Meta-Analysis of Outcomes and Evolution of Pulmonary Hypertension Before and After Transcatheter Aortic Valve Implantation

Accepted Manuscript Meta-Analysis of Outcomes and Evolution of Pulmonary Hypertension Before and After Transcatheter Aortic Valve Implantation Mengyao Tang, MD, Xianbao Liu, MD, Chiayu Lin, MD, Yuxin He, MD, Xianlei Cai, MD, Qiyuan Xu, MD, Po Hu, MD, Feng Gao, MD, Jubo Jiang, MD, Xiaoping Lin, MD, PhD, Qifeng Zhu, MS, Lihan Wang, MD, Huijia Kong, MD, Yunxian Yu, PhD, Jian’an Wang, MD, PhD PII:

S0002-9149(16)31575-2

DOI:

10.1016/j.amjcard.2016.09.015

Reference:

AJC 22157

To appear in:

The American Journal of Cardiology

Received Date: 30 May 2016 Revised Date:

11 September 2016

Accepted Date: 19 September 2016

Please cite this article as: Tang M, Liu X, Lin C, He Y, Cai X, Xu Q, Hu P, Gao F, Jiang J, Lin X, Zhu Q, Wang L, Kong H, Yu Y, Wang J’a, Meta-Analysis of Outcomes and Evolution of Pulmonary Hypertension Before and After Transcatheter Aortic Valve Implantation, The American Journal of Cardiology (2016), doi: 10.1016/j.amjcard.2016.09.015. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT

Meta-Analysis of Outcomes and Evolution of Pulmonary Hypertension Before and After Transcatheter Aortic Valve Implantation

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Mengyao Tang, MDa, Xianbao Liu, MDa, Chiayu Lin, MDa, Yuxin He, MDa, Xianlei Cai, MDb, Qiyuan Xu, MDa, Po Hu, MDa, Feng Gao, MDa, Jubo Jiang, MDa, Xiaoping Lin,

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MD, PhDa, Qifeng Zhu, MSa, Lihan Wang, MDa, Huijia Kong, MDa, Yunxian Yu, PhDc, and Jian’an Wang, MD, PhDa,* a

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Department of Cardiology, Second Affiliated Hospital Zhejiang University School of

Medicine, Hangzhou, People’s Republic of China; bDepartment of General Surgery, Ningbo Medical Treatment Center Lihuili Hospital, Ningbo, People’s Republic of China; and cDepartment of Epidemiology and Health Statistics, School of Public Health,

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School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China.

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Drs. Tang and Liu contributed equally to the manuscript. *Corresponding author: Tel: +86-571-87783992; fax: +86-571-87037885

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E-mail address: [email protected] (J. Wang). Mailing address: Department of Cardiology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China.

Running head Pulmonary Hypertension and TAVI Outcomes Meta-Analysis

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ACCEPTED MANUSCRIPT Abstract Pulmonary hypertension (PH) is a common entity in patients with severe aortic stenosis (AS) undergoing transcatheter aortic valve implantation (TAVI), but its role on clinical outcomes remains undetermined. We evaluated the impact of baseline and

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postprocedural PH on clinical outcomes and changes in pulmonary artery systolic pressure (PASP) following TAVI by performing a meta-analysis of 16 studies enrolling 9,204 patients with AS undergoing TAVI. In patients with baseline PH, all-cause mortality was significantly increased, as shown by pooled ORs for overall 30-day

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(odds ratio [OR] 1.52, 95% confidence interval [CI] 1.28 to 1.80), 1-year (OR 1.39, 95% CI 1.27 to 1.51), and 2-year all-cause mortality (OR 2.00, 95% CI 1.49 to 2.69),

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compared to patients without PH, independent of different methods of PH assessment. The presence of post-TAVI PH was associated with a significant increase in 2-year all-cause mortality (OR 2.32, 95% CI 1.43 to 3.74). Nevertheless, PASP decreased at 3-month to 1-year follow-up (standardized mean difference [SMD] -1.12, 95% CI -1.46

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to -0.78). Baseline PH was associated with higher 30-day and 1-year cardiovascular mortality. Patients with baseline PH had higher risk of stroke at 1 year and acute kidney injury (AKI) at 30 days. But the risk of major vascular complications was

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significantly lower in patients with baseline PH. In conclusion, the presence of PH is associated with increased short- and long-term mortality, also higher risk of stroke and

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AKI following TAVI. A significant decrease in PSAP is detected in AS patients in midterm follow-up after TAVI.

Key Words

Transcatheter aortic valve implantation; Pulmonary hypertension; Aortic stenosis; Meta-analysis.

