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Does diabetes mellitus impact prognosis after transcatheter aortic valve implantation? Insights from a meta-analysis

Open AccessPublished:June 07, 2017DOI:https://doi.org/10.1016/j.jjcc.2017.01.005

      Abstract

      Background

      Diabetes mellitus (DM) is well known to increase mortality in several cardiovascular diseases. However, the prognostic impact of DM following transcatheter aortic valve implantation (TAVI) remains controversial. We sought to assess the impact of DM on perioperative (in-hospital or 30-day) complications and mid-term (≥1 year) all-cause mortality after TAVI through meta-analysis.

      Methods

      A comprehensive literature search of PUBMED and EMBASE was conducted through January 1st 2002 to May 15th 2016. Articles that reported adjusted hazards ratio (HRs) or unadjusted HR for mid-term all-cause mortality with 95% confidence intervals (CIs) of DM or insulin dependent DM (IDDM) on mid-term all-cause mortality post TAVI were included in the analysis. A meta-analysis was performed with combination of both adjusted HR and un-adjusted HR. Sensitivity analysis was performed with only the adjusted HR. Random-effects model was used to calculate the pooled effect size.

      Results

      A total of 22 observational cohort studies were identified with 28,440 (8998 DM and 19,442 non-DM) patients. The risk of perioperative complications (myocardial infarction, bleeding, major vascular complications, stroke, and new-onset atrial fibrillation) was similar between DM and non-DM cohorts. A meta-analysis of all-cause mortality of DM (19 studies after excluding 3 studies that only reported HR of IDDM on mid-term all-cause mortality, 8808 DM and 17,829 non-DM patients) resulted in significantly worse outcome (HR 1.21, 95%CI 1.10–1.34, p = 0.0002, I2 = 53%) in DM patients compared to non-DM patients post-TAVI. Sensitivity analysis showed consistent results. Subgroup analysis (4 studies with 267 IDDM versus 2161 non-IDDM) demonstrated that IDDM was associated with higher all-cause mortality (HR 2.05, 95%CI 1.54–2.73, p < 0.00001, I2 = 0%) following TAVI.

      Conclusions

      DM was associated with similar perioperative complications but was associated with increased mid-term all-cause mortality after TAVI. Further study of the causes of increased mortality during the follow-up may lead to improved outcome.

      Keywords

      Introduction

      Diabetes mellitus (DM) is a major public health issue, which affects more than 400 million people and is expected to surpass 600 million by 2040 worldwide [

      International Diabetes Federation. IDF diabetes atlas (7th edition). http://www.idf.org/diabetesatlas (accessed 17.09.16).

      ]. DM accounted for 15% of mortality and its burden on mortality nearly doubled in the past few decades [
      Global Burden of Metabolic Risk Factors for Chronic Diseases Collaboration
      Cardiovascular disease, chronic kidney disease, and diabetes mortality burden of cardiometabolic risk factors from 1980 to 2010: a comparative risk assessment.
      ]. DM has been reported to be associated with increased mortality in a wide variety of cardiovascular diseases [
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      ].
      Transcatheter aortic valve implantation (TAVI) has initially emerged as a viable option for the treatment of severe symptomatic aortic stenosis (AS) in inoperable and high-risk patients for open-heart surgery [
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      • et al.
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      ]. Recently, those at intermediate risk for surgery also exhibited similar clinical outcomes [
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      • Kodali S.K.
      • Thourani V.H.
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      • Doshi D.
      • Cohen D.J.
      • Pichard A.D.
      • Kapadia S.
      • Dewey T.
      • et al.
      Transcatheter or surgical aortic-valve replacement in intermediate-risk patients.
      ]. The number of TAVI procedures has been increasing exponentially and is expected to continue to rise considering that it demonstrated comparable outcomes with surgical aortic valve replacement (SAVR) at intermediate surgical risk [
      • Leon M.B.
      • Smith C.R.
      • Mack M.J.
      • Makkar R.R.
      • Svensson L.G.
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      • Thourani V.H.
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      • Miller D.C.
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      • et al.
      Transcatheter or surgical aortic-valve replacement in intermediate-risk patients.
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      ].
      DM in TAVI candidates is one of the most common comorbidities, reaching approximately 30% of the entire cohort [
      • Adams D.H.
      • Popma J.J.
      • Reardon M.J.
      • Yakubov S.J.
      • Coselli J.S.
      • Deeb G.M.
      • Gleason T.G.
      • Buchbinder M.
      • Hermiller Jr., J.
      • Kleiman N.S.
      • Chetcuti S.
      • Heiser J.
      • Merhi W.
      • Zorn G.
      • Tadros P.
      • et al.
      Transcatheter aortic-valve replacement with a self-expanding prosthesis.
      ,
      • Leon M.B.
      • Smith C.R.
      • Mack M.J.
      • Makkar R.R.
      • Svensson L.G.
      • Kodali S.K.
      • Thourani V.H.
      • Tuzcu E.M.
      • Miller D.C.
      • Herrmann H.C.
      • Doshi D.
      • Cohen D.J.
      • Pichard A.D.
      • Kapadia S.
      • Dewey T.
      • et al.
      Transcatheter or surgical aortic-valve replacement in intermediate-risk patients.
      ]. Although DM is an established risk factor for increased morality in certain cardiovascular diseases (i.e. coronary artery disease), its impact after TAVI has not been well studied. With increasing numbers of procedures performed and given the frequency of DM as one of the comorbidities for patients undergoing TAVI, it is of paramount clinical importance to assess the impact of DM following TAVI. Therefore, the purpose of this systematic review was to investigate the clinical impact of DM on perioperative (in-hospital or 30-day) complications and all-cause mortality during mid-term (≥1 year) follow-up in TAVI patients.

