Abstract: Background. Data are limited regarding the clinical impact of permanent pacemaker implantation (PPI) in patients with low left ventricular ejection fraction (LVEF) after transcatheter aortic valve replacement (TAVR). The aim of this study was to determine the impact of new PPI in patients with baseline low LVEF at 2-year follow-up after TAVR. Methods. A total of 659 patients undergoing TAVR between January 2013 and December 2015 were included in the study. Patients were divided into two groups according to the need for PPI after TAVR. These patients were further divided by their baseline LVEF: low LVEF (≤50%) and preserved LVEF (>50%). Results. A total of 104 patients (15.8%) needed PPI following TAVR. After a median follow-up of 19.1 months (interquartile range, 11.4-24.4 months), overall and cardiovascular survival showed no significant differences between new PPI and no PPI (overall, log-rank P=.94; cardiovascular, log-rank P=.51). Nonetheless, patients requiring PPI who had low LVEF had higher cardiovascular mortality compared to patients with low LVEF who didn’t need PPI (log-rank P<.001). Multivariable Cox hazard model demonstrated that patients with new PPI and low LVEF had higher 2-year cardiovascular mortality after TAVR (hazard ratio, 5.76; P<.001). Conclusion. New PPI following TAVR was not associated with overall survival or cardiovascular survival difference at 2 years. However, receiving a new PPI in the setting of low LVEF adversely impacts mid-term cardiovascular survival.
J INVASIVE CARDIOL 2019;31(2):E15-E22.
Key words: mortality, pacemaker, TAVI, TAVR
Transcatheter aortic valve replacement (TAVR) is a rapidly growing alternative to surgical aortic valve replacement for intermediate to high surgical risk patients with severe, symptomatic aortic valve stenosis (AS).1,2 Even with improvements in device technology, increasing operator experience, and various identified predictors of new permanent pacemaker implantation (PPI), the incidence of new PPI after TAVR remains a major concern compared with surgical aortic valve replacement.1-7 As the frontier of TAVR starts to include patients with lower surgical risk in the near future, the prognostic impact of new PPI after TAVR warrants special attention – especially in younger patients with new PPI. Previous studies demonstrated that patients who received PPI had largely the same benefits from TAVR as did those who did not require PPI.7-11 On the other hand, a recent large trial and registry have reported that new PPI was associated with higher long-term mortality.6,12 Differing from long-term all-cause mortality after new PPI, only a few studies have examined the impact of new PPI on cardiovascular mortality.3,6-9,11-13 New PPI was shown to have a negative effect on left ventricular ejection fraction (LVEF) after TAVR compared with no PPI.9,11,13 Therefore, we hypothesized that the impact of new PPI on long-term prognosis, especially cardiovascular mortality, may be influenced by LVEF. The aim of this study was to determine the impact of new PPI on mid-term survival in patients with low baseline LVEF after TAVR.
Between January 2013 and December 2015, a total of 826 patients with severe, symptomatic AS underwent TAVR with preprocedural contrast cardiac computed tomography (CT) at our institution. We excluded patients with pre-existing PPI (n = 167). A final cohort of 659 patients was included in the present analysis (Figure 1). All patients were divided into two groups according to the need for PPI following TAVR. These patients were further divided by their baseline LVEF into two subgroups: low LVEF (≤50%) and preserved LVEF (>50%)9 (Figure 1). Severe AS was defined by aortic valve area <1.0 cm2, mean aortic valve gradient of 40 mm Hg, or a peak aortic jet velocity of 4.0 m/s. All patients had New York Heart Association class II to IV symptoms. The decision to proceed with TAVR or not was adjudicated with the consensus of a dedicated heart team, including experienced clinical and interventional cardiologists and cardiovascular surgeons. Implanted valves included Edwards Sapien, Sapien XT, and Sapien 3 (Edwards Lifesciences), as well as CoreValve and EvolutR (Medtronic). Valve size and type were based on preprocedural CT or immediate preprocedural three-dimensional transesophageal echocardiography. Aortic root measurements were performed using 3mensio Valves software, version 8.1 (Pie Medical Imaging) by our CT core laboratory. An 850 Hounsfield unit (HU) threshold was used to detect areas of calcium in the region of valve leaflets.5,14 Procedural success and complications during the TAVR procedure were evaluated according to the Valve Academic Research Consortium 2 criteria.15 The decision to perform in-hospital new PPI and the selection of a single- or dual-chamber PPI was made by an experienced cardiac electrophysiology specialists team. Baseline clinical data, patient characteristics, echocardiographic data, and procedural variables were prospectively recorded. Information about patient death was obtained from electronic medical charts with the use of information on scanned records or telephone encounters.