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ACCEPTED MANUSCRIPT Concomitant pulmonary hypertension (PH) is common in patients with severe aortic stenosis (AS) and poses a clinical dilemma. PH with left heart disease results from backward transmission of increased left ventricular and left atrial filling pressures, and also secondary pulmonary vasoconstriction and remodeling.1 The literature has

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unequivocally demonstrated that AS patients with preoperative PH undergoing surgical aortic valve replacement (SAVR) usually experience increased morbidity and mortality.2,3 However, the evidence of the impact of PH on transcatheter aortic valve implantation (TAVI) is limited and the role of PH on survival and outcomes remains

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controversial.4-19 Currently, the commonly used Society of Thoracic Surgeons (STS) score does not include PH as one of the risk factors during mortality assessment,20

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while the EuroSCORE only considers the presence of severe PH with pulmonary artery systolic pressure (PASP) > 60 mmHg. Moreover, it is unclear whether TAVI could relieve pulmonary arterial pressure after the procedure. Thus, the aims of our meta-analysis were to assess the impact of baseline PH on clinical outcomes and to

Methods

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evaluate changes in PASP in patients undergoing TAVI.

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A systemic review of the published studies on concomitant PH in patients undergoing TAVI was designed and conducted according to the Cochrane Handbook

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of Systemic Reviews and also following the Preferred Reporting Items for Systemic Reviews and Meta-Analyses Requirements (PRISMA) and Meta-Analysis of Observational Studies in Epidemiology.21,22 We performed a computerized search to identify all relevant studies published

from January 2002 to April 2016, in the PubMed database and EMBASE database. We used the following search terms: “TAVI OR TAVR OR transcatheter aortic valve OR percutaneous aortic valve OR transcutaneous aortic valve” combined with “pulmonary”. Language was limited to English only. Potential articles were screened at the level of title and abstract by 2 independent reviewers (MT and CL) and retrieved 3

ACCEPTED MANUSCRIPT as a full report if they reported the data on clinical outcomes after TAVI on the basis of PH or changes in PASPs following TAVI. We also searched reference lists of included studies manually. Studies were included if (1) enrollment for TAVI procedure was based on

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existing guidelines; and (2) reported either data on clinical outcomes after TAVI on the basis of PH or changes in pre-TAVI and post-TAVI PASPs. When 2 duplicate studies were reported, the study with the largest patient size or the most complete information was included.

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Studies were excluded if any of the following criteria applied: (1) duplicate publication or overlapping data; (2) abstracts, case reports, animal experiments,

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conference presentations, reviews or editorials; or (3) outcomes of interest were not clearly reported or were impossible to calculate from the published studies. Reports were screened independently by 2 reviewers (MT and CL) for fulfillment of the inclusion criteria. Reviewers compared selected studies and

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discrepancies were resolved by discussion or a third reviewer (XC) for adjudication. Relevant information was extracted, including but not limited to first author, year of publication, region of study, study design, number of patients included, type of device

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and approach, population baseline characteristics, duration of follow-up, clinical outcomes, and PASP variations (mean ± SD). The quality of included observational

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studies was evaluated with the Newcastle-Ottawa scale ranging from 0 to 8.23 PH was diagnosed based on either PASP estimated by Doppler

echocardiography or pulmonary artery mean pressure (PAMP) measured by right heart catheterization (RHC). Doppler echocardiography is considered to be the best screening method as it is non-invasive, relatively cheap and convenient to use, while RHC is the gold standard for the diagnosis of PH.24 The primary end point was the 30-day, 1-year and 2-year all-cause mortality in patients with baseline PH who underwent TAVI. The secondary end points were (1) the event rates of other adverse clinical outcomes including stroke, myocardial 4

ACCEPTED MANUSCRIPT infarction (MI), acute kidney injury (AKI), permanent pacemaker implantation (PPI), major vascular complications, life-threatening and major bleedings, and rehospitalization; (2) the change in PASPs after TAVI; (3) impact of post-TAVI PH on mortality.

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The odds ratios (ORs) for estimated rates of clinical outcomes were retrieved or calculated with the corresponding 95% confidence intervals (CIs) from each

included study. We used I2 test and its p value to evaluate heterogeneity among the

included studies. We considered moderate-to-high heterogeneity present for p <0.10

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and I2 >50%. ORs were pooled across studies using either fixed- or random-effect

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model based on heterogeneity test result. If I2 >50% and p <0.10，we would use the DerSimonian-Laird random-effect model; otherwise, the Mantel-Haenszel fixed-effect model would be used. We also performed a subgroup analysis to determine whether the impact of baseline PH on mortality outcomes was statistically different according to different methods of PH assessment. Pooled estimates of the mean differences in

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pre-TAVI and post-TAVI PASPs were also calculated to evaluate the change in PASPs from baseline to follow-up period. In order to verify the robustness of the results, sensitivity analysis was performed by removing 1 study at a time. Meta-regression

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analysis was also employed with the method of residual maximum likelihood to test baseline characteristics for the influence of potential effect modifiers. Publication bias