      Materials and methods

      Data source and literature search

      A systematic review was conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) and MOOSE (Meta-analysis of Observational Studies in Epidemiology) guidelines [
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      • Moher D.
      The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration.
      ,
      • Stroup D.F.
      • Berlin J.A.
      • Morton S.C.
      • Olkin I.
      • Williamson G.D.
      • Rennie D.
      • Moher D.
      • Becker B.J.
      • Sipe T.A.
      • Thacker S.B.
      Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group.
      ]. A systematic literature search was conducted through PUBMED and EMBASE from January 1st 2002 to May 15th 2016. The search terms included aortic valve, percutaneous, transcatheter, transluminal, transarterial, transapical, transaortic, transcarotid, transaxillary, transsubclavian, transiliac, transfemoral, transiliofemoral, transcatheter aortic valve replacement, mortality, death, deaths, survival, insulin, diabetes, diabetic, diabetics, diabetes mellitus. Language was restricted to English and conference abstracts were excluded. Two independent reviewers (T.A and H.T) searched the literature for related studies and abstracted data. Abstracted data were stored in a pre-specified Excel sheet. In case of disagreement, an agreement was reached through arbitration (T.U.). References of included manuscripts were manually reviewed to avoid missing relevant articles. When there was considered to exist an overlap of the data from different literatures, articles that reported the adjusted hazards ratio (HRs) instead on un-adjusted HR were included.

      Inclusion and exclusion criteria

      Inclusion criteria were (1) the study was a comparative (the study compared the outcomes between DM and non-DM patients who underwent TAVI) or cohort study [the study reported either adjusted or un-adjusted HR of DM or insulin dependent DM (IDDM) for all-cause mortality in cohorts who received TAVI]; (2) the study design was prospective or retrospective; (3) adjusted or unadjusted HR of the impact of DM on the mid-term (≥1 year) all-cause mortality after TAVI is available or able to calculate by methods reported by Tierney et al. [
      • Tierney J.F.
      • Stewart L.A.
      • Ghersi D.
      • Burdett S.
      • Sydes M.R.
      Practical methods for incorporating summary time-to-event data into meta-analysis.
      ]. Exclusion criteria were (1) if adjusted or unadjusted HR were not available or calculable; (2) Studies that reported only the perioperative all-cause mortality (in hospital or 30 days); (3) Studies that only reported odds ratio (OR) or provided data that only allowed to calculate the OR on mid-term mortality.

      Clinical outcomes

      Outcomes were all-cause mortality during mid-term (≥1 year) follow-up and perioperative (in-hospital or 30-day) complications (myocardial infarction, bleeding, major vascular complication, stroke, and new-onset atrial fibrillation) in TAVI patients with or without DM.

      Data synthesis and statistical analysis

      Review Manager (RevMan) Version 5.3 (Nordic Cochrane Centre, The Cochrane Collaboration, 2012, Copenhagen, Denmark) and Comprehensive Meta-Analysis version 2 (Biostat, Englewood, NJ, USA) were used for statistical analysis. Inverse-variance analysis was used to calculate the pooled HR in the random-effects model with 95% confidence interval (CI). Study heterogeneity was assessed by I2 index with 25%, 50%, and 75% representing low, moderate, and high heterogeneity, respectively. Primary meta-analysis was performed with combining both the adjusted HR and non-adjusted HR and assessed all-cause mortality during mid-term follow up. The incidence of perioperative complications was assessed with OR. Publication bias was utilized by visually assessing the asymmetry of funnel plot. In case asymmetry was noticed, Begg's test was used to quantitate publication bias. Trim and fill methods were utilized when significant publication bias was observed. Meta-regression analysis was performed by unrestricted maximum likelihood method with pre-specified continuous variables (mean age, maximum length of follow-up duration, and proportion of females) as a moderator for only the meta-analysis of mid-term all cause mortality. A p-value <0.05 was considered significant.

