Clinical and Echocardiographic Outcomes Following ...

Structural Heart Disease Clinical and Echocardiographic Outcomes Following Permanent Pacemaker Implantation After Transcatheter Aortic Valve Replacement Meta-Analysis and Meta-Regression Divyanshu Mohananey, MD; Yash Jobanputra, MD; Arnav Kumar, MD; Amar Krishnaswamy, MD; Stephanie Mick, MD; Jonathon M. White, MD; Samir R. Kapadia, MD

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Background—Transcatheter aortic valve replacement has become the procedure of choice for inoperable, high-risk, and many intermediate-risk patients with aortic stenosis. Conduction abnormalities are a common finding after transcatheter aortic valve replacement and often result in permanent pacemaker (PPM) implantation. Data pertaining to the clinical impact of PPM implantation are controversial. We used meta-analysis techniques to summarize the effect of PPM implantation on clinical and echocardiographic outcomes after transcatheter aortic valve replacement. Methods and Results—Data were summarized as Mantel–Haenszel relative risk (RR) and 95% confidence intervals (CIs) for dichotomous variables and as standardized mean difference and 95% CI for continuous variables We used the Higgins I2 statistic to evaluate heterogeneity. We found that patients with and without PPM have similar all-cause mortality (RR, 0.85; 95% CI, 0.70–1.03), cardiovascular mortality (RR, 0.84; 95% CI, 0.59–1.18), myocardial infarction (RR, 0.47; 95% CI, 0.20– 1.11), and stroke (RR, 1.26; 95% CI, 0.70–2.26) at 30 days. The groups were also comparable in all-cause mortality (RR, 1.03; 95% CI, 0.92–1.16), cardiovascular mortality (RR, 0.69; 95% CI, 0.39–1.24), myocardial infarction (RR, 0.58; 95% CI, 0.30–1.13), and stroke (RR, 0.70; 95% CI, 0.47–1.04) at 1 year. We observed that the improvement in left ventricular ejection fraction was significantly greater in the patients without PPM (standardized mean difference, 0.22; 95% CI, 0.12–0.32). Conclusions—PPM implantation is not associated with increased risk of all-cause mortality, cardiovascular mortality, stroke, or myocardial infarction both at short- and long-term follow-up. However, PPM is associated with impaired left ventricular ejection fraction recovery post-transcatheter aortic valve replacement. (Circ Cardiovasc Interv. 2017;10:e005046. DOI: 10.1161/CIRCINTERVENTIONS.117.005046.) Key Words: aortic valve ◼ meta-analysis ◼ myocardial infarction ◼ permanent pacemaker ◼ transcatheter aortic valve replacement

T

ranscatheter aortic valve replacement (TAVR) has become the treatment of choice for inoperable patients with symptomatic, severe aortic stenosis and is a viable alternative to surgical aortic valve replacement for high and intermediate surgical risk patients.1–3 However, TAVR is frequently complicated by conduction abnormalities, and between 10% and 40% of the patients undergoing TAVR with contemporary valves require permanent pacemaker (PPM) implantation.4,5 The rate of PPM implantation is significantly higher in patients undergoing TAVR when compared with those undergoing surgical aortic valve replacement.6 A high prevalence of comorbidities and advanced age in the TAVR population and the anatomic proximity of the infranodal conduction system to the aortic valvular complex contribute to this increased risk.7,8 Right ventricular pacing has been linked to an increased composite

outcome of mortality and rehospitalization in patients with left ventricular (LV) dysfunction and to tachyarrhythmias and pacing-induced cardiomyopathies.9–11

See Editorial by Franzone and Windecker Although the factors contributing to post-TAVR PPM implantation have been studied in great detail, its impact on short- and long-term clinical outcomes remains controversial. A recent large cohort study showed significantly increased mortality in patients with PPM implantation, although other analyses have not revealed any substantial survival differences.12–14 Recent literature also suggests that PPM implantation may impair post-TAVR improvement in LV ejection fraction (LVEF) at 6- to 12-month follow-up.15–17 Previous meta-analyses on this topic have been limited by small number

Received January 25, 2017; accepted May 15, 2017. From the Department of Hospital Medicine (D.M., A.K.), Department of Cardiovascular Medicine (Y.J., A.K., J.M.W., S.R.K.), and Department of Cadiothoracic Surgery (S.M.), Cleveland Clinic, OH. The Data Supplement is available at http://circinterventions.ahajournals.org/lookup/suppl/doi:10.1161/CIRCINTERVENTIONS.117.005046/-/DC1. Correspondence to Divyanshu Mohananey, MD, Department of Hospital Medicine, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195. E-mail [email protected] © 2017 American Heart Association, Inc. Circ Cardiovasc Interv is available at http://circinterventions.ahajournals.org

1

DOI: 10.1161/CIRCINTERVENTIONS.117.005046

2 Mohananey et al Impact of Post-TAVR Pacemaker

WHAT IS KNOWN?

• Pacemaker implantation is a common adverse effect

of transcatheter aortic valve replacement, and the rates of implantation have not decreased despite recent advancements in this field. • Data are controversial on effect of pacemaker implantation on clinical events after transcatheter aortic valve replacement.

WHAT THE STUDY ADDS?

