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Valvular heart disease
Original research article
Renin–angiotensin system blockade therapy after transcatheter aortic valve implantation
  1. Tomoki Ochiai1,
  2. Shigeru Saito1,
  3. Futoshi Yamanaka1,
  4. Koki Shishido1,
  5. Yutaka Tanaka1,
  6. Tsuyoshi Yamabe2,
  7. Shinichi Shirai3,
  8. Norio Tada4,
  9. Motoharu Araki5,
  10. Toru Naganuma6,
  11. Yusuke Watanabe7,
  12. Masanori Yamamoto8,9,
  13. Kentaro Hayashida10
  1. 1 Department of Cardiology, Shonan Kamakura General Hospital, Kamakura, Kanagawa, Japan
  2. 2 Department of Cardiovascular Surgery, Shonan Kamakura General Hospital, Kamakura, Japan
  3. 3 Department of Cardiology, Kokura Memorial Hospital, Kokura, Japan
  4. 4 Department of Cardiology, Sendai Kousei Hospital, Miyagi, Japan
  5. 5 Department of Cardiology, Saiseikai Yokohama City Eastern Hospital, Yokohama, Japan
  6. 6 Department of Cardiology, New Tokyo Hospital, Chiba, Japan
  7. 7 Department of Cardiology, Teikyo University School of Medicine, Tokyo, Japan
  8. 8 Department of Cardiology, Toyohashi Heart Center, Toyohashi, Japan
  9. 9 Department of Cardiology, Nagoya Heart Center, Nagoya, Japan
  10. 10 Department of Cardiology, Keio University School of Medicine, Tokyo, Japan
  1. Correspondence to Dr Tomoki Ochiai, Department of Cardiology, Shonan Kamakura General Hospital 1370-1 Okamoto, Kamakura, Kanagawa 247-8533, Japan; tomoki.ochiai.0307{at}gmail.com

Abstract

Objective The persistence of left ventricular (LV) hypertrophy is associated with poor clinical outcomes after transcatheter aortic valve implantation (TAVI) for aortic stenosis. However, the optimal medical therapy after TAVI remains unknown. We investigated the effect of renin−angiotensin system (RAS) blockade therapy on LV hypertrophy and mortality in patients undergoing TAVI.

Methods Between October 2013 and April 2016, 1215 patients undergoing TAVI were prospectively enrolled in the Optimized CathEter vAlvular iNtervention (OCEAN)-TAVI registry. This cohort was stratified according to the postoperative usage of RAS blockade therapy with angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs). Patients with at least two prescriptions dispensed 180 days apart after TAVI and at least a 6-month follow-up constituted the RAS blockade group (n=371), while those not prescribed any ACE inhibitors or ARBs after TAVI were included in the no RAS blockade group (n=189).

Results At 6 months postoperatively, the RAS blockade group had significantly greater LV mass index regression than the no RAS blockade group (−9±24% vs −2±25%, p=0.024). Kaplan-Meier analysis revealed a significantly lower cumulative 2-year mortality in the RAS blockade than that in the no RAS blockade group (7.5% vs 12.5%; log-rank test, p=0.031). After adjusting for confounding factors, RAS blockade therapy was associated with significantly lower all-cause mortality (HR, 0.45; 95% CI 0.22 to 0.91; p=0.025).

Conclusions Postoperative RAS blockade therapy is associated with greater LV mass index regression and reduced all-cause mortality. These data need to be confirmed by a prospective randomised controlled outcome trial.

  • transcatheter aortic valve replacement
  • aortic valve stenosis
  • renin-angiotensin system
  • angiotensin-converting enzyme inhibitors
  • angiotensin receptor blockers

https://doi.org/10.1136/heartjnl-2017-311738

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    Introduction

    Severe aortic stenosis (AS) is associated with progressive left ventricular (LV) hypertrophy and diastolic dysfunction. In patients who have undergone surgical aortic valve replacement (SAVR) for AS, the persistence of LV hypertrophy is associated with reduced long-term survival.1–3 For such patients, inhibition of the renin−angiotensin system (RAS) using angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs) is associated with augmented reverse LV remodelling and reduced myocardial hypertrophy,4 5 as well as increased survival rates.6

    Transcatheter aortic valve implantation (TAVI) has emerged as an alternative to SAVR in patients considered to be either inoperable or at high surgical risk.7 8 However, the persistence of LV hypertrophy after TAVI for AS is also associated with an increased rate of repeat hospitalisations, principally for heart failure, over the first postprocedure year.9 Moreover, in patients undergoing TAVI, paravalvular regurgitation (PVR) is a critical issue because it is associated with less LV mass regression and higher mortality,10 11 and the optimal medical therapy for these patients remains unknown. We hypothesised that RAS inhibition therapy after TAVI for severe AS may be beneficial in terms of LV reverse remodelling and clinical outcomes. Thus, we investigated the effect of RAS blockade therapy on LV mass index regression and mortality in patients who underwent TAVI for severe AS.