Continuous variables were tested for normality of distribution using the Shapiro-Wilk test and reported appropriately thereafter. Categorical variables were compared using Chi-square analysis and Fisher’s exact test. Mann-Whitney U-test was used in cases of abnormal distribution. Continuous variables were reported as medians with interquartile ranges (IQRs). All-cause mortality at 2 years and cardiovascular death at 2 years were analyzed with Kaplan-Meier estimates and compared between groups with the log-rank test. For the Cox hazard model, univariate analysis of each possible predictor of 2-year all-cause mortality and cardiovascular death was tested, and only those variables with significance of P-value <.10 were included in a stepwise Cox multivariable model. All statistical tests were 2-sided, and P-values <.05 were considered significant. Statistical analyses were performed using SPSS statistics software 22.0 (SPSS).
From January 2013 to December 2015, a total of 104 patients (15.8%) required new PPI after TAVR in our institution. The indication for new PPI was high-grade atrioventricular block in 81 patients (77.9%). The remaining patients had sick sinus syndrome (n = 12) or severe symptomatic bradycardia with lesser degrees of conduction disturbances (n = 11). Of those patients needing PPI, a total of 13 were required to have permanent single-chamber pacing (12.5%). Baseline patient characteristics stratified by new PPI are summarized in Table 1. Compared with the no-PPI group, patients requiring new PPI had lower logistic EuroScore (12.6% [IQR, 8.5%-22.9%] vs 16.1% [IQR, 9.8%-17.5%]; P=.02) and were more likely to have baseline electrocardiographic finding of right bundle-branch block (36.5% vs 11.4%; P<.001). For baseline imaging characteristics, patients with new PPI had a trend toward smaller aortic valve area (0.60 mm2 [IQR, 0.50-0.70 mm2] vs 0.61 mm2 [IQR, 0.50-0.74 mm2]; P=.06). Patients who required new PPI had a trend for increased mean aortic valve gradient (45.0 mm Hg [IQR, 41.0-54.0 mm Hg] vs 44.0 mm Hg [IQR, 40.0-52.0 mm Hg]; P=.05) and increased peak aortic jet velocity (4.4 m/s [IQR, 4.2-4.7 m/s] vs 4.3 m/s [IQR, 4.0-4.6 m/s]; P=.02). Preprocedural CT measurements showed greater aortic valve calcium volume in patients requiring new PPI (Table 1). Other baseline clinical parameters were similar.
Details on procedural outcomes are shown in Table 2. The incidence of in-hospital PPI was higher with self-expanding devices compared with balloon-expandable devices (29.8% vs 9.6%; P<.001). Alternative access was more frequently performed in the no-PPI group (10.3% vs 1.9%; P<.01). Patients who required new PPI were significantly more likely to require postdilation (17.3% vs 10.3%; P=.04). There was a higher rate of mild or greater paravalvular leak for patients with new PPI (Table 2). At the 30-day follow-up, no differences were observed concerning the incidence of stroke, all-cause mortality, and cardiovascular death between both groups (Table 2).