• Pacemaker implantation is not associated with increased


risk of all-cause death, cardiovascular death, stroke, or myocardial infarction at short- or long-term follow-up. • The comparable risk for adverse events in patients with pacemakers is not dependent on baseline patient and echocardiographic characteristics. • Recovery of left ventricular ejection fraction is impaired in patients with post-transcatheter aortic valve replacement pacemaker implantation.

of studies, analysis of only mortality outcomes, and inclusion of data at a maximum of 1-year follow-up.18,19 We therefore used meta-analysis techniques in an effort to summarize the impact of postprocedural PPM implantation on a broad assessment of short- and long-term clinical and echocardiographic outcomes such as all-cause mortality, cardiovascular mortality, risk of stroke, risk of myocardial infarction (MI),

and improvement in LVEF after TAVR. Using meta-regression techniques, we further evaluated the impact of baseline characteristics such as sex, valve type, atrial fibrillation, renal disease, age, European System for Cardiac Operative Risk Evaluation Score (EUROSCORE), and LVEF on mortality outcomes. To the best of our knowledge, this is the largest and most comprehensive meta-analysis on this topic.

Methods Search Strategy A computerized literature search of all publications in the PubMed and EMBASE databases was made. We then manually searched the reference lists of included articles. This was last assessed as up-todate on December 1, 2016 (Figure 1).

Inclusion Criteria The Preferred Reporting Items for Systematic reviews and MetaAnalyses statement of reporting systematic reviews and meta-analysis was applied to the methods for this study.20 The following inclusion criteria were used: 1. Studies on TAVR comparing patients with postprocedural PPM with those without PPM. 2. Studies which evaluated at least 1 of the primary and secondary outcomes of interest. 3. Studies on all TAVR valve types and TAVR approaches. The following exclusion criteria were used: 1. Studies on PPM implantation post-TAVR. 2. Studies which failed to exclude (or create a separate category for) patients with PPM present before TAVR. 3. Studies where data pertaining to none of the outcomes of interest could not be extracted. 4. Studies without a minimum follow-up of 30 days and studies where LVEF was evaluated only in the immediate postprocedure period. 5. Conference abstracts and studies in languages other than English

Figure 1. Flow chart describing search strategy for the meta-analysis.

2011

2012

2012

2012

2011

PPM implantation after transapical transcatheter aortic valve implantation

Safety of a conservative strategy of PPM implantation after transcatheter aortic CoreValve implantation

LBBB induced by transcatheter aortic valve implantation increases risk of death

Impact of PPM implantation on clinical outcome among patients undergoing transcatheter aortic valve implantation

Incidence, predictors, and outcome of conduction disorders after transcatheter self-expandable aortic valve implantation

Cause of death after transcatheter aortic valve implantation

D’Ancona et al23

De Carlo et al24

Houthuizen et al25

Buellesfeld et al26

Fraccaro et al27

Van Mieghem et al28

2012

2010

Factors associated with cardiac conduction disorders and PPM implantation after percutaneous aortic valve implantation with CoreValve prosthesis

Study Name

Baan et al22

Authors

2005–2011

2007–2009

2007–2010

2005–2010

2007–2010

2008–2011

Year of Publication Year of Study

237

64

305

816

293

322

34

No. of Patients

Transfemoral, subclavian, transapical

Transfemoral, Transapical

Transfemoral

Transfemoral, subclavian, transapical

Transfemoral, subclavian

Transapical

Approach for TAVR

50

25

98

118

66

20

7

No. of PPM

ESV (5.1%), MCV (94.9%)

MCV (100%)

ESV (9.6%), MCV (90.4%)

ESV (43%), MCV (57%)

MCV (100%)

ESV (100%)

MCV (100%)

Type of Valve Used (Percentage of Total TAVR Cases)

Permanent or transient CHB, second-degree block with LBBB, SSS, trifascicular block

High-grade AV block, new-onset LBBB, PR prolongation >300 ms, AF with inadequate ventricular escape rhythm

Unresolved AV block after 3 d, LBBB or new LBBB and firstdegree AV block with severe bradycardia

CHB, symptomatic bradycardia (with LV replacement rhythm) or symptomatic bradycardia on fifth postoperative day, and usually on third postoperative day in patients without ventricular rhythm

CHB or symptomatic bradycardia persisting after at least the second postprocedural day

Indications for PPM


Table. Description of Included Studies

6.2%

≤30 d

Postprocedural

8.9%

39%

32.1%

≤30 d

During hospitalization for TAVR

14.4%

Postprocedural

24%

20.5%

≤30 d

0–2 d

PPM Implantation Rate

Timing of PPM

(Continued )

24 mo

6 mo (mean)

12 mo

15.2 mo; y (median)

12 mo

36 mo

1 mo

Maximum Follow-Up


2014

2014

2015

2015

Predictors of PPM requirement after transcatheter aortic valve implantation: insights from a Brazilian Registry

PPM implantation after transcatheter aortic valve implantation: impact on late clinical outcomes and LV function

Hemodynamic impact and outcome of PPM implantation after transcatheter aortic valve implantation

Clinical impact of a new LBBB after TAVR implantation: 1-y results of the TAVIK cohort

Impact on LV function and remodeling and on 1-y outcome in patients with LBBB after transcatheter aortic valve implantation

Gensas et al31

Urena et al16

Biner et al14

Schymik et al32

Carrabba et al21

2015

2014

Transcatheter aortic valve implantation and requirements of pacing over time

Pereira et al30

Incidence and predictors of pacemaker implantation in patients undergoing TAVR

2013

Incidence and predictors of PPM implantation after transcatheter aortic valve implantation: analysis from the German Transcatheter Aortic Valve Interventions Registry