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was evaluated with Egger’s test if the pooled analysis was based on more than 10 studies, and significant bias was defined as a p value <0.10. The Duval-Tweedie trim and fill method was conducted to further test and adjust the potential influence of publication bias. Statistical significance was set at p <0.05 (2-tailed). Data analysis was performed using STATA 12.0 software (StataCorp LP, College Station, TX, USA). Results Through a search by keywords, we identified a total of 1,014 published manuscripts. Manual search of the references further identified 1 relevant publication. 5

ACCEPTED MANUSCRIPT After inclusion and exclusion criteria were applied, 16 studies were finally included in the analyses, enrolling 9,204 patients (Figure 1). No significant limitations were identified in the 16 included articles, 1 of which was a randomized trial and continued registry,7 while the other 15 were observational studies.4-6,8-19 There were 2 studies

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which had overlapping data yet were both included in our analysis because they reported different end points.7,18 The characteristics of enrolled patients, studies and quality ratings are summarized in Tables 1 and 2.

In patients with baseline PH, all-cause mortality following TAVI was

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significantly increased, as shown by the pooled ORs for overall 30-day (OR 1.52, 95% CI 1.28 to 1.80, I2= 0, p=0.502; Figure 2), 1-year (OR 1.39, 95% CI 1.27 to 1.51, I2=

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49.8%, p=0.025; Figure 2), and 2-year all-cause mortality (OR 2.00, 95% CI 1.49 to 2.69, I2= 32.2%, p=0.225; Figure 2), compared to patients without baseline PH. The result of subgroup analysis in patients with different methods of PH assessment showed similar result, but statistical heterogeneity was greatest for the subgroup of

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PASP >60mmHg compared to other subgroups (Figure 2). Meta-regression analysis revealed that when the method of PH assessment was considered as a categorical modifier, no significant influence was shown on 30-day and 1-year all-cause mortality.

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Impact of the presence of baseline PH on other adverse clinical outcomes is listed in Table 3.

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Among the 400 patients with PH at baseline, PASP decreased at midterm (3 months to 1 year) follow-up, with statistically significant heterogeneity (standardized mean difference [SMD] -1.12, 95% CI -1.46 to -0.78, I2= 71.6%, p=0.014; Figure 3) The presence of post-TAVI PH was associated with a statistically significant

increase in 2-year all-cause mortality (OR 2.32, 95% CI 1.43 to 3.74, I2= 0, p=0.570; Figure 4). When the sensitivity analysis was performed by excluding 1 study at a time, the results were not changed. Meta-regression analysis was also performed to explore whether the increased all-cause mortality in patients with PH was influenced 6

ACCEPTED MANUSCRIPT by the prespecified baseline characteristics. Baseline left ventricular ejection fraction was significantly associated with increased 30-day all-cause mortality. The result was not significantly influenced by proportions of baseline systemic hypertension, gender, valve type, New York Heart Association functional classes III/IV, chronic obstructive

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pulmonary disease (COPD), or coronary artery disease (Table 4). We only evaluated the publication bias of the pooled analysis of 30-day and 1-year all-cause mortality because of limited studies in other end points. Evidence of publication bias was observed according to the Egger’s test in the pooled analysis of

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30-day all-cause mortality (p=0.018), but was not present in in the pooled analysis of 1-year all-cause mortality (p=0.107). In order to clarify the influence of potential

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publication bias, the trim and fill method was adopted to calculate an adjusted pooled OR. Additional 4 estimates were added to balance the funnel plot and the adjusted result showed even stronger risk (OR 4.35, 95% CI 3.66 to 5.18). Discussion

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Our meta-analysis is the first to describe the influence of PH on clinical outcomes following TAVI. We include 16 studies enrolling 9,204 patients and find that (1) baseline PH is associated with increased 30-day, 1-year and 2-year all-cause

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mortality following TAVI; (2) PASPs in patients with pre-TAVI PH decrease at 3-month to 1-year follow-up after the procedure; (3) persistent post-TAVI PH is associated with

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increased 2-year mortality; (4) pre-TAVI PH is also associated with increased 30-day and 1-year cardiovascular mortality, higher risk of stroke at 1 year and AKI at 30 days, but lower risk of major vascular complications; and (5) the risk of MI, PPI and life-threatening and major bleedings, and rehospitalization following the procedure is not different between patients with and without pre-TAVI PH. The prevalence of PH in AS patients varies due to inconsistent definition of PH and ranges from 20% to 70%.18,25 In general, PH is a surrogate for more advanced disease, sicker patients and a greater disease burden.26 However, there is lack of definitive evidence regarding the clinical outcomes in AS patients with preprocedeural 7

ACCEPTED MANUSCRIPT PH undergoing TAVI. In our pooled analysis, we found that the coexistence of PH in AS patients is associated with increased all-cause mortality following TAVI. Such result is consistent with surgical literatures revealing preoperative PH entails higher mortality after SAVR compared with AS patients without PH,2,3 and severe PH was