In this study, a median follow-up was 19.1 months (IQR, 11.4-24.4 months). At the 2-year follow-up, overall survival was 84.4% for all patients, with no differences between the new-PPI and no-PPI groups (83.7% vs 84.5%, respectively; log-rank P=.94) (Figure 2A). For cardiovascular survival, patients with new PPI also had similar 2-year survival compared with those in the no-PPI group (92.3% vs 94.2%, respectively; log-rank P=.51) (Figure 2B). However, for various PPI/LVEF categories, cardiovascular survival revealed significant differences between patients with new PPI and low LVEF vs all other subgroups, including patients with low LVEF who did not require PPI (log-rank P<.001) (Figure 3; Supplemental Table S1). Cox regression analysis for cumulative 2-year all-cause mortality and cardiovascular death is shown in Table 3. Patients with new PPI and low LVEF had independently increased risk for 2-year cardiovascular mortality, but not 2-year all-cause mortality (cardiovascular mortality hazard ratio [HR], 5.76; 95% confidence interval [CI], 2.18-15.24; P<.001) (Table 3). Other significant predictors of 2-year cardiovascular mortality included peripheral artery disease (HR, 2.52; 95% CI, 1.29-4.91; P<.01), logistic EuroScore (HR, 1.02; 95% CI, 1.01-1.04; P=.02), and moderate or more paravalvular leak (HR, 4.89; 95% CI, 2.36-10.14; P<.001) (Table 3). Furthermore, on multivariate analysis of 2-year cardiovascular mortality in patients with PPI, low LVEF was a significant predictor of 2-year cardiovascular mortality, but not moderate or more paravalvular leak (HR, 0.93; 95% CI, 0.89-0.98; P<.01) (Supplemental Table S2).
Baseline clinical characteristics, procedural findings, and clinical outcomes for patients requiring new PPI who had low LVEF are shown in Supplemental Table S3. The median LVEF in patients with new PPI and low LVEF was 42.5% (IQR, 35.0%-48.5%). Compared with the three remaining subgroups, patients with new PPI and low LVEF had a higher prevalence of coronary artery disease (80.8% vs 59.1%; P=.03), old myocardial infarction (38.5% vs 13.4%; P<.01), and higher logistic EuroScore (24.1% [IQR, 12.8%-40.5%] vs 15.6% [IQR, 9.6%-26.7%]; P=.04). Self-expanding devices were more frequently implanted in patients requiring new PPI who had low LVEF (38.5% vs 14.2%; P<.01). For clinical outcomes at 30 days, both all-cause mortality and cardiovascular death were higher in patients with new PPI and low LVEF (all-cause mortality, 11.5% vs 2.2% [P=.03]; cardiovascular death, 11.5% vs 1.3% [P<.01]).
Conduction disturbances requiring new PPI remain a frequent complication after TAVR, even with newer-generation devices.1-4 Accordingly, many studies have identified risk factors for the need of new PPI following TAVR.5-8 Similarly, the long-term prognosis of new PPI has been well examined.6-13 A recent meta-analysis showed new PPI not being associated with any increased risk of adverse clinical outcomes.11 This was consistent with other previous reports.7-11,13 Similarly, our findings revealed that patients with or without new PPI had similar mid-term overall survival. Only a few studies have examined this effect on cardiovascular survival.6-13 In the present study, cardiovascular survival did not differ between the two groups, which was similar to the findings of prior studies.7-11 It is well known that long-term right ventricular pacing causes mechanical dyssynchrony, which is associated with increased heart failure hospitalization and mortality.16 In contrast, more than 50% of patients requiring new PPI after TAVR are not pacing dependent at 1-year follow-up,17 thus minimizing this adverse survival effect.