Ledwoch et al29

Maan et al33

2013

Study Name

Authors

2008–2012

2008–2012

2005–2013

2008–2012

2007–2011

2009–2010


137

101

634

230

1556

353

65

1346

No. of Patients

Transapical and transfemoral

Transfemoral, transapical

Transfemoral

Transapical, transfemoral, subclavian

Transfemoral, subclavian, direct aortic

Approach for TAVR

31

31

69

58

239

89

19

396

No. of PPM

ESV (100%)

MCV (100%)

ESV (80.6), MCV (19.2%)

ESV (12.6%), MCV (87.3%)

ESV (55.1%), MCV (44.8%)

ESV (14.1%), MCV (85.8%)

MCV (100%)

MCV (79.5%), ESV (20.4%)


CHB, advance AV block, non-AV block bradycardia

CHB, Advanced second-degree AV block, sinus node dysfunction with symptomatic bradycardia

Used guidelines by Cardiac Society

CHB, LBBB with prolonged PR >280 ms, alternating BBB, RBBB

CHB, advanced AV block not expected to resolve, LBBB with PR >200 ms not expected to resolve, sinus node dysfunction with symptomatic bradycardia

CHB, Mobitz II second-degree AV block, AF with CHB, and trifascicular block

Observational

Indications for PPM


Table. Continued

15.3%

≤30 d

28.2%

31.6%

≤30 d

5 d (median)

10.8%

12–24 h

25.2%

25.2%

≤30 d

Postprocedural

32.8%

33.7%




Timing of PPM

(Continued )

1 mo

12 mo (median)

12 mo

19.5 mo (median)

22 mo (mean)

60 mo

12 mo

1 mo

Maximum Follow-Up


2015

2015

2015

2015

2016

Outcomes following pacemaker implantation after transcatheter aortic valve implantation with CoreValve® devices: results from the FRANCE 2 Registry

Chronic pacing and adverse outcomes after transcatheter aortic valve implantation

Ventricular conduction defects after transcatheter aortic valve implantation: a single-institute analysis

Impact of LV conduction defect with or without need for permanent right ventricular pacing on functional and clinical recovery after TAVR

Effect of PPM on mortality after TAVR

Incidence and predictors of PPM implantation after treatment with the repositionable Lotus transcatheter aortic valve

Incidence, predictors, and outcomes of PPM implantation after TAVR

Mouillet et al35

Dizon et al13

Kawaguchi et al37

Weber et al17

Engborg et al36

Zaman et al38

Fadahunsi et al12

2011–2014

2012–2015

2008–2012

2010–2012

2010–2011

2010–2012

9785

128

212

160

2531

833

50

No. of Patients

Femoral, axillary/ subclavian, transapical, transaortic

95

Transfemoral, subclavian

Transfemoral

Transfemoral, transclavicular, transapical, or direct aortic

Transfemoral and transapical

Approach for TAVR

651

27

41

65

28

173

252

No. of PPM

ESV (88.2%), MCV (11.2%)

Lotus Valve (100%)

ESV (21.8%), MCV (78.1%)

MCV (100%)

ESV (33.7%), MCV (66.3%)

ESV (100%)

MCV (CoreValve and CoreValve Accutrack) (100%)

MCV (100%)

CHB, episodic high-grade seconddegree heart block, trifascicular block, AF with slow ventricular response or pauses, and ventricular standstill

CHB, advanced second-degree AV block, SSS, first-degree AV block, and LBBB

CHB, bradyarrhythmia, SSS, implantation of CTR-D

High-grade AV block, SSS

High grade AV block

CHB, type II seconddegree AV block, new LBBB in combination with infra-Hisian conduction delay

Indications for PPM

30.2%

8.8%

≤1 y

≤30 d

30.6%

32%

28.4%

6.7%

78% within 2 wk, 22% >2 wk ≤30 d

≤30 d

≤30 d

17.5%

22%

≤30 d

Post-operative


Timing of PPM

12 mo

1 mo

46.2 mo (median)

9 mo

24.3 mo

12 mo

12 mo

24 mo

Maximum Follow-Up

AF indicates atrial fibrillation; AV, atrioventricular; BBB, bundle branch block; CHB, complete heart block; CRT-d, cardiac resynchronization therapy with defibrillator; ESV, Edwards SAPIEN Valve; LBBB, left bundle branch block; LV, left ventricular; MCV, Medtronic CoreValve; PPM, permanent pacemaker; RBBB, right bundle branch block; SSS, sick sinus syndrome; TAVR, transcatheter aortic valve replacement.

2016

2016

2015

Permanent pacing after transcatheter aortic valve implantation of a CoreValve prosthesis as determined by electrocardiographic and electrophysiological predictors: a single-center experience

Study Name

Kostopoulou et al34

Authors




Table. Continued




Figure 2. Forest plots comparing (A) risk of 1-y all-cause mortality and (B) 1-y cardiovascular mortality between patients with and without post-transcatheter aortic valve replacement (TAVR) permanent pacemaker (PPM) implantation. The diamond indicates the overall summary estimate for the analysis. The center of the diamond represents the point estimate, and the width represents 95% confidence interval (CI). Studies included in these analyses are Fadahunsi et al,12 Dizon et al,13 Biner et al,14 D’Ancona et al,23 De Carlo et al,24 Houthuizen et al,25 Buellesfeld et al,26 Van Mieghem et al,28 Pereira et al,30 Schymik et al,32 Maan et al,33 Kostopoulou et al,34 Mouillet et al,35 Engborg et al,36 and Kawaguchi et al.37 CI indicates confidence interval; MH, Mantel-Haenszel; and PPM, permanent pacemaker.