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proved to be an independent early- and long-term mortality predictor in patients undergoing SVAR.27 Meanwhile, we find PASPs in patients with baseline PH decrease at 3-month to 1-year follow-up after TAVI. However, surgical literatures have demonstrated that the reoccurrence of preoperative PH is usually detected during

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longer follow-up of 3 to 4 years.3 The cutoff values of PASPs for the diagnosis of PH were chosen based on the included primary studies in our meta-analysis. PH

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represents a complex and heterogeneous entity with 3 hemodynamic presentations, which are pre-capillary, isolated post-capillary and combined.5 We recommend for patients with isolated post-capillary PH, and baseline PASP > 60 mmHg (the most commonly adopted diagnostic value in our 16 included studies; also used as an

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important determinant in calculating EuroSCORE), PH may be used as an indication to TAVI. More benefit could be rendered for the subgroup of patients mentioned above, in comparison with patients with pre-capillary or combined PH, who are more

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susceptible to permanent myocardial damage and irreversible pulmonary vascular remodeling.6 Our findings highlight the importance of incorporating PH into a

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TAVI-specific risk scoring system, which will improve patient selection of heart teams. Besides the accurate preoperative risk stratification, an endeavor on

improvement of co-morbidity becomes imperative to optimize the clinical outcome of TAVI. PH in a few patients suffering from concomitant severe AS and lung disease usually does not improve or even deteriorates after TAVI.11 Our study reveals persistent post-TAVI PH is associated with increased 2-year mortality. Many medications,

including

endothelin

receptor

antagonists,

prostanoids

and

phosphodiesterase inhibitors, have been proved effective and commonly used in Group I pulmonary arterial hypertension.24 We suggest reducing PASPs to 8

ACCEPTED MANUSCRIPT 40-60mmHg before/during/after TAVI with these medications might play a role in better clinical outcomes. It attempts to safely and acutely improve pulmonary hemodynamics in severe AS patients.28 More studies and meticulous evaluations are needed to address the effectiveness of these medications and identify the optimal

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cutoff value of PASPs. This meta-analysis assents to the viewpoints on increased risk of cardiovascular mortality, stroke and AKI in concomitant PH patients following TAVI. However, interestingly, we discover baseline PH is unusually associated with slightly decreased

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risk of major vascular complications. It is mainly pivoted in the study by Lindman et al, with the etiology mostly fitting in Group II PH due to left heart disease.7 The left

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ventricle and left atrium are inclined to sustain more severe backward transmission force;1 meanwhile, aorta receives less forward transmission force and filling pressure, compared with the patients free of baseline PH. Thus, patients with pre-TAVI PH might be less susceptible to aortic dissection and rupture, both of which are major

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components of major vascular complications.29 Also, vasculature tends to become more fragile with aging. In the study by Lindman et al, patients without baseline PH are statistically significantly older than those with baseline PH.7 We contend this

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interesting phenomenon is probably not a play of chance, rather it may serve as a schema for further exploration.

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Our study has several limitations: (1) our meta-analysis was pooled mainly in observational studies, some of which were not specifically designed to assess the impact of PH on clinical outcomes; (2) there was publication bias in one of the pooled endpoints, however, it was neglectable based on our trim and fill result; (3) different methods were used in the included studies for the assessment and diagnosis of PH, but it did not introduce heterogeneity across studies based on the result of meta-regression; (4) there was a moderate-to-high heterogeneity in the studies for PASP change, the result of which should be regarded as provisional and verified in future trials; (5) some of the end points were pooled in only a few studies because of 9

ACCEPTED MANUSCRIPT the limited or incomplete data reporting, therefore requiring cautious interpretation; (6) the accurate definitions of stroke, MI and AKI might vary among across studies, however, the Valve Academic Research Consortium-2 criteria were most commonly used;29 and (7) we are unable to further analyze the potential impact of different

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hemodynamic presentations of PH on clinical outcomes and changes following TAVI due to limited data. Despite all those limitations mentioned above, our large sample size and robust findings demonstrate the necessity for future new trials to be designed

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and conducted to evaluate the impact of PH on clinical outcomes.

Disclosures

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The authors have no conflicts of interest to disclose.

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ACCEPTED MANUSCRIPT 1. Moraes DL, Colucci WS, Givertz MM. Secondary pulmonary hypertension in chronic heart failure: the role of the endothelium in pathophysiology and management. Circulation 2000;102:1718-1723.

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2. Melby SJ, Moon MR, Lindman BR, Bailey MS, Hill LL, Damiano RJ, Jr. Impact of pulmonary hypertension on outcomes after aortic valve replacement for aortic valve stenosis. J Thorac Cardiovasc Surg 2011;141:1424-1430.

