Causes of Peri-Operative Mortality After Transcatheter Aortic Valve Implantation: A Pooled Analysis of 12 Studies and 1,223 Patients

ABSTRACT: Background. In order to improve technique and to prevent serious procedural complications during transcatheter aortic valve implantation (TAVI), it is crucial to identify the causes of death of patients undergoing this procedure. Objective. The objective of this study was to identify the causes of death during the procedure and at 1 month in patients with severe aortic stenosis undergoing TAVI. Methods. 12 published studies with information about the causes of death in patients undergoing TAVI were selected. Overall, 1,223 patients were included in these studies, and 249 deaths were reported (119 at 1 month and 130 at > 1 month post-procedure). Mortality during the procedure and at 1 month was 2.3% and 9.7%, respectively. The proportion of cardiac deaths was higher at < 1 month in comparison with > 1 month (56% versus 34%, respectively; p = 0.001). At 1 month, the most frequent causes of death were cardiac failure/multi-organ failure (24%), sudden death/cardiac arrest (17%), vascular and bleeding complications (17%), stroke (11%), sepsis (11%), and cardiac tamponade (10%). During the procedure, the most frequent causes of death were cardiac tamponade (39%), cardiac failure (21%), cardiac arrest (18%), and vascular and/or bleeding complications (18%). In patients treated with the CoreValve system (Medtronic, Minneapolis, Minnesota) versus those treated with Edwards valves (Cribier-Edwards, Edwards-SAPIEN or SAPIEN XT valve, Edward Lifesciences, Irvine, California), deaths at 1 month due to vascular and bleeding complications were less frequent (3% versus 22%, respectively; p = 0.019), but those due to cardiac tamponade (26% versus 6%, respectively; p = 0.019), and because of aortic regurgitation (10% versus 0%, respectively; p = 0.03) were more frequent. Conclusion. In this pooled analysis, mortality at 1 month after TAVI was 9.7%. The causes of death were widely variable, and of both cardiac and non-cardiac origin. There were some important differences between both devices in the cause of mortality.

J INVASIVE CARDIOL 2011;23:180–184

Key words: aortic stenosis, outcome, transcatheter valve implantation

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Transcatheter aortic valve implantation (TAVI) has emerged as a valid treatment for patients with severe aortic stenosis (SAS) unsuitable for surgical aortic valve replacement due to unacceptably high surgical risk.¹ However, TAVI still constitutes a technique with a relatively high procedural and peri-procedural rate of serious complications and mortality, which makes necessary a high degree of experience for physicians performing the procedure.

In order to improve the technique and to correctly select the patients, as well as to prevent procedural complications, it is crucial to identify the causes of death in patients undergoing TAVI. The objective of this study was to identify the causes of death during the procedure and in the peri-operative period (within 30 days post-procedure) in patients with SAS undergoing TAVI. For this purpose, we performed a pooled analysis of 12 studies of patients undergoing TAVI in which the causes of death at 1 month were reported.^2–13

Methods

Only studies published in the English language up to November 10, 2010 were included. Using the MEDLINE database, manuscripts reporting series of patients with transcatheter aortic valve implantation were selected. Thirty-seven trials were identified. Out of them, 25 were excluded because of nonexistent or insufficient data about the cause of death at 1 month. The remaining 12 studies were selected.^2–13

Table 1 shows the main characteristics of the studies. Overall, 1,223 patients were included. In 8 studies, the Cribier-Edwards, Edwards-SAPIEN or SAPIEN XT valve (ES; Edwards Lifesciences, Irvine, California) was used, in 3 studies the CoreValve system (CS) was used, and in one study both systems were used. Overall, 892 patients were treated with ES, and 331 with CS. Six studies were performed in a single center, whereas the other 6 studies included more than 1 center.

In all studies, the mortality at 1 month was reported. In many trials, mortality at longer follow-up was also reported. However, cause of death during the first month was the primary endpoint for this work for the following reasons: 1) Most serious events and mortality occur shortly after TAVI, in the peri-operative period (within 30 days of the procedure); 2) events occurring later than 1 month post-procedure, mainly mortality, may be more likely related to non-cardiac conditions of the patients, rather than to the procedure itself; and 3) the follow-up of the trials beyond 1 month had a highly variable duration, thus making it difficult to compare the mortality rate among different studies and between the two devices used.

The following outcomes were considered for each study: 1) mortality at 1 month; 2) procedural mortality, i.e., deaths occurring in the operating room or in the catheterization laboratory; and 3) post-procedural mortality, i.e., mortality occurring within 1 month post-procedure, but not in the operating room or catheterization laboratory. Mortality was considered cardiac in cases in which death was due to cardiac insufficiency, arrhythmia, myocardial infarction, cardiac tamponade, and valve or prosthesis dysfunction. Sudden unexpected deaths and those deaths attributed to “multi-organ failure” were considered cardiac deaths in the absence of any evident noncardiac cause.

A secondary endpoint was to compare the causes of death between the 2 valve systems (ES and CS).