      Results

      Our search result yielded 2333 studies. A detailed study selection flow chart is shown in supplement 1. A total of 22 observational studies [
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      Impact of diabetes mellitus on outcomes after transcatheter aortic valve implantation.
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      Clinical impact of diabetes mellitus in patients undergoing transcatheter aortic valve replacement.
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      Long-term outcome after transcatheter aortic valve implantation.
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      Impact of diabetes mellitus and hemoglobin A1C on outcome after transcatheter aortic valve implantation.
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      Four-year durability of clinical and haemodynamic outcomes of transcatheter aortic valve implantation with the self-expanding CoreValve.
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      Late survival and heart failure after transcatheter aortic valve implantation.
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      Ibero-American registry investigators. The Ibero-American transcatheter aortic valve implantation registry with the CoreValve prosthesis. Early and long-term results.
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      Revisiting sex equality with transcatheter aortic valve replacement outcomes: a collaborative, patient-level meta-analysis of 11,310 patients.
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      Impact of frailty on short- and long-term morbidity and mortality after transcatheter aortic valve implantation: risk assessment by Katz Index of activities of daily living.
      ,
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      ,
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      Clinical impact of a new left bundle branch block following TAVI implantation: 1-year results of the TAVIK cohort.
      ,
      • Seiffert M.
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      • Grube E.
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      ,
      • Toggweiler S.
      • Humphries K.H.
      • Lee M.
      • Binder R.K.
      • Moss R.R.
      • Freeman M.
      • Ye J.
      • Cheung A.
      • Wood D.A.
      • Webb J.G.
      5-year outcome after transcatheter aortic valve implantation.
      ,
      • Yoon S.H.
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      • Shirai S.
      • Kao H.L.
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      ,
      • Zahn R.
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      ] including a total of 28,440 (8998 DM and 19,442 non-DM) patients were included. Nineteen studies reported either adjusted or un-adjusted HR of DM on mid-term all-cause mortality, three studies with either adjusted or un-adjusted HR of IDDM on mid-term all-cause mortality, and one study reported adjusted HR on all-cause mid-term mortality in both DM and IDDM. Four studies were comparative studies while the rest of the studies were cohort studies.
      Perioperative complications between DM and non-DM patients were available only from four studies. The perioperative complications were similar for myocardial infarction, bleeding events, major vascular complication, cerebrovascular events, and new onset atrial fibrillation (p-value non-significant for all complications). The results are summarized in Fig. 1.
      Figure thumbnail gr1
      Fig. 1Forest plot of meta-analysis for perioperative complications with odds ratio and 95% CI. The left and right end of the horizontal line denotes 95% of lower and upper CI, respectively. The rhombus represents the odds ratio. CI, confidence interval; MI, myocardial infarction; MVC, major vascular complication; NOAF, new-onset atrial fibrillation.
      The meta-analysis of all-cause mortality between DM and non-DM patients after TAVI with both the adjusted and un-adjusted HR (19 studies included after excluding three studies that only reported HR of IDDM on mid-term all-cause mortality with 8808 DM and 17,829 non-DM patients) showed worse all-cause mortality in DM patients (HR 1.21, 95%CI 1.10–1.34, p = 0.0002, I2 = 53%, p for heterogeneity 0.003) (Fig. 2A) . We performed several sensitivity analyses. First, we removed studies with less number of cohort (total cohort <200 patients) [
      • Bouleti C.
      • Himbert D.
      • Iung B.
      • Alos B.
      • Kerneis C.
      • Ghodbane W.
      • Messika-Zeitoun D.