6. Studies with previous PPM use were only included if data for post-TAVR PPM implantation could be abstracted. We did not include patients with previous PPM in our analysis.

Study End-Points The primary outcome of interest for our study was all-cause mortality at 1 year. Secondary outcomes included (1) all-cause mortality at 30 days, (2) cardiovascular mortality at 30 days, (3) stroke risk at 30 days, (4) MI at 30 days, (5) cardiovascular mortality at 1 year, (6) stroke at 1 year, (7) MI at 1 year, (8) improvement in LVEF, and (9) all-cause mortality at longest follow-up (>1 year).

cohort (S1); selection of the nonexposed cohort (S2); ascertainment of exposure (S3); demonstration that the outcome of interest was not present at the start of the study (S4); comparability (C1 and C2); assessment of outcome (E1); follow-up long enough for outcomes to occur (E2); and adequacy of follow-up of cohorts (E3; Table I in the Data Supplement). Discrepancies were resolved by discussion or adjudication by a third author (A.K.). For the purposes of this study, a point was given for S2 if controls came from the same hospitalized cohort. Points were given for C1 and C2 if adjusted risk was provided for any of the outcomes of interest, and points were given for E3 if follow-up (or rate of loss to follow-up) was similar between patients with and without pacemaker. Sensitivity analysis was done with inclusion of only high-quality studies (≥6/9) for the primary outcome.

Data Abstraction and Individual Study Quality Appraisal

Study Analysis

Two authors (D.M., S.R.K.) abstracted data from all included studies on to a standardized worksheet. The following data were collected: name of author, study title, year of publication, TAVR access site, study period, number of patients included, number of PPM implanted, type of study, timing of PPM implantation, indications for PPM, total duration of follow-up, percentage of valve type, percentage of certain baseline variables (male sex, atrial fibrillation, and renal failure), mean age, and mean EUROSCORE. Also, data required for comparative analysis of all outcomes were abstracted. For 2 studies,16,21 changes in LVEF were not mentioned in the text and were obtained from figures using the graphical analytic software-Plot Digitizer v 2.1. Two authors (D.M., S.R.K.) independently assessed the risk of bias of included studies using the standardized Newcastle–Ottawa scale. This validated instrument for appraising observational studies measures risk of bias in 8 categories: representativeness of the exposed

Categorical dichotomous data were summarized across treatment arms using the Mantel–Haenszel risk ratio (RR) along with 95% confidence intervals (CIs). Continuous data were summarized across treatment arms as standardized mean difference with 95% CI. We evaluated heterogeneity of effects using the Higgins I2 statistic. Fixed-effects model was used except in cases where heterogeneity was significant (defined as I2>40%). In these cases, random-effects models were used. For studies where patients without PPM were subdivided into groups (such as with and without conduction abnormalities), we combined the means and SD of these groups based on formulae specified by the Cochrane Collaboration. In addition, for calculation of improvement in LVEF, there were 3 studies16,17,21 where SDs for change (improvement) in LVEF were not available. Here, we imputed the SD based on other studies in the meta-analysis with similar follow-up duration based on guidelines



Figure 3. Forest plots comparing risk of (A) all-cause mortality at longest follow-up (>1 y) and (B) improvement in left ventricular ejection fraction (LVEF) between patients with and without post-transcatheter aortic valve replacement (TAVR) permanent pacemaker (PPM) implantation between patients with and without post-TAVR PPM implantation. The diamond indicates the overall summary estimate for the analysis. The center of the diamond represents the point estimate and the width represents 95% confidence interval (CI). Studies included in these analyses are Dizon et al,13 Biner et al,14 Urena et al,16 Weber et al,17 Carrabba et al,21 Houthuizen et al,25 Van Mieghem et al,28 Gensas et al,31 Kostopoulou et al,34 Engborg et al,36 and Kawaguchi et al.37 CI indicates confidence interval; MH, Mantel-Haenszel; and PPM, permanent pacemaker.

for systematic reviews provided by the Cochrane Collaboration. We also performed meta-regression analyses for 30-day and 1-year mortality to determine whether effects of PPM were modulated by prespecified study-level factors such as age, male sex, atrial fibrillation, EUROSCORE, previous renal impairment, LVEF, and type of valve (Figures I and II in the Data Supplement). This analysis was not possible for other outcomes because of smaller number of included studies for these analyses. We also performed sensitivity analysis to evaluate how removal of each study impacts overall outcome. To address publication bias, we used 2 methods: (1) visual inspection of funnel plots and (2) Egger test. Publication bias could not be assessed in outcomes where 1 Year), and Cardiovascular Mortality at 1 Year There was no evidence of difference in 1-year all-cause mortality between patients with and without PPM implantation (RR, 1.03; 95% CI, 0.92–1.16; Figure 2). Meta-regression showed that age, male sex, atrial fibrillation, EUROSCORE, previous renal impairment, LVEF, proportion of

Medtronic CoreValve (Medtronic, Minneapolis, MN) were not significantly associated with the 1-year all-cause mortality (Figure II in the Data Supplement). Sensitivity analysis after removal of low-quality studies did not change the overall result (RR, 1.03; 95% CI, 0.92–1.16; Figure IV in the Data Supplement). Cardiovascular mortality at 1 year was similar between the 2 groups (RR, 0.69; 95% CI, 0.39–1.24) (Figure 2). There was no evidence of difference in the mortality at longest follow-up (RR, 1.05; 95% CI, 0.91–1.22) (Figure 3).