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3. Roselli EE, Abdel Azim A, Houghtaling PL, Jaber WA, Blackstone EH. Pulmonary

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hypertension is associated with worse early and late outcomes after aortic valve replacement: implications for transcatheter aortic valve replacement. J Thorac Cardiovasc Surg 2012;144:1067-1074.e1062.

4. Schewel D, Schewel J, Martin J, Voigtlander L, Frerker C, Wohlmuth P, Thielsen T,

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Kuck KH, Schafer U. Impact of transcatheter aortic valve implantation (TAVI) on pulmonary hyper-tension and clinical outcome in patients with severe aortic valvular stenosis. Clin Res Cardiol 2015;104:164-174.

EP

5. O'Sullivan CJ, Wenaweser P, Ceylan O, Rat-Wirtzler J, Stortecky S, Heg D, Spitzer

AC C

E, Zanchin T, Praz F, Tuller D, Huber C, Pilgrim T, Nietlispach F, Khattab AA, Carrel T, Meier B, Windecker S, Buellesfeld L. Effect of Pulmonary Hypertension Hemodynamic Presentation on Clinical Outcomes in Patients With Severe Symptomatic Aortic Valve Stenosis Undergoing Transcatheter Aortic Valve Implantation: Insights From the New Proposed Pulmonary Hypertension Classification. Circ Cardiovasc Interv 2015;8:e002358. 6. Medvedofsky D, Klempfner R, Fefer P, Chernomordik F, Hamdan A, Hay I, 11

ACCEPTED MANUSCRIPT Goldenberg I, Raanani E, Guetta V, Segev A. The significance of pulmonary arterial hypertension pre- and post-transfemoral aortic valve implantation for severe aortic stenosis. J Cardiol 2015;65:337-342.

RI PT

7. Lindman BR, Zajarias A, Maniar HS, Miller DC, Suri RM, Arnold SV, Webb J, Svensson LG, Kodali S, Xu K, Ayele GM, Lin F, Wong SC, Babaliaros V, Thourani VH, Douglas PS, Lim S, Leon MB, Mack MJ. Risk stratification in patients with pulmonary undergoing

transcatheter

valve

replacement.

Heart

M AN U

2015;101:1656-1664.

aortic

SC

hypertension

8. Durmaz T, Ayhan H, Keles T, Aslan AN, Kasapkara HA, Sari C, Bilen E, Akar Bayram N, Akcay M, Bozkurt E. The effect of transcatheter aortic valve implantation on pulmonary hypertension. Echocardiography 2015;32:1057-1063.

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9. D'Ascenzo F, Conrotto F, Salizzoni S, Rossi ML, Nijhoff F, Gasparetto V, Barbanti M, Mennuni M, Omede P, Grosso Marra W, Quadri G, Giordana F, Tamburino C, Tarantini G, Presbitero P, Napodanno M, Stella P, Biondi-Zoccai G, Agostoni P, D'Amico M,

EP

Moretti C, Rinaldi M, Marra S, Gaita F. Incidence, predictors, and impact on prognosis

AC C

of systolic pulmonary artery pressure and its improvement after transcatheter aortic valve implantation: a multicenter registry. J Invasive Cardiol 2015;27:114-119. 10. Barbash IM, Escarcega RO, Minha S, Ben-Dor I, Torguson R, Goldstein SA, Wang Z, Okubagzi P, Satler LF, Pichard AD, Waksman R. Prevalence and impact of pulmonary hypertension on patients with aortic stenosis who underwent transcatheter aortic valve replacement. Am J Cardiol 2015;115:1435-1442. 11. Sinning JM, Hammerstingl C, Chin D, Ghanem A, Schueler R, Sedaghat A, Bence 12

ACCEPTED MANUSCRIPT J, Spyt T, Werner N, Kovac J, Grube E, Nickenig G, Vasa-Nicotera M. Decrease of pulmonary hypertension impacts on prognosis after transcatheter aortic valve replacement. EuroIntervention 2014;9:1042-1049.

RI PT

12. Lucon A, Oger E, Bedossa M, Boulmier D, Verhoye JP, Eltchaninoff H, Iung B, Leguerrier A, Laskar M, Leprince P, Gilard M, Le Breton H. Prognostic implications of pulmonary hypertension in patients with severe aortic stenosis undergoing

SC

transcatheter aortic valve implantation: study from the FRANCE 2 Registry. Circ

M AN U

Cardiovasc Interv 2014;7:240-247.

13. Bishu K, Suri RM, Nkomo VT, Kane GC, Greason KL, Reeder GS, Mathew V, Holmes DR, Rihal CS, Melduni RM. Prognostic impact of pulmonary artery systolic pressure in patients undergoing transcatheter aortic valve replacement for aortic

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stenosis. Am J Cardiol 2014;114:1562-1567.