    Methods

    Study population

    The Optimized CathEter vAlvular iNtervention (OCEAN)-TAVI registry is an ongoing, prospective, multicentre registry of patients undergoing TAVI.12 Between October 2013 and April 2016, consecutive patients with symptomatic severe AS indicated for TAVI at any of nine participating institutions in Japan were prospectively enrolled in the registry. Patients selected for TAVI were considered unsuitable or at high risk for SAVR according to the common guidelines followed by the participating institutions and heart teams. Written informed consent was obtained from all patients before planning the TAVI procedures.

    For the purpose of the present analysis, the following exclusion criteria were applied: death within 6 months of the procedure, lack of data from the 6-month follow-up visit and only one prescription of ACE inhibitors or ARBs during the follow-up after TAVI (cross-over). The remaining cohort constituted the study population and was divided into two groups according to the postoperative usage of RAS blockade therapy with ACE inhibitors or ARBs. Specifically, patients who were prescribed ACE inhibitors or ARBs at TAVI and received two or more confirmed refills (ie, the prescription was dispensed to the patient twice, 180 days apart) were included in the RAS blockade group, while those never prescribed ACE inhibitors or ARBs postoperatively were included in the no RAS blockade group (figure 1).

    Figure 1
    Figure 1

    Study flow diagram. ACEIs, angiotensin-converting enzyme inhibitors; ARBs, angiotensin-receptor blockers; AS, aortic stenosis; RAS, renin−angiotensin system; TAVI, transcatheter aortic valve implantation.

    TAVI procedure

    Two commercially available valves were used over the study period: the Edwards SAPIEN-XT (Edwards Lifesciences, Irvine, California, USA) balloon-expandable prosthesis, introduced in October 2013, and the Medtronic CoreValve Revalving System (Medtronic, Minneapolis, Minnesota, USA) self-expandable prosthesis, introduced in January 2016. The prosthesis size of the SAPIEN-XT (20, 23, 26 and 29 mm) or CoreValve (26 and 29 mm) was determined based on preoperative echocardiographic and multidetector computed tomographic findings. The SAPIEN-XT devices were delivered via the iliofemoral artery or apical routes, while the CoreValve devices were delivered via the femoral artery, subclavian artery or direct aortic approach. The patients were monitored over the course of hospitalisation after TAVI and followed up on an outpatient basis after discharge.

    Echocardiography

    Standard 2D B-mode and Doppler transthoracic echocardiography was performed at baseline, before hospital discharge and at 6 months, 1 year and 2 years postoperatively. Conventional echocardiographic parameters were measured according to the American Society of Echocardiography guidelines.13 14 Standard linear LV dimensions were obtained, and LV mass was calculated using the formula recommended by the American Society of Echocardiography and indexed to the body surface area.13 LV end-diastolic and end-systolic volumes were measured from the standard apical views according to the biplane Simpson method.13 The degree of PVR after TAVI was measured in accordance with current guidelines13 and translated into a semiquantitative grade: none, trace, mild, moderate or severe. Prosthesis-patient mismatch (PPM) was defined as an indexed effective orifice area ≤0.85 cm2/m2.

    Data collection and outcomes

    Follow-up data were recorded during outpatient visits or telephone interviews at 30 days, 6 months and then annually after TAVI. All valve-related events were defined according to the Valve Academic Research Consortium-2 criteria.15 Regarding the use of medication after discharge, it was assumed that the patient filled the prescription and took the medication as advised when the prescription was dispensed.

    The study endpoints were regression of LV mass index at the 6-month follow-up and all-cause mortality at 2 years after the procedure. These outcomes were evaluated for the RAS blockade group and the no RAS blockade group.