All-Cause Mortality, Cardiovascular Mortality, MI, and Stroke at 30 Days There was no evidence of difference in all-cause mortality (RR, 0.85; 95% CI, 0.70–1.03), cardiovascular mortality (RR, 0.84; 95% CI, 0.59–1.18), stroke (RR, 1.26; 95% CI, 0.70–2.26), or MI (RR, 0.47; 95% CI, 0.20–1.11) at 30 days between patients with and without PPM implantation (Figures 4 and 5). Meta-regression techniques showed that age, male sex, atrial fibrillation, EUROSCORE, previous renal impairment, LVEF, and proportion of Medtronic CoreValve were not significantly associated with 30-day all-cause mortality (Figure I in the Data Supplement). However, we observed that after removal of the study by Fadahunsi et al,12 patients with PPM had a significantly decreased 30-day mortality (RR, 0.75; 95% CI, 0.59–0.96; Figure V in the Data Supplement).



Figure 4. Forest plots comparing risk of (A) 30-d all-cause mortality and (B) 30-d cardiovascular mortality between patients with and without post-transcatheter aortic valve replacement (TAVR) permanent pacemaker (PPM) implantation. The diamond indicates the overall summary estimate for the analysis. The center of the diamond represents the point estimate, and the width represents 95% confidence interval (CI). Studies included in these analyses are Fadahunsi et al,12 Dizon et al,13 Biner et al,14 Urena et al,16 Baan et al,22 D’Ancona et al,23 De Carlo et al,24 Houthuizen et al,25 Buellesfeld et al,26 Fraccaro et al,27 Ledwoch et al,29 Maan et al,33 Kostopoulou et al,34 Mouillet et al,35 Engborg et al,36 and Zaman et al.38 CI indicates confidence interval; MH, Mantel-Haenszel; and PPM, permanent pacemaker.

MI and Stroke at 1 Year There was no evidence of difference between the 2 groups for MI (RR, 0.58; 95% CI, 0.30–1.13) and stroke at 1 year (RR, 0.70; 95% CI 0.47–1.04; Figure 6).

Improvement in LVEF We observed that the improvement in LVEF was significantly greater in the patients who did not have PPM implantation (standardized mean difference, 0.22; 95% CI, 0.12–0.32; Figure 3).

Publication Bias There was no evidence of publication bias in all-cause mortality at 30 days (Egger test P=0.262), cardiovascular mortality at 30 days (Egger test P=0.243), stroke risk at 30 days (Egger test P=0.773), MI at 30 days (Egger test P=0.784), stroke at 1 year (Egger test P=0.243), and improvement in LVEF (Egger test P=0.660). Although visual inspection of the funnel plot for all-cause mortality at 30 days did not reveal publication bias, Egger test indicated possibility of publication bias (P=0.050). Both funnel plot analysis and Egger test suggested publication bias for all-cause mortality at longest follow-up (Egger test P=0.026). Funnel plots for individual analyses are provided in Figure III in the Data Supplement.

Discussion In our analysis of 23 studies, including >20 000 patients undergoing TAVR, we observed that PPM implantation does not increase the risk of all-cause mortality, cardiovascular mortality, MI, or stroke at 30-day or 1-year follow-up. We also observed that mortality at follow-up >1 year remains unaffected by PPM implantation. However, we did observe that patients who receive PPM experienced a significantly lower improvement in LVEF. Conduction disturbances are a frequent post-TAVR complication, and PPM is required in around 10% to 40% of patients undergoing TAVR.4,5 The risk for PPM implantation is 5× higher when placing the Medtronic CoreValve when compared with the Edwards SAPIEN Valve (Edwards Lifesciences, Irvine, CA).4,39 Although use of the newer Accutrak delivery system for Medtronic CoreValve is associated with a decreased need for PPM implantation, close to 10% of patients still require postprocedural PPM.40 Furthermore, the rates of PPM implantation are significantly higher in TAVR when compared with surgical aortic valve replacement and continue to remain high for newer valve types, such as the SAPIEN 3 and the repositionable LOTUS valve system (Boston Scientific, Natick, MA).6,41 Therefore, as the horizon of TAVR expands to include lower-risk patients, it is important to evaluate the clinical impact of this complication both in the short term and at longer durations of follow-up.



Figure 5. Forest plots comparing (A) 30-d risk of myocardial infarction (MI) and (B) 30-d risk of stroke between patients with and without post-transcatheter aortic valve replacement (TAVR) permanent pacemaker (PPM) implantation. The diamond indicates the overall summary estimate for the analysis. The center of the diamond represents the point estimate, and the width represents 95% confidence interval (CI). Studies included in these analyses are Fadahunsi et al,12 Urena et al,16 Buellesfeld et al,26 Ledwoch et al,29 and Maan et al.33 CI indicates confidence interval; MH, Mantel-Haenszel; and PPM, permanent pacemaker.