14. Zahn R, Gerckens U, Linke A, Sievert H, Kahlert P, Hambrecht R, Sack S, Abdel-Wahab M, Hoffmann E, Schiele R, Schneider S, Senges J. Predictors of

EP

one-year mortality after transcatheter aortic valve implantation for severe

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symptomatic aortic stenosis. Am J Cardiol 2013;112:272-279. 15. Piazza N, Kalesan B, van Mieghem N, Head S, Wenaweser P, Carrel TP, Bleiziffer S, de Jaegere PP, Gahl B, Anderson RH, Kappetein AP, Lange R, Serruys PW, Windecker S, Juni P. A 3-center comparison of 1-year mortality outcomes between transcatheter aortic valve implantation and surgical aortic valve replacement on the basis of propensity score matching among intermediate-risk surgical patients. JACC Cardiovasc Interv 2013;6:443-451. 13

ACCEPTED MANUSCRIPT 16. Munoz-Garcia AJ, del Valle R, Trillo-Nouche R, Elizaga J, Gimeno F, Hernandez-Antolin R, Teles R, de Gama Ribeiro V, Molina E, Cequier A, Urbano-Carrillo C, Cruz-Gonzalez I, Payaslian M, Patricio L, Sztejfman M, Iniguez A,

RI PT

Rodriguez V, Scuteri A, Caorsi C, Lopez-Otero D, Avanzas P, Alonso-Briales JH, Hernandez-Garcia JM, Moris C. The Ibero-American transcatheter aortic valve implantation registry with the CoreValve prosthesis. Early and long-term results. Int J

SC

Cardiol 2013;169:359-365.

M AN U

17. Tamburino C, Capodanno D, Ramondo A, Petronio AS, Ettori F, Santoro G, Klugmann S, Bedogni F, Maisano F, Marzocchi A, Poli A, Antoniucci D, Napodano M, De Carlo M, Fiorina C, Ussia GP. Incidence and predictors of early and late mortality after transcatheter aortic valve implantation in 663 patients with severe aortic stenosis.

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Circulation 2011;123:299-308.

18. Ben-Dor I, Goldstein SA, Pichard AD, Satler LF, Maluenda G, Li Y, Syed AI, Gonzalez MA, Gaglia MA, Jr., Wakabayashi K, Delhaye C, Belle L, Wang Z, Collins

EP

SD, Torguson R, Okubagzi P, Aderotoye A, Xue Z, Suddath WO, Kent KM, Epstein SE,

AC C

Lindsay J, Waksman R. Clinical profile, prognostic implication, and response to treatment of pulmonary hypertension in patients with severe aortic stenosis. Am J Cardiol 2011;107:1046-1051. 19. Rodes-Cabau J, Webb JG, Cheung A, Ye J, Dumont E, Feindel CM, Osten M, Natarajan MK, Velianou JL, Martucci G, DeVarennes B, Chisholm R, Peterson MD, Lichtenstein SV, Nietlispach F, Doyle D, DeLarochelliere R, Teoh K, Chu V, Dancea A, Lachapelle K, Cheema A, Latter D, Horlick E. Transcatheter aortic valve implantation 14

ACCEPTED MANUSCRIPT for the treatment of severe symptomatic aortic stenosis in patients at very high or prohibitive surgical risk: acute and late outcomes of the multicenter Canadian experience. J Am Coll Cardiol 2010;55:1080-1090.

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20. Brown JM, O'Brien SM, Wu C, Sikora JA, Griffith BP, Gammie JS. Isolated aortic valve replacement in North America comprising 108,687 patients in 10 years: changes in risks, valve types, and outcomes in the Society of Thoracic Surgeons

SC

National Database. J Thorac Cardiovasc Surg 2009;137:82-90.

M AN U

21. Moher D, Liberati A, Tetzlaff J, Altman DG, Group P. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J Clin Epidemiol 2009;62:1006-1012.

22. Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, Moher D,

TE D

Becker BJ, Sipe TA, Thacker SB. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA 2000;283:2008-2012.

EP

23. Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of

AC C

the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol 2010;25:603-605.

24. McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, Mathier MA, McGoon MD, Park MH, Rosenson RS, Rubin LJ, Tapson VF, Varga J, American College of Cardiology Foundation Task Force on Expert Consensus D, American Heart A, American College of Chest P, American Thoracic Society I, Pulmonary Hypertension A. ACCF/AHA 2009 expert consensus document on 15

ACCEPTED MANUSCRIPT pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American

RI PT

Thoracic Society, Inc.; and the Pulmonary Hypertension Association. J Am Coll Cardiol 2009;53:1573-1619.

25. Silver K, Aurigemma G, Krendel S, Barry N, Ockene I, Alpert J. Pulmonary artery

SC

hypertension in severe aortic stenosis: incidence and mechanism. Am Heart J

M AN U

1993;125:146-150.