In the present study, we systematically examined the impact of the different new PPI/LVEF categories on mid-term outcomes. Only a few small studies have reported the association between new PPI and clinical impact after TAVR for patients with low LVEF.9,12 Moreover, these studies generally included small cohorts with long-term follow-up and cardiovascular mortality.9,12 In patients with low LVEF, the clinical impact of new PPI on cardiovascular mortality is controversial. Our findings demonstrate that patients with new PPI and low LVEF were at increased risk for 2-year cardiovascular mortality but not 2-year all-cause mortality. The results of the present study are dissimilar from previously published data. For long-term cardiovascular mortality, Urena et al reported no differences between patients with and without new PPI when analyzing the data by LVEF subgroups.9 A possible explanation for the discrepancies presented above may derive from patient characteristics. In our study, patients with new PPI and low LVEF had a higher prevalence of coronary artery disease, especially old myocardial infarction. Therefore, low LVEF might result from myocardial ischemia and fibrosis after myocardial infarction. In patients with severe AS presenting with low LVEF, TAVR was associated with increased recovery of LVEF,18 whereas low LVEF due to coronary artery disease was associated with decreased LVEF improvement following TAVR, and resulted in greater 30-day and 1-year mortality.19 In addition, as described above, the need for right ventricular pacing after TAVR caused increased left ventricular dyssynchrony at 30 days and decreased recovery of LVEF.20 Therefore, in patients with low LVEF, especially due to coronary artery disease, the acute effects of right ventricular pacing on LVEF might be more pronounced. There are few available data regarding the impact of new PPI in low LVEF patients on long-term prognosis. Ultimately, prospective multicenter validation studies with larger study cohorts should elucidate this subject further.
Study limitations. The study represents a retrospective analysis from a single-center experience. The decision to perform new PPI was not made based on prespecified clinical criteria. The number of patients with new PPI and low LVEF was relatively small. Moreover, due to the small number of patients who had echocardiographic examinations at 12-month follow-up exam, the association between LVEF changes over time and mid-term mortality was not assessed. Echocardiographic data were not assessed by an echocardiography core laboratory. No data were available on pacing dependency that was associated with adverse cardiovascular clinical events.21
Overall, new PPI was not associated with overall survival or cardiovascular survival difference 2 years following TAVR. Receiving a new PPI in the setting of low LVEF adversely impacts mid-term cardiovascular survival, but not overall survival for patients undergoing TAVR.
- Leon MB, Smith CR, Mack MJ, et al. Transcatheter or surgical aortic-valve replacement in intermediate-risk patients. N Engl J Med. 2016;374:1609-1620.
- Reardon MJ, Van Mieghem NM, Popma JJ, et al. Surgical or transcatheter aortic-valve replacement in intermediate-risk patients. N Engl J Med. 2017;376:1321-1331.
- Popma JJ, Reardon MJ, Khabbaz K, et al. Early clinical outcomes after transcatheter aortic valve replacement using a novel self-expanding bioprosthesis in patients with severe aortic stenosis who are suboptimal for surgery: results of the Evolut R U.S. study. JACC Cardiovasc Interv. 2017;10:268-275.
- Herrmann HC, Thourani VH, Kodali SK, et al. One-year clinical outcomes with SAPIEN 3 transcatheter aortic valve replacement in high-risk and inoperable patients with severe aortic stenosis. Circulation. 2016;134:130-140.
- Maeno Y, Abramowitz Y, Kawamori H, et al. A highly predictive risk model for pacemaker implantation after TAVR. JACC Cardiovasc Imaging. 2017;10:1139-1147.
- Fadahunsi OO, Olowoyeye A, Ukaigwe A, et al. Incidence, predictors, and outcomes of permanent pacemaker implantation following transcatheter aortic valve replacement: analysis from the U.S. Society of Thoracic Surgeons/American College of Cardiology TVT registry. JACC Cardiovasc Interv. 2016;9:2189-2199.
- Mouillet G, Lellouche N, Yamamoto M, et al. Outcomes following pacemaker implantation after transcatheter aortic valve implantation with CoreValve(®) devices: results from the FRANCE 2 registry. Catheter Cardiovasc Interv. 2015;86:E158-166.
- Nazif TM, Dizon JM, Hahn RT, et al. Predictors and clinical outcomes of permanent pacemaker implantation after transcatheter aortic valve replacement: the PARTNER (Placement of AoRtic TraNscathetER Valves) trial and registry. JACC Cardiovasc Interv. 2015;8:60-69.
- Urena M, Webb JG, Cheema A, et al. Impact of new-onset persistent left bundle branch block on late clinical outcomes in patients undergoing transcatheter aortic valve implantation with a balloon-expandable valve. JACC Cardiovasc Interv. 2014;7:128-136.