Statistical analyses were done with the SPSS 15.0 statistical package (Chicago, Illinois). Continuous variables are expressed as mean ± standard deviation, and discrete variables as percentages (proportions). Continuous variables were compared between groups using the t-test, and proportions were compared with the Chi-square test (with Fisher’s correction when necessary). In order to evaluate possible improvements on mortality through the years, the Mantel-Haenzsel test for trend was used. Differences between variables were considered statistically significant when p-value was < 0.05, although all p-values are reported.

Results

Mortality of TAVI. In the 12 trials collected, 249 deaths were reported in the 1,223 patients. Out of these, 119 (47.8%) occurred within 1 month post-procedure, and 130 (52.2%) occurred beyond 1 month.

Out of the peri-procedural deaths, 28 (23.5%) occurred in the operating room or in the catheterization laboratory, and 91 (76.5%) occurred in the post-operative period. Thus, mortality at 1 month was 9.7%, and procedural mortality was 2.3%. A significant reduction of 1-month mortality was found through the years, from 60.0% in 2004 to 4.4–11.3% in studies published in 2010 (Mantel-Haenszel test for trend: p = 0.001). Also, a significant reduction of procedural mortality was found through the years, from 16.7% in 2004 to 0.0–1.8% in studies published in 2010 (Mantel-Haenszel test for trend: p = 0.005) (Figure 1). Mortality at 30 days was higher for transapical in comparison with transfemoral approach, but differences did not reach statistical significance (12.3% versus 8.9%, respectively; p = 0.10).

Causes of death according to the timing of death. Out of the 249 deaths, 25 of those occurring > 1 month post-procedure were considered to have unknown etiology (not specifying whether it was cardiac or non-cardiac in origin). In the remaining 224 cases (all the early deaths, and 105 late deaths), data about the cause of death were available. Out of these 224 episodes of death, 103 (46.0%) were cardiac, and 121 (54.0%) were non-cardiac. During the first month post-procedure, 56.3% of deaths (n = 67) were cardiac, in comparison with 34.3% (n = 36) > 1 month after TAVI (p = 0.001; Chi-square = 10.9).

Causes of death after TAVI are shown in Table 2. At 1 month, 56.3% of deaths were cardiac (n = 67), and 43.7% were non-cardiac. The causes of cardiac death were cardiac failure/multi-organ failure (n = 28), cardiac arrest/sudden death (n = 20), cardiac tamponade (n = 12), aortic regurgitation (n = 3), acute myocardial infarction (n = 2), and prosthesis embolization (n = 2). Out of the 52 peri-procedural non-cardiac deaths, 20 were related with bleeding and/or vascular complications (including one subdural hematoma and one severe rectal bleeding due to rectal cancer), 13 with stroke, 13 with sepsis, 4 with respiratory diseases, and 2 because of other reasons.

Among the 119 deaths ocurring within the first month after TAVI, 28 (23.5%) ocurred in the operating room or the catheterization laboratory. The most frequent cause of procedural mortality was cardiac tamponade (n = 11) due to left or right ventricle perforation. Other causes of procedural death were cardiac failure (n = 6), cardiac arrest (n = 5), vascular and/or bleeding complications (n = 5), and prosthesis embolization (n = 1).

Comparison between both types of prosthesis. Causes of death within the first month according to the type of prosthesis (ES versus CS) are shown in Table 3. There were no statistically significant differences in overall mortality or rate of cardiac or non-cardiac mortality. However, three important significant differences were found: 1) deaths due to vascular and/or bleeding complications were more frequent with the ES valve (21.6% versus 3.2% in patients treated with CS; p = 0.019); 2) deaths due to cardiac tamponade were more frequent with CS (26.1% versus 5.7% in patients treated with ES; p = 0.007); and 3) deaths due to severe aortic regurgitation only occurred with CS (9.7% versus 0.0%; p = 0.003).

Discussion

Mortality rate of TAVI. In this study, pooling the results of 12 series, mortality at 1 month in patients treated with TAVI was 9.7%, and mortality during the procedure was 2.3%. These data compare favorably with the predicted surgical mortality, since EuroSCOREs ranged from 12–28%. In the randomized PARTNER trial, a significant reduction (~20% absolute risk reduction) in the 1-year mortality was obtained for patients with severe aortic stenosis and considered not suitable for surgery due to a very high surgical risk when treated with TAVI in comparison with medical treatment.¹¹ Importantly, mortality significantly reduced through the years, from 2004 to 2010, probably reflecting not only the learning curve and the technical improvements, but also a better patient selection proccess.¹⁴ This reduction in mortality over time has also been observed in single-center experiences.⁴

Although not statistically significant, mortality at 30 days was higher in patients treated by transapical approach in comparison with transfemoral approach. Probably, the worse clinical profile of patients undergoing transapical TAVI justifies, at least in part, these findings.^7,12