    Statistical analysis

    Quantitative variables are expressed as mean± standard deviation or as median and interquartile range (25–75%), as appropriate. Qualitative variables are expressed as numeric values and percentages. Quantitative variables were compared by unpaired Student’s t-test or Wilcoxon rank sum test, depending on the variable distributions. Χ2 test or Fisher’s exact test was used to compare qualitative variables. Kaplan-Meier analysis was performed using log-rank test in order to compare survival rates between the RAS blockade and no RAS blockade groups. Cox multivariable regression analysis (with a landmark analysis at 6 months) was performed to identify the independent predictors of all-cause mortality. The multivariable model was built by stepwise selection, with candidate variables included if they satisfied the entry criterion of p<0.10 in the univariate analysis. Percent and absolute changes in LV mass index were calculated using paired data (at baseline and at 6 months postoperatively) and were compared between the two groups (RAS blockade and no RAS blockade) using analysis of covariance (ANCOVA) to adjust for baseline LV mass index values. Multivariable analysis was performed with linear regression. When we found significant difference of clinical outcomes between RAS blockade and no RAS blockade groups, we performed sensitivity analysis for the selected subgroups. We selected patients with PVR or PPM for the sensitivity analysis because such events can affect the clinical outcome. In addition, given the difference in baseline clinical and echocardiographic characteristics, the clinical outcomes of propensity score-matched cohorts were compared. The propensity score has been developed using a logistic regression model according to non-parsimonious approach, and clinical variables (age, sex, body mass index, body surface area, New York Heart Association functional class III/IV, prior percutaneous coronary intervention, prior coronary artery bypass grafting, prior cerebrovascular disease, diabetes mellitus, hypertension, chronic obstructive pulmonary disease, atrial fibrillation, chronic kidney disease, calcium antagonists, digoxin, diuretic agents, statins, transfemoral approach, LV ejection fraction and LV mass index) were included in the analysis.

    After matching, continuous variables with a normal distribution were compared using the paired-sample t-test; otherwise, the Wilcoxon signed-rank test was used. Differences for matched categorical variables were analysed with McNemar’s test. Kaplan-Meier analysis was performed using stratified log-rank test to compare survival rates between the RAS blockade and no RAS blockade groups. All statistical analyses were performed using IBM SPSS Statistics for Windows, V.19.0 (IBM, Armonk, New York, USA). p<0.05 was considered to indicate statistical significance.

    Results

    Between October 2013 and April 2016, a total of 1215 consecutive patients with symptomatic severe AS undergoing TAVI at any of nine participating centres were prospectively enrolled in the OCEAN-TAVI registry. Of these patients, over half were excluded from the present analysis for the following reasons: death within 6 months of the procedure (n=70), lack of 6-month follow-up visit data (n=429) or treated with ACE inhibitors or ARBs after TAVI at only one point during follow-up (cross-over patients, n=156). The remaining study population (560 patients) was divided into the RAS blockade group (n=371) and the no RAS blockade group (n=189), according to the postoperative prescription of RAS inhibition medication (figure 1).

    Patient characteristics

    The baseline characteristics of the study population are shown in table 1. There were differences between the RAS blockade and no RAS blockade groups in terms of body mass index (22.6±3.7 kg/m2 vs 21.5±3.5 kg/m2, p=0.001), body surface area (1.44±0.16 m2 vs 1.39±0.17 m2, p=0.001), history of hypertension (83.8% vs 61.4%, p<0.001), chronic kidney disease (66.3% vs 57.1%, p=0.033) and eGFR (52.8±19.8 mL/min/1.73 m2 vs 56.6±21.0 mL/min/1.73 m2, p=0.038). Patients in the RAS blockade group were more likely to use calcium antagonists (54.7% vs 32.8%, p<0.001) or statins (49.9% vs 37.6%, p=0.005) but less likely to use digoxin (2.4% vs 6.3%, p=0.045). Baseline LV mass index was greater in the RAS blockade group (136±36 g/m2 vs 125±39 g/m2, p=0.001). There were no significant differences between the two groups in terms of aortic valve area and mean gradient. The other baseline characteristics were similar between the two groups.

    View this table:
    Table 1

    Baseline characteristics of patients undergoing TAVI for severe aortic stenosis

    The procedural characteristics are summarised in online supplementary table S1. The transfemoral approach was implemented in 79.5% of the patients in the RAS blockade group and in 85.7% of the patients in the no RAS blockade group. The most commonly used device was the SAPIEN-XT 23 mm valve, which was used in 64.0% and 67.0% of the patients in the RAS blockade and no RAS blockade groups, respectively. No significant differences were observed between the two groups in terms of procedural characteristics.