In this large meta-analysis, we show that all-cause mortality does not differ between patients with and without PPM. Although our findings are concordant with previous meta-analyses, they are in stark contrast with a recent analysis of over 9000 patients from the Society of Thoracic Surgeons American College of Cardiology Transcatheter Valve Therapy registry. This study suggested that patients with PPM are at significantly increased risk of all-cause mortality on 1-year follow-up (hazard ratio, 1.31; 95% CI, 1.09–1.58). There are several important points to consider relative to this study. First, the 6.7% incidence of PPM implantation in this study was significantly lower than rates reported by previous studies.4,42 In addition, this study showed comparable mortality between the 2 groups at 30 days, indicating that the difference in effect occurs toward the later part of follow-up (30 days to 1 year). However, a review of the cumulative incidence curves for 1-year mortality in this work reveals a significant and unequal loss to follow-up of 76% for the PPM group and 36% for the no-PPM group. Of note, when the results of this study were imputed as RR (thereby removing the effect of time) for the purposes of this meta-analysis, the comparative risk became nonsignificant.12 Our study also demonstrates that the effect of PPM implantation on mortality is unaffected by type of valve, sex, renal failure, presence of atrial fibrillation, baseline LVEF, and age. Of note, we did observe that on sensitivity analysis (after removal of the study by Fadahunsi et al,12 patients in the PPM group had a significantly decreased 30-day mortality. Urena et al16 noted a similar reduction in 30-day sudden deaths and postulated that the presence of a new-onset left bundle branch block leading to complete atrioventricular block may explain the increased risk of sudden death in the non-PPM group.12,16 It is also possible that unrecognized episodic high-grade conduction disease before

TAVR resulted in higher mortality in the non-PPM group.43 We also found that although difference in risk of stroke at 1 year did not reach statistical significance, there was a trend toward reduced risk in patients with PPM (RR, 0.70; 95% CI, 0.47– 1.04). One possible explanation for this may be unmatched baseline characteristics. Both Dizon et al13 and Buellesfeld et al26 reported a higher prevalence of atrial fibrillation in patients who did not receive PPM after TAVR. Dizon et al13 also reported a higher prevalence of previous stroke/transient ischemic attack at baseline. It is also possible that atrial pacing in patients with sinus node dysfunction may lead to reduced prevalence of atrial fibrillation and stroke at 1 year. Dizon et al13 demonstrated a differential prevalence of atrial fibrillation at 1 year between patients with previous PPM, new PPM, and those without PPM (12.3%, 17.1%, and 20.7%, respectively).13,26,44 We also showed that patients with PPM have a decreased improvement in LVEF. Right ventricular pacing has previously been shown to cause reduction in cardiac output, stroke volume, impaired diastolic relaxation, and increased LV enddiastolic pressure in patients with and without LV dysfunction.10,45 Acute right ventricular pacing has also been linked to significant reduction in LVEF.45 However, for patients undergoing TAVR, this deleterious effect on LVEF has not shown to correlate with diagnosis of clinical heart failure, readmissions, or worsening mortality outcomes. Both Fadahunsi et al12 and Urena et al16 reported similar rates of heart failure readmission in both groups at 12 and 22 months, respectively. There are several possible explanations for this. First, in patients with normal LVEF (who constitute two third of the TAVR population), a long duration of pacing (usually >3 years) is usually required to develop adverse clinical outcomes.46–49 Among studies included in our analysis, only 3 had follow-up



Figure 6. Forest plots comparing (A) 1-y risk of myocardial infarction (MI) and (B) 1-y risk of stroke between patients with and without post-transcatheter aortic valve replacement (TAVR) permanent pacemaker (PPM) implantation. The diamond indicates the overall summary estimate for the analysis. The center of the diamond represents the point estimate, and the width represents 95% confidence interval (CI). Studies included in these analyses are Fadahunsi et al,12 Dizon et al,13 and Buellesfeld et al.26 CI indicates confidence interval; MH, Mantel-Haenszel; and PPM, permanent pacemaker.

longer than 3 years.23,31,36 In addition, higher cumulative ventricular pacing percentage has been shown to be a strong predictor of negative outcomes.47 However, Van der Boon et al50 showed that over 50% of patients with PPM after TAVR are not pacemaker dependent on 1-year follow-up.46,50 Among the studies included in our analysis, Fraccaro et al27 reported that at 6 months, 12 of 17 patients with PPM had a spontaneous rhythm, and mean ventricular pacing percentage was only 19%. Pereira et al30 reported a slightly higher ventricular pacing percentage of 49.5% at 12 months with 26.7% PPM dependency. We therefore suggest that a biventricular pacemaker be considered in patients with low pre-TAVR LVEF who require postprocedural PPM implantation. Although our large meta-analysis corroborates the safety of pacemaker use in TAVR, there are a few limitations to our analysis. First, this is a meta-analysis performed on study-level data encompassing varying degrees of selection bias that is difficult to ascertain. Second, there was an insufficient number of studies that reported ventricular pacing percentage to include this measure in our meta-regression model. This would be a useful analysis and should be considered in future prospective research. Third, the studies differed in methodology, definition of outcomes, and baseline characteristics. In addition, only 3 of the included studies included follow-up data >3 years which may be required to experience the adverse effects of PPM in patients with normal LVEF. Therefore, it is possible that a difference between the groups may have been evident, if outcomes had been measured at a longer duration of follow-up. Furthermore, we do not have granular data to study other morbidities of PPM implantation, such as infection, pneumothorax, pocket hematoma, etc, which may result in significant clinical consequences outside of mortality. Also, our analysis of cardiovascular mortality and MI at 1 year was limited by small number of studies,

and hence results from these analyses should be extrapolated with caution. Last, none of the studies included in our analysis of LVEF recovery had significant LV dysfunction at baseline, and, therefore, our findings may not extend to this subgroup of patients. To address some of these limitations, we performed sensitivity analysis based on quality of studies and by using the one-study removal method. In addition, despite small differences in study methodology, it is reassuring that heterogeneity was low to nil for the majority of our outcomes.