- Regueiro A, Abdul-Jawad Altisent O, Del Trigo M, et al. Impact of new-onset left bundle branch block and periprocedural permanent pacemaker implantation on clinical outcomes in patients undergoing transcatheter aortic valve replacement: a systematic review and meta-analysis. Circ Cardiovasc Interv. 2016;9:e003635.
- Mohananey D, Jobanputra Y, Kumar A, et al. Clinical and echocardiographic outcomes following permanent pacemaker implantation after transcatheter aortic valve replacement: meta-analysis and meta-regression. Circ Cardiovasc Interv. 2017;10(11).
- Dizon JM, Nazif TM, Hess PL, et al. Chronic pacing and adverse outcomes after transcatheter aortic valve implantation. Heart. 2015;101:1665-1671.
- Giustino G, Van der Boon RMA, Molina-Martin de Nicolas J, et al. Impact of permanent pacemaker on mortality after transcatheter aortic valve implantation: the PRAGMATIC (Pooled Rotterdam-Milan-Toulouse in Collaboration) pacemaker substudy. EuroIntervention. 2016;12:1185-1193.
- Jilaihawi H, Makkar RR, Kashif M, et al. A revised methodology for aortic-valvar complex calcium quantification for transcatheter aortic valve implantation. Eur Heart J Cardiovasc Imaging. 2014;15:1324-1332.
- Kappetein AP, Head SJ, Généreux P, et al. Updated standardized endpoint definitions for transcatheter aortic valve implantation: the Valve Academic Research Consortium-2 consensus document. J Am Coll Cardiol. 2012;60:1438-1454.
- Connolly SJ, Kerr CR, Gent M, et al. Effects of physiologic pacing versus ventricular pacing on the risk of stroke and death due to cardiovascular causes. Canadian Trial of Physiologic Pacing Investigators. N Engl J Med. 2000;342:1385-1391.
- Boon RMA van der, Van Mieghem NM, Theuns DA, et al. Pacemaker dependency after transcatheter aortic valve implantation with the self-expanding Medtronic CoreValve System. Int J Cardiol. 2013;168:1269-1273.
- Clavel MA, Webb JG, Rodés-Cabau J, et al. Comparison between transcatheter and surgical prosthetic valve implantation in patients with severe aortic stenosis and reduced left ventricular ejection fraction. Circulation. 2010;122:1928-1936.
- Freixa X, Chan J, Bonan R, et al. Impact of coronary artery disease on left ventricular ejection fraction recovery following transcatheter aortic valve implantation. Catheter Cardiovasc Interv. 2015;85:450-458.
- Hoffmann R, Herpertz R, Lotfipour S, et al. Impact of a new conduction defect after transcatheter aortic valve implantation on left ventricular function. JACC Cardiovasc Interv. 2012;5:1257-1263.
- Sweeney MO, Hellkamp AS, Ellenbogen KA, et al. Adverse effect of ventricular pacing on heart failure and atrial fibrillation among patients with normal baseline QRS duration in a clinical trial of pacemaker therapy for sinus node dysfunction. Circulation. 2003;107:2932-2937.
From the 1Cedars-Sinai Heart Institute, Los Angeles, California; and 2New York University, Langone Medical Center, New York.
Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Jilaihawi is a consultant for Edwards Lifesciences Corporation, St. Jude Medical, and Venus MedTech. Dr Sharma is a proctor for Edwards Lifesciences. Dr Makkar reports grant support from Edwards Lifesciences and St. Jude Medical; consultant income from Abbott Vascular, Cordis, and Medtronic; equity in Entourage Medical. The remaining authors report no conflict of interests regarding the content herein.
Manuscript submitted June 26, 2018, provisional acceptance given September 20, 2018, final version accepted October 15, 2018.
Address for correspondence: Yoshio Maeno, MD, PhD, Cedars-Sinai Heart Institute, 127 S. San Vicente Blvd #A3600, Los Angeles, CA 90048. Email: email@example.com