    Supplementary file 1

    Postprocedural outcomes and follow-up

    An overview of postprocedural outcomes and follow-up data is provided in table 2. There were no significant differences between the groups in postprocedural outcomes or postprocedural indicators, including LV mass index (131±35 g/m2 vs 126±35 g/m2, p=0.15), LV ejection fraction (64.8±12.1% vs 65.4±9.4%, p=0.57), mean pressure gradient (10.6±3.8 mm Hg vs 10.4±4.0 mm Hg, p=0.52), incidence of PPM (7.5% vs 10.1%, p=0.31) and aortic regurgitation ≥moderate (0.5% vs 1.1%, p=0.49).

    View this table:
    Table 2

    Postprocedural outcomes and follow-up data of patients undergoing TAVI for severe aortic stenosis

    Changes in LV mass index

    At the 6-month follow-up, significantly greater LV mass index regression was noted in the RAS blockade than that in the no RAS blockade group (−9±24% vs −2±25%, p=0.024) (figure 2, table 3). Among the patients with PVR (n=462), those in the RAS blockade group (n=307) experienced significantly more LV mass regression than did those in the no RAS blockade group (n=155) (−8±24% vs 0±25%, p=0.025). Among the patients with PPM (n=47), LV mass index regression between the value at baseline and that at the 6-month follow-up was numerically greater in the RAS blockade group (n=28) than that in the no RAS blockade group (n=19), although the difference did not reach statistical significance (–18±29% vs. 4±25%, p=0.066).  On the other hand, the change in systolic blood pressure between the baseline value and that at the 6-month follow-up was similar between the RAS blockade and no RAS blockade groups (3±20 mmHg vs. 9±19mmHg, p=0.11) (table 3).

    View this table:
    Table 3

    Impact of RAS blockade therapy on LV mass index regression at 6 months after TAVI for severe aortic stenosis

    View this table:
    Figure 2
    Figure 2

    Impact of RAS blockade therapy on LV mass regression at 6 months after TAVI. LV, left ventricular; RAS, renin−angiotensin system; TAVI, transcatheter aortic valve implantation.

    The predictors of change in LV mass index at 6 months, as assessed via univariate regression, are listed in online supplementary table S2. In multivariable regression analysis including baseline LV mass index, PVR and postprocedural mitral regurgitation, RAS blockade therapy was found to independently predict increased percent LV mass regression at 6 months (β-coefficient, −9.0 to −0.1; p=0.046). No significant association was found between RAS blockade therapy and change in LV ejection fraction (between the baseline value and that at the 6-month follow-up).

    Mortality

    The median follow-up period for this cohort was 414 days (IQR, 320−660 days). In total, 32 patients (16 each in the RAS blockade and in the no RAS blockade groups) died during the follow-up period. The baseline and procedural characteristics of the surviving patients and the deceased patients are shown in online supplementary table S3. The impact of RAS blockade therapy on long-term survival was evaluated. Kaplan-Meier analysis revealed a significantly higher overall survival probability in the RAS blockade group, as the cumulative 2-year mortality was significantly lower in the RAS blockade group than that in the no RAS blockade group (7.5% vs 12.5%; log-rank test, p=0.031) (figure 3). Among patients with PVR (n=462), the cumulative 2-year mortality was also significantly lower in the RAS blockade group than that in the no RAS blockade group (7.8% vs 13.7%; log-rank test, p=0.034).

    Figure 3
    Figure 3

    Kaplan-Meier curves of overall survival probability in patients with or without RAS blockade therapy following TAVI. RAS, renin−angiotensin system; TAVI, transcatheter aortic valve implantation.

    Predictors of long-term mortality

    Univariate analysis revealed that RAS blockade therapy was associated with lower mortality (HR, 0.47; 95% CI 0.24 to 0.95; p=0.035). Other factors associated with mortality were diabetes mellitus, prior cerebrovascular disease and each 1-point increment in EuroSCORE II value. The multivariate Cox regression model indicated that RAS blockade therapy (HR, 0.45; 95% CI 0.22 to 0.91; p=0.025), diabetes mellitus (HR, 2.37; 95% CI 1.16 to 4.81; p=0.018) and prior cerebrovascular disease (HR, 2.29; 95% CI 1.05 to 4.98; p=0.037) were the only independent predictors of all-cause mortality (table 4). In the subset of patients with PVR, RAS blockade therapy was also independently associated with lower all-cause mortality (HR, 0.44; 95% CI 0.21 to 0.93; p=0.033).