Conclusions In this large meta-analysis, we show that PPM implantation after TAVR is not associated with increased risk of all-cause mortality, cardiovascular mortality, stroke, or MI at short- or long-term follow-up. However, PPM implantation does result in impaired recovery of LVEF after TAVR.

Disclosures None.

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Clinical and Echocardiographic Outcomes Following Permanent Pacemaker Implantation After Transcatheter Aortic Valve Replacement: Meta-Analysis and Meta-Regression Divyanshu Mohananey, Yash Jobanputra, Arnav Kumar, Amar Krishnaswamy, Stephanie Mick, Jonathon M. White and Samir R. Kapadia Downloaded from http://circinterventions.ahajournals.org/ by guest on July 11, 2017

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SUPPLEMENTARY APPENDIX Supplementary table 1: Assessment of study quality using the New-castle Ottawa Scale Selection Author(s)

S1*

S2*

S3*

S4*

Comparibility

Exposure

C1*

E1*

C2*

E2*

E3*

Total stars

Baan et al1

*

*

*

*

D’Ancona et al2

*

*

*

*

Houthuizen et al3

*

*

*

De Carlo et al4

*

*

Buellesfeld et al5

*

Carraba et al 6

*

*

*

7

*

*

*

9

*

*

*

6

*

*

*

*

6

*

*

*

*

*

*

9

*

*

*

*

*

*

*

7

Fraccaro et al7

*

*

*

*

*

*

5

Van Mieghem et al8

*

*

*

*

*

5

Ledwoch et al9

*

*

*

*

*

*

Pereira et al10

*

*

*

*

*

*

6

Gensas et al11

*

*

*

*

*

*

6

Urena et al12

*

*

*

*

*

*

Biner et al13

*

*

*

*

*

*

6

Schymik et al14

*

*

*

*

*

*

8

Maan et al 15

*

*

*

*

*

*

6

Kostopoulou et al

*

*

*

*

*

*

*

7

*

*

*

*

*

*

*

8

*

*

*

*

*

*

*

*

*

*

7

9

16

Mouillet et al17

*

Dizon et al18

*

*

*

*

Kawaguchi et al19

*

*

*

Weber20

*

*

Engborg et al21

*

Zaman et al 22 Fadahunsi et al23

*

*

*

*

*

*

*

*

*

*

*

*

*

*

*

*

*

*

*

*

*

*

7

*

*

*

*

*

*

*

9

*

*

*

*

*

*

9 6

*

7 8

Representativeness of the exposed cohort (S1); selection of the non-exposed cohort (S2); ascertainment of exposure (S3); demonstration that the outcome of interest was not present at the start of the study (S4); comparability (C1 and C2); assessment of outcome (E1); was follow-up long enough for outcomes to occur (E2); adequacy of follow-up of cohorts (E3)

Supplementary Figure 1: Meta-regression for variables- male gender, LVEF, age, EUROSCORE, MCV, renal failure and atrial fibrillation for 30 day all-cause mortality

1.1 Regression of Log odds ratio on Male 1.50

1.00

0.50

Log odds ratio

0.00

-0.50

-1.00

-1.50

Y = 0.5308 - 0.0139 * Male

-2.00

-2.50 32.5

35.0

37.5

40.0

42.5

45.0

47.5

50.0

52.5

55.0

57.5

60.0

62.5

Male

1.2

Regression of Log odds ratio on LVEF 2.00

1.50

1.00

Log odds ratio

0.50

0.00

-0.50

-1.00

-1.50

Y = -3.5000 + 0.0633 * LVEF

-2.00

-2.50 48.0

50.0

52.0

54.0

LVEF

56.0

58.0

60.0

1.3 Regression of Log odds ratio on Age 1.50

1.00

Log odds ratio

0.50

0.00

-0.50

-1.00

-1.50

Y = -11.0007 + 0.1316 * Age

-2.00

-2.50 80.0

80.5

81.0

81.5

82.0

82.5

83.0

83.5

84.0

84.5

85.0

Age

1.4

Regression of Log odds ratio on Euroscore 2.00

1.50

1.00

Log odds ratio

0.50

0.00

-0.50

-1.00

-1.50

-2.00 Y = -1.0000 + 0.0387 * Euroscore

-2.50

-3.00 10.0

12.0

14.0

16.0

18.0

20.0

Euroscore

22.0

24.0

26.0

28.0

1.5

Regression of Log odds ratio on %MCV 0.60

0.40

0.20

Log odds ratio

0.00

-0.20

-0.40

-0.60

-0.80

-1.00 Y = 0.0443 - 0.0039 * %MCV

-1.20

-1.40 -20.0

0.0

20.0

40.0

60.0

80.0

100.0

120.0

%MCV

1.6

Regression of Log odds ratio on Renal Failure 0.60

0.40

Log odds ratio

0.20

0.00

-0.20

-0.40

-0.60

Y = 0.0319 - 0.0045 * Renal Failure

-0.80

-1.00 -20.0

-10.0

0.0

10.0

20.0

30.0

Renal Failure

40.0

50.0

60.0

70.0

80.0

1.7 Regression of Log odds ratio on Atrial Fibrillation 2.00

1.50

1.00

Log odds ratio

0.50

0.00

-0.50

-1.00

-1.50

Y = -0.3907 + 0.0101 * Atrial Fibrillation

-2.00

-2.50 5.0

10.0

15.0

20.0

25.0

30.0

35.0

40.0

45.0

50.0

55.0

60.0

Atrial Fibrillation

Abbreviations: LVEF: left ventricular ejection fraction; EUROSCORE: European System for Cardiac