Causes of death and timing of death. Within the first month after TAVI, 56% of deaths were cardiac, but it is important to note that a very high proportion of deaths (44%) was non-cardiac. The most important causes of death within the first month were cardiac failure and cardiac arrest (40.3% of deaths), illustrating the complexity of the patients referred to TAVI from a cardiological point of view and therefore the importance that anesthesiologists attending during and shortly after TAVI procedures are highly experienced in high-risk cardiac surgery.¹⁵ Vascular and/or bleeding complications were the second leading cause of death within the first month after TAVI (16.8% of deaths). This shows not only that TAVI needs to be performed by experienced interventional cardiologists, but also highlights the importance of correct patient selection.¹⁴ Importantly, stroke constituted the third leading cause of mortality (10.9% of deaths) in relation not only to the procedure itself, but probably also to the high complexity of the patients (very advanced age and high prevalence of some comorbidities, such as peripheral artery disease). The fourth leading cause of mortality within the first month post-TAVI was sepsis (10.9% of deaths). Probably, most of these deaths were very difficult to prevent given the high prevalence of some comorbitities of the patients, such as chronic respiratory disease, renal failure, and advanced age. However, it is important to stress the importance of applying all means necessary to prevent nosocomial infections in this population. Finally, cardiac tamponade explained the 10.1% of deaths during the first month, and — very importantly — was the first leading cause of mortality during the procedure. These findings make it necessary to recommend careful manipulation of the transvenous catheter with the wire inserted in the left ventricle during the procedure, and that TAVI should be performed by personnel experienced in pericardiocentesis. Also, the occurrence of cardiac tamponade in this procedure highly supports the routine use of a continuous echocardiographic monitoring of TAVI. In our center, up to October 2010, 24 patients have undergone TAVI, and the only death at 1 month occurred due to cardiac tamponade 4 days post-procedure in relation to a perforation of a transvenous pacemaker.¹⁶

Beyond the first month post-procedure, only one-third of deaths were cardiac, and two-thirds were non-cardiac, mainly due to respiratory diseases, sepsis, renal failure, cancer and stroke. This reflects the clinical profile of the patients that currently are considered candidates for TAVI, who have a very high prevalence of severe non-cardiac comorbidities. This also illustrates the importance of excluding patients with shortened life expectancy due to non-cardiac causes when selecting patients for TAVI.

Causes of death depending on the type of prosthesis. There were three important differences between the causes of death with the two different commercially available aortic valve prostheses for transcatheter implantation. First, the proportion of deaths due to vascular and/or bleeding complications was significantly higher with ES. This is probably related to the larger catheter size of this device in comparison to the CS. However, the new-generation Edwards-Sapien XT device is available in 18 French size, which is comparable to the CS, and therefore the current results of both devices in terms of vascular complications are probably similar. Second, the only three deaths due to aortic regurgitation occurred in patients treated with CS. This is probably due to the self-expandable design of this prosthesis, which may be associated with a higher rate of significant paravalvular regurgitation in comparison with the ES device. Conversely, the only two deaths due to prosthesis embolization occurred in patients treated with the ES device, probably due to the balloon-expandable design of the device and to the shorter length in comparison with the CS. Finally, cardiac tamponade as the cause of death was significantly higher with the CS. This could be related to reasons inherent to the procedure itself, and also with the more frequent need for prolonged use of transvenous pacemaker with the CS, but the explanation for this finding is not clear.

Study limitations. This study has several limitations. First, data do not come from a single large study, but from different series from different centers. However, it is not currently possible to obtain data about a high number of post-TAVI deaths without pooling the results of several studies. Second, the causes of death were not codified by an independent clinical events committee, but by the local investigators of each study. Finally, comparisons between ES and CS were not randomized. However, there are no randomized studies comparing different aortic prostheses for transcatheter implantation, and our data are the first, to the best of our knowledge, that compare the cause of death post-TAVI between CS and ES.

Conclusion

In the pooled analysis of the studies included, with 1,223 patients undergoing TAVI, mortality rate at 1 month was 9.7%, which may be considered low taking into account the high predicted mortality accordingly to the EuroSCORE. A significant reduction in mortality occurred over the years, reflecting improvements in technique and also in patient selection. The causes of death during the procedure and within the first month post-TAVI are quite variable, including different causes of cardiac and non-cardiac deaths due to the severity of the cardiac disease (cardiac failure, sudden death), the procedure itself (e.g., cardiac tamponade, vascular and bleeding complications), and the underlying clinical profile of the patients (sepsis, stroke). Finally, some interesting differences between both device types were found.

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From the Departments of 1Interventional Cardiology, 2Vascular Surgery, 3Car- diovascular Anesthesia, and 4Cardiac Surgery, University Hospital La Paz, Madrid, Spain; and 5Hospital Infanta Sofia, San Sebastian de los Reyes, Madrid, Spain.
The authors report no conflicts of interest regarding the content herein.
Manuscript submitted February 1, 2011, provisional acceptance given Feb- ruary 28, 2011, final version accepted March 3, 2011.
Address for correspondence: Raul Moreno, MD, FESC, University Hospital La Paz, Interventional Cardiology (Diagonal, 1), Paseo La Castellana, 261. Di- agonal 1, Madrid, 28046, Spain. Email: raulmorenog@terra.es