26. Park MH, Mehra MR. Pulmonary hypertension: the great leveler. J Am Coll Cardiol 2012;59:232-234.

27. Di Eusanio M, Fortuna D, De Palma R, Dell'Amore A, Lamarra M, Contini GA,

TE D

Gherli T, Gabbieri D, Ghidoni I, Cristell D, Zussa C, Pigini F, Pugliese P, Pacini D, Di Bartolomeo R. Aortic valve replacement: results and predictors of mortality from a contemporary series of 2256 patients. J Thorac Cardiovasc Surg 2011;141:940-947.

EP

28. Lindman BR, Zajarias A, Madrazo JA, Shah J, Gage BF, Novak E, Johnson SN,

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Chakinala MM, Hohn TA, Saghir M, Mann DL. Effects of phosphodiesterase type 5 inhibition on systemic and pulmonary hemodynamics and ventricular function in patients with severe symptomatic aortic stenosis. Circulation 2012;125:2353-2362. 29. Kappetein AP, Head SJ, Genereux P, Piazza N, van Mieghem NM, Blackstone EH, Brott TG, Cohen DJ, Cutlip DE, van Es GA, Hahn RT, Kirtane AJ, Krucoff MW, Kodali S, Mack MJ, Mehran R, Rodes-Cabau J, Vranckx P, Webb JG, Windecker S, Serruys PW, Leon MB. Updated standardized endpoint definitions for transcatheter aortic 16

ACCEPTED MANUSCRIPT valve implantation: the Valve Academic Research Consortium-2 consensus document.

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17

ACCEPTED MANUSCRIPT Figure 1. PRISMA flow diagram demonstrating study selection.

Figure 2. Mortality outcomes following TAVI in patient with baseline PH. (A) Forest plot

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demonstrating the individual and pooled analysis for overall 30-day all-cause mortality in patients with baseline PH. (B) Forest plot demonstrating the individual and pooled analysis for overall 1-year all-cause mortality in patients with baseline PH. (C) Forest

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mortality in patients with baseline PH.

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plot demonstrating the individual and pooled analysis for overall 2-year all-cause

Figure 3. Forest plot showing changes in PASPs at 3-month to 1-year follow-up.

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mortality.

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Figure 4. Forest plot showing the pooled OR of post-TAVI PH on 2-year all-cause

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Study characteristics and quality Year

Location

Number

Valve

Approach

Follow-up

Age(years)