Operative

Risk

Evaluation

score;

MCV:

Medtronic

Core

Valve

Supplementary Figure 2: Meta-regression for variables- male gender, LVEF, age, EUROSCORE, MCV, renal failure and atrial fibrillation for 1 year all-cause mortality

2.1 Regression of Log risk ratio on Male 1.50

1.00

0.50

Log risk ratio

0.00

-0.50

-1.00

-1.50

-2.00

Y = 0.0173 + 0.0006 * Male

-2.50

-3.00 32.5

35.0

37.5

40.0

42.5

45.0

47.5

50.0

52.5

55.0

57.5

60.0

62.5

Male

2.2

Regression of Log risk ratio on LVEF 1.50

1.00

0.50

Log risk ratio

0.00

-0.50

-1.00

-1.50

-2.00

Y = -0.0539 + 0.0023 * LVEF

-2.50

-3.00 46.0

48.0

50.0

52.0

54.0

LVEF

56.0

58.0

60.0

62.0

2.3

Regression of Log risk ratio on Age 1.50

1.00

0.50

Log risk ratio

0.00

-0.50

-1.00

-1.50

-2.00

Y = -4.0857 + 0.0498 * Age

-2.50

-3.00 77.0

78.0

79.0

80.0

81.0

82.0

83.0

84.0

85.0

86.0

Age

2.4

Regression of Log odds ratio on Euroscore 2.00

1.50

1.00

Log odds ratio

0.50

0.00

-0.50

-1.00

-1.50

-2.00 Y = -1.2878 + 0.0601 * Euroscore

-2.50

-3.00 10.0

12.0

14.0

16.0

18.0

20.0

Euroscore

22.0

24.0

26.0

28.0

2.5 Regression of Log risk ratio on %MCV 0.75 0.50 0.25 0.00 -0.25

Log risk ratio

-0.50 -0.75 -1.00 -1.25 -1.50 -1.75 -2.00 Y = 0.0831 - 0.0011 * %MCV

-2.25 -2.50 -20.0

0.0

20.0

40.0

60.0

80.0

100.0

120.0

%MCV

2.6

Regression of Log risk ratio on Renal Failure 2.00

1.50

1.00

Log risk ratio

0.50

0.00

-0.50

-1.00

-1.50

-2.00 Y = 0.0601 - 0.0024 * Renal Failure

-2.50

-3.00 0.0

10.0

20.0

30.0

40.0

Renal Failure

50.0

60.0

70.0

80.0

2.7 Regression of Log odds ratio on Atrial Fibrillation 2.00

1.50

1.00

Log odds ratio

0.50

0.00

-0.50

-1.00

-1.50

-2.00 Y = 0.1786 - 0.0005 * Atrial Fibrillation

-2.50

-3.00 5.0

10.0

15.0

20.0

25.0

30.0

35.0

40.0

45.0

50.0

55.0

Atrial Fibrillation

Abbreviations: LVEF: left ventricular ejection fraction; EUROSCORE: European System for Cardiac

Operative

Risk

Evaluation

score;

MCV:

Medtronic

Core

Valv

60.0

Supplementary Figure 3: Funnel plots for (1)All cause mortality at 1-year (2) all-cause mortality at 30 days (3) cardiovascular mortality at 30 days (4) stroke risk at 30 days (5) Myocardial infarction (MI) at 30 days (6) Stroke at 1 year (7) improvement in LVEF (8) all-cause mortality at longest follow up (>1 year).

Funnel Plot of Standard Error by Log odds ratio

(3.1)

0.0

Standard Error

0.5

1.0

1.5

2.0

-2.0

-1.5

-1.0

-0.5

0.0

0.5

1.0

1.5

2.0

Log odds ratio

(3.2) Funnel Plot of Standard Error by MH log risk ratio 0.0

Standard Error

0.5

1.0

1.5

2.0

-2.0

-1.5

-1.0

-0.5

0.0

MH log risk ratio

0.5

1.0

1.5

2.0

(3.3) Funnel Plot of Standard Error by Log odds ratio 0.0

0.2

Standard Error

0.4

0.6

0.8

1.0

-2.0

-1.5

-1.0

-0.5

0.0

0.5

1.0

1.5

2.0

Log odds ratio


Standard Error

0.2

0.4

0.6

0.8

-2.0

-1.5

-1.0

-0.5

0.0

Log odds ratio

0.5

1.0

1.5

2.0

(3.5)

Funnel Plot of Standard Error by MH log risk ratio 0.0

Standard Error

0.5

1.0

1.5

2.0

-2.0

-1.5

-1.0

-0.5

0.0

0.5

1.0

1.5

2.0

MH log risk ratio


0.2

Standard Error

0.4

0.6

0.8

1.0

-2.0

-1.5

-1.0

-0.5

0.0

Log odds ratio

0.5

1.0

1.5

2.0

(3.7) Funnel Plot of Standard Error by Std diff in means 0.0

Standard Error

0.1

0.2

0.3

0.4

-2.0

-1.5

-1.0

-0.5

0.0

Std diff in means

0.5

1.0

1.5

2.0

(3.8) Funnel Plot of Standard Error by MH log risk ratio 0.0

Standard Error

0.2

0.4

0.6

0.8

-2.0

-1.5

-1.0

-0.5

0.0

MH log risk ratio

0.5

1.0

1.5

2.0

Supplementary Figure 4: Sensitivity analysis on 1-year mortality after removing low quality (