    View this table:
    Table 4

    Predictors of all-cause mortality in patients undergoing TAVI for severe aortic stenosis

    Repeat hospitalisations for heart failure and cardiovascular events

    In total, 39 patients (22 in the RAS blockade and 17 in the no RAS blockade group) were hospitalised for heart failure during the follow-up period (hospitalisations within 6 months of the procedure were excluded). There was no significant difference between RAS blockade and no RAS blockade groups in terms of repeat hospitalisations for heart failure (5.9% vs 9.0%; log-rank test, p=0.18). As for cardiovascular events (myocardial infarction or stroke), 12 events (seven in the RAS blockade and five in the no RAS blockade groups) occurred during the follow-up period. There was no significant difference between RAS blockade and no RAS blockade groups (1.9% vs 2.6%; log-rank test, p=0.38) in terms of cardiovascular events.

    Propensity score-matched cohort analysis

    To minimise the potential bias between the RAS blockade and no RAS blockade groups, we also performed a propensity score-matched cohort analysis. This particular cohort consisted of 282individuals (141 each in the RAS blockade and in the no RAS blockade groups). Baseline and procedural characteristics are shown in online supplementary table S4. In total, 19 patients (6 in the RAS blockade and 13 in the no RAS blockade groups) died during the follow-up period. Kaplan-Meier analysis revealed there was a trend toward lower the cumulative 2-year mortality in the RAS blockade group than that in the no RAS blockade group (5.2% vs 14.3%; stratified log-rank test, p=0.055). At the 6-month follow-up, significantly greater LV mass index regression was noted in the RAS blockade than that in the no RAS blockade group (−9±23% vs −2±23%, p=0.043).

    Discussion

    Our study found that RAS blockade therapy with ACE inhibitors or ARBs after TAVI was independently associated with increased reverse LV remodelling and lower mortality rates; these findings were true also in the subset of patients with PVR. To our knowledge, this is the first study evaluating the effect of RAS blockade therapy on LV hypertrophy and mortality in patients undergoing TAVI.

    LV hypertrophy commonly occurs in patients with severe AS to compensate for increased afterload and maintains effective cardiac output. Progressive myocardial hypertrophy causes fibrosis and myocyte degeneration, which contribute significantly to LV dysfunction.16 Several studies have demonstrated that persistent LV hypertrophy after SAVR is associated with worse clinical outcome and mortality,1 2 17 and regression of LV hypertrophy has been related to improved survival rates,1 as well as lower risk of myocardial infarction and stroke.18 19 Moreover, in patients who underwent SAVR for AS, postoperative RAS blockade therapy with ACE inhibitors or ARBs was associated with augmented regression of LV hypertrophy,4 20 as well as increased survival rates.6 However, such effects of RAS blockade therapy have not been previously demonstrated in patients who underwent TAVI for AS. Therefore, our finding that postoperative RAS blockade therapy with ACE inhibitors or ARBs is independently associated with increased reverse LV remodelling and reduced all-cause mortality after TAVI is a novel and important insight.

    It is well known that the risk factors for AS and atherosclerosis are similar.21 Previous studies demonstrated that RAS blockade therapy improves clinical outcomes in patients with hypertension and heart failure,22–24 as well as in those at high risk for vascular events.25 In the present study, 76.2% of patients had hypertension, 26.6% had diabetes mellitus, 13.0% had prior cerebrovascular disease and 38.9% had coronary artery disease. One potential explanation for the increased survival rates associated with RAS blockade therapy observed in our study is that the patients in our cohort may have benefited from the cardioprotective effect of ACE inhibitors or ARBs. The present study did not show a significant association between RAS blockade therapy and cardiovascular events or heart failure; however, our cohort was underpowered for such an evaluation. Future studies with longer-term follow-up and a larger number of patients are necessary in order to investigate this possible explanation.

    Another explanation for the increased survival rate associated with RAS blockade therapy after TAVI may be related to LV mass regression. LV mass regression after SAVR for AS is considered a favourable effect of LV unloading.26 Although the relationship between greater LV mass regression and improved clinical outcomes has not been clearly established, an observational study demonstrated that patients with greater LV mass index regression early after TAVI had half the rate of repeat hospitalisations during the first year after the procedure.9 It is possible that RAS blockade therapy after TAVI may be related to regression of myocardial fibrosis that occurred as part of adverse LV remodelling, which led to improved clinical outcome.RAS blockade therapy may indeed deliver its beneficial effects solely by systolic blood pressure reduction. In the present study, the changes of the systolic blood pressure were similar between the RAS blockade and no RAS blockade groups, however, follow-up rates were low and accurate measurement of blood pressure is critical for making appropriate assessment. This was beyond the scope of the present study.

