000 Commissural opening* Group Group 2 Group [ ].7 [.-2.8] [.0-2.5].6 [.0-2.6] Final mitral regurgitation Grade 0 Grades [0.9-.7] [0.8-.5] 0.66 Total of subgroups may be < 25 because of missing data. *: data available in 232 of the 25 patients CI: confidence interval NYHA: New York Heart Association. PMC: percutaneous mitral commissurotomy. 3

14 Supplemental Table 3: Baseline characteristics of patients with and without valve calcification in propensity-matched subgroups. Calcified valves (n=96) Mean SD or n (%) Non-calcified valves (n=96) Mean SD or n (%) Standardized difference Age (years) 53. ± ± Female gender 57 (80) 57 (80) 0 NYHA functional class I-II III-IV 39 (20) 57 (80) 39 (20) 57 (80) 0 Previous commissurotomy 35 (8) 32 (6) 0.57 Previous embolism 28 (4) 28 (4) 0 Atrial fibrillation 96 (49) 97 (49) -0.4 Left atrial diameter (mm) 5.2 ± ± Mitral valve area (cm²).05 ± ± Mean mitral gradient (mmhg) 0. ± ± Mitral regurgitation Grade 0 Grade (55) 89 (45) 4 (58) 82 (42) 0.92 Balloon Inoue balloon Single or double-balloon 22 (62) 74 (38) 4 (58) 82 (42).7 NYHA: New York Heart Association. 4

15 Supplemental Figure : Analysis of hazard ratios and 95% confidence intervals related to the risk of death (A) and of poor functional results (B) according to age decades. 5

16 Supplemental Figure 2: Kaplan-Meier curves for good functional results according to the presence of valve calcification using the -month landmark analysis. A: overall population (n=965) B: patients aged 50 years (n=550) C: patients aged >50 years (n=45) 6