Male

Hypertension

DM

Zahn14

2013

Germany

1306

MC/ES

TF/SC/TA/TAo

1 year

NA

41.5%

NA

Tamburino17

2011

Italy

663

MC

TF/SC

1 year

81.0

44.0%

75.1%

Sinning11

2014

Germany and UK

353

MC/ES

TF/SC

2 years

81.1

52.6%

NA

Lucon12

2014

France

435

MC/ES

TF/SC/TA

1 year

83.0

49.8%

69.0%

Durmaz8

2015

Turkey

70

MC/ES

TF/SC/TA

6 months

77.6

Rodes-Cabau19

2010

Canada

339

ES

TF/TA

2 years

81.0

Munoz-Garcia16

2013

1218

MC

TF/SC

2 years

80.7

255

MC

NA

1 year

80.6

MC/ES

TF

2 years

NA 81.0

2015

Israel

104

28.1%

88.3%

NA

26.4%

16.4%

48.3%

21.3%

71.5%

52.1%

III/IV

CABG

PCI

Score

quality

18.2%

34.2%

NA

6.5/8

15.7%

28.5%

NA

6.5/8

NA

27.2%

64.0%

32.0%

NA

47.9%

21.1%

36.0%

8.7%

8/8

24.4%

28.5%

47.4%

22.9%

77.0%

NA

15.7%

NA

NA

7.5/8

27.1%

24.3%

67.1%

28.6%

90.0%

54.5%

NA

NA

7.7%

6/8

69.0%

29.5%

90.9%

55.0%

34.2%

29.2%

9.8%

6.5/8

45.3%

79.4%

31.2%

NA

36.1%

26.5%

79.4%

55.8%

9.5%

20.7%

NA

6.5/8

38.8%

87.2%

31.0%

NA

61.6%

18.8%

76.9%

NA

NA

NA

NA

6.5/8

51.6%

NA

32.0%

NA

56.6%

NA

99.2%

NA

NA

NA

NA

7/8

56.0%

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58.9%

Study

33.9%

Netherlands Medvedofsky6

24.9%

STS

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34.1%

Prior

LVEF

23.3%

Switzerland, Germany and Piazza15

COPD

74.3%

Ibero-America

80.0%

prior

CAD

44.8%

Spain, Portugal and

27.1%

NYHA

AF

SC

First Author

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USA

251

NA

NA

2 years

86.9%

39.4%

NA

NA

NA

86.1%

NA

NA

NA

NA

7.5/8

2015

USA

415

MC/ES

TF/TA/TAo

1 year

84.0

47.0%

89.2%

31.0%

39.8%

55.9%

29.7%

NA

NA

31.0%

28.9%

10.0%

7.5/8

D'Ascenzo9

2015

Italy and Netherlands

674

MC/ES

TF/SC/TA/TAo

1 year

81.0

49.7%

NA

37.5%

NA

NA

32.3%

NA

53.6%

13.5%

33.1%

9.1%

7/8

O'Sullivan5

2015

Switzerland

433

MC/ES

TF/SC/TA

1 year

82.0

45.3%

85.2%

29.1%

13.9%

62.4%

17.6%

69.5%

NA

6.9%

27.5%

NA

7/8

Schewel4

2014

Germany

439

MC/ES

TF/TX/TA/TAo

1 year

80.0

46.9%

87.2%

29.2%

47.4%

62.0%

15.7%

NA

53.0%

NA

NA

NA

7.5/8

Lindman7

2015

USA, Canada and Germany

2180

ES

TF/TA

1 year

84.0

52.8%

91.5%

42.1%

NA

77.7%

19.4%

NA

NA

42.8%

NA

NA

7/8

Ben-Dor18

2011

USA

69

ES

TF/TA

44.4%

92.1%

33.8%

NA

63.5%

16．1%

NA

NA

31.6%

NA

NA

7/8

EP

2014

Barbash10

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1 year

81.0

AF= atrial fibrillation; CABG= coronary artery bypass graft; CAD= coronary artery disease; COPD= chronic obstructive pulmonary disease; DM= diabetes mellitus; ES= Edwards Sapien; LVEF= left ventricular ejection fraction; MC= Medtronic CoreValve; NA= not applicable; NYHA= New York Heart Association; PCI= percutaneous coronary intervention; STS= Society of Thoracic Surgery; TA= transapical; TAo= transaortic; TF= transfemoral; TX= transaxillary; SC= subclavian.

ACCEPTED MANUSCRIPT Table 2 Methods of PH assessment number

Method of PH assessment

Diagnostic value of PH

Zahn Tamburino17 Sinning11 Lucon12 Durmaz8 Rodes-Cabau19 Munoz-Garcia16

2013 2011 2014 2014 2015 2010 2013

1306 663 353 435 70 339 1218

Doppler echocardiography Doppler echocardiography Doppler echocardiography Doppler echocardiography Doppler echocardiography Doppler echocardiography Doppler echocardiography

PASP > 60 mmHg PASP > 60 mmHg PASP > 60 mmHg PASP > 60 mmHg PASP > 60 mmHg PASP > 60 mmHg PASP > 60 mmHg

Piazza15

2013

255

Doppler echocardiography

2011 2015 2014 2015 2015 2015 2014 2015

69 104 251 415 674 433 439 2180

Doppler echocardiography Doppler echocardiography Doppler echocardiography Doppler echocardiography Doppler echocardiography RHC RHC RHC

Ben-Dor Medvedofsky6 Bishu13 Barbash10 D'Ascenzo9 O'Sullivan5 Schewel4 Lindman7

PASP > 60 mmHg

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PASP > 60 mmHg PASP > 50 mmHg PASP > 50 mmHg PASP > 50 mmHg PASP > 40 mmHg PAMP > 25 mmHg PAMP > 25 mmHg PAMP > 25 mmHg

PAMP= pulmonary artery mean pressure; PASP= pulmonary artery systolic pressure;

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ACCEPTED MANUSCRIPT Table 3 ORs for other adverse clinical outcomes in patients with baseline PH undergoing TAVI

Cardiovascular mortality 30 days 4 5722 1 year 4 5722 Stroke 30 days 7 6827 1 year 4 5722 MI 30 days 4 3722 1 year

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p-value

1.53 1.15-2.03 1.56 1.29-1.88

0 7.4%

0.580 0.356

1.24 0.91-1.70 1.39 1.04-1.86

16% 0

0.308 0.494

OR

95% CI

0.91 0.32-2.57

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Studies, Patients, n n

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Outcome

0

0.794

0

0.450

3

3542

0.59

30 days

5

3718

1.39 1.04-1.86 46.4%

0.113

PPI 30 days

3

975

0.87 0.67-1.13

0

0.395

Major vascular complications 30 days 6 4263 0.76 0.62-0.94 Life-threatening and major bleedings

0

0.452

30 days

0.32-1.11

Rehospitalization 30 days 2

4141

0.94 0.81-1.09

0

0.837

2431

1.25 0.91-1.72

0

0.416

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p 0.518 0.510 0.145 0.764 0.703 0.264 0.861

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p 0.776 0.373 0.045 0.157 0.299 0.464 0.545

1-year Tau2 0.077 0.123 0.026 0.123 0.131 0.106 0.146

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30-day Tau2 Hypertension 0.223 Male gender 0.229 LVEF 0.011 Valve type 0.215 NYHA III/IV 0 COPD 0.253 CAD 0.347

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all-cause mortality

CAD= coronary artery disease; COPD= chronic obstructive pulmonary disease;

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