      • Brochet E.
      • Fassa A.A.
      • Depoix J.P.
      • Ou P.
      • Nataf P.
      • Vahanian A.
      Long-term outcome after transcatheter aortic valve implantation.
      ,
      • Gulino S.
      • Barbanti M.
      • Deste W.
      • Immè S.
      • Aruta P.
      • Bottari V.
      • Benvenuto E.
      • Tamburino C.
      • Di Landro A.
      • Liberto D.
      • Santonoceto L.
      • Sicuso R.
      • Di Stefano D.
      • Todaro D.
      • Di Simone E.
      • et al.
      Four-year durability of clinical and haemodynamic outcomes of transcatheter aortic valve implantation with the self-expanding CoreValve.
      ,
      • Johansson M.
      • Nozohoor S.
      • Bjursten H.
      • Ragnarsson S.
      • Götberg M.
      • Kimblad P.O.
      • Zindovic I.
      • Sjögren J.
      Late survival and heart failure after transcatheter aortic valve implantation.
      ,
      • Toggweiler S.
      • Humphries K.H.
      • Lee M.
      • Binder R.K.
      • Moss R.R.
      • Freeman M.
      • Ye J.
      • Cheung A.
      • Wood D.A.
      • Webb J.G.
      5-year outcome after transcatheter aortic valve implantation.
      ], which still showed consistent results. Second, we combined only the adjusted HR (12 studies with 4886 DM and 7880 non-DM patients), which consistently demonstrated worse all-cause mortality in DM patients (HR 1.28, 95%CI 1.12–1.46, p for effect 0.0004, I2 = 58%, p for heterogeneity 0.0004). Third, meta-analysis of only the comparative studies [
      • Abramowitz Y.
      • Jilaihawi H.
      • Chakravarty T.
      • Mangat G.
      • Maeno Y.
      • Kazuno Y.
      • Takahashi N.
      • Kawamori H.
      • Cheng W.
      • Makkar R.R.
      Impact of diabetes mellitus on outcomes after transcatheter aortic valve implantation.
      ,
      • Berkovitch A.
      • Segev A.
      • Barbash I.
      • Grossman Y.
      • Maor E.
      • Erez A.
      • Regev E.
      • Fink N.
      • Mazin I.
      • Hamdan A.
      • Goldenberg I.
      • Hay I.
      • Spiegelstien D.
      • Guetta V.
      • Fefer P.
      Clinical impact of diabetes mellitus in patients undergoing transcatheter aortic valve replacement.
      ,
      • Chorin E.
      • Finkelstein A.
      • Banai S.
      • Aviram G.
      • Barkagan M.
      • Barak L.
      • Keren G.
      • Steinvil A.
      Impact of diabetes mellitus and hemoglobin A1C on outcome after transcatheter aortic valve implantation.
      ] showed similar mid-term all-cause mortality (HR 1.18, 95%CI 0.84–1.66, p = 0.35, I2 = 42%, p for heterogeneity 0.18) while meta-analysis of only the cohort studies showed worse mortality in DM cohorts (HR 1.22, 95%CI 1.09–1.35, p = 0.0003, I2 = 56%, p for heterogeneity 0.002). Lastly, we removed each study one by one and recalculated the HR to estimate its effect on the pooled HR, which did not significantly alter the result.
      Figure thumbnail gr2
      Fig. 2(A) Forest plot of hazards ratio of DM versus non-DM patients for all-cause mortality. (B) Forest plot of hazards ratio of IDDM patients for all-cause mortality. The closed rhombus located at the right lower part of the figure denotes the pooled effect size included studies. The width of the black rhombus represents 95% CI. The vertical line that connects the upper and lower corner of the rhombus shows the hazards ratio. NIDDM, insulin-dependent diabetes mellitus; DM, diabetes; CI, confidence interval.
      Mid-term cardiovascular mortality was reported only from one study. Conrotto et al. demonstrated similar mortality between DM versus non-DM (12.7% versus 11.6%) during 2-year follow-up [
      • Conrotto F.
      • D’Ascenzo F.
      • Giordana F.
      • Salizzoni S.
      • Tamburino C.
      • Tarantini G.
      • Presbitero P.
      • Barbanti M.
      • Gasparetto V.
      • Mennuni M.
      • Napodano M.
      • Rossi M.L.
      • La Torre M.
      • Ferraro G.
      • Omedè P.
      • et al.
      Impact of diabetes mellitus on early and midterm outcomes after transcatheter aortic valve implantation (from a multicenter registry).
      ]. Because there was only one study, meta-analysis was not performed for cardiovascular mortality.
      A meta-analysis of IDDM (4 studies with 267 IDDM versus 2141 without IDDM) demonstrated that IDDM was associated with higher all-cause mortality (HR 2.05, 95%CI 1.54–2.73, p < 0.00001, I2 = 0%) (Fig. 2B). Sensitivity analysis was performed by removing each study one at a time and recalculating the pooled effect size. This did not