    Our study has important potential clinical implications. PVR after TAVI is associated with decreased regression of LV hypertrophy, and several studies have suggested that postprocedural PVR is associated with higher mortality.10 11 Although the development of new devices and techniques has reduced the incidence of PVR,27 there are still several clinical issues associated with poor clinical outcome in patients with PVR. In the present study, positive effect of RAS blockade therapy on LV mass index regression and survival was observed even in the patients with PVR. This result suggests that RAS blockade therapy may be beneficial and improve prognosis in this population. A large retrospective study reported that the prescription of ACE inhibitors or ARBs in patients with moderate to severe aortic regurgitation was associated with significantly reduced all-cause mortality.28 This finding may be applicable to patients with PVR after TAVI. Our study also revealed that RAS blockade therapy had a positive effect even in patients with PPM with respect to greater LV mass regression. As PPM is associated with reduced LV mass regression,29 30 RAS blockade therapy might be a suitable therapeutic option for these patients.

    Since TAVI has become a routine procedure and smaller and safer devices have become available, recent trials are reporting fewer procedural complications and improved early mortality after TAVI.27 Therefore, in future, it will be more important to address the factors associated with long-term mortality. RAS blockade therapy may play an important role in this aspect.

    Study limitations

    The present study has several limitations. First, this is a retrospective, non-randomised, observational study conducted on a TAVI cohort involving a relatively small number of patients. We have accounted for the baseline differences and the influence of potential confounders by performing a multivariate analysis for the outcome and a propensity score-matched cohort analysis. Second, although the echocardiographic parameters were evaluated by experienced cardiologists in each centre, there was no centralised core laboratory for echocardiographic assessment. Third, we do not have the complete data of patient usage and administration period of ACE inhibitors or ARBs prior to TAVI. There is a possibility that cardioprotective and beneficial effects on the LV remodelling of RAS blockade therapy prior to TAVI last even after TAVI. Finally, the association between RAS blockade therapy and short-term outcomes could not be evaluated because patients who died within 180 days after TAVI were excluded from the study.

    Conclusions

    The present study found that postoperative RAS blockade therapy with ACE inhibitors or ARBs is associated with increased LV mass index regression and reduced mortality in patients who underwent TAVI for severe AS. Future studies involving a larger sample population and longer-term follow-up are warranted to confirm our results.

    Key messages

    What is already known on this subject?

    The persistence of left ventricular (LV) hypertrophy is associated with poor clinical outcomes after transcatheter aortic valve implantation (TAVI) for aortic stenosis. However, the optimal medical therapy after TAVI remains unknown.

    What might this study add?

    In patients undergoing TAVI, postoperative renin−angiotensin system (RAS) blockade therapy is associated with greater LV mass index regression (−9±24% vs -2±25%, p=0.024) and significantly lower all-cause mortality (7.5% vs 12.5%; log-rank test, p=0.031).

    How might this impact on clinical practice?

    Postoperative RAS blockade therapy is associated with greater LV mass index regression and reduced all-cause mortality. However, future studies involving a larger sample population and longer-term follow-up are warranted to confirm our results.

    Acknowledgments

    None

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    Footnotes

    • Contributors TO, SS (SS), FY, KS, YT: conception, design, analysis and interpretation of data; drafting of the manuscript and critically revising it for important intellectual content and final approval of the submitted manuscript. TY, SS (SS), NT, MA, TN, YW, MY, KH: drafting of the manuscript and critically revising it for important intellectual content and final approval of the submitted manuscript.

    • Competing interests Drs SS, MY, NT, TN, MA, SS, YW and KH are proctors for Edwards Lifesciences (transfemoral-TAVI with SAPIEN-XT valves).

    • Ethics approval The medical ethics committee of each participating hospital approved the study protocol.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Correction notice This article has been corrected since it was published Online First. In the "Changes in lV mass index" section the values "(18±29% vs. 4±25%, p=0.66)" have been changed to "(-18±29% vs. 4±25%, p=0.066)". In tables 1 and 4 the rows ’Male sex' have also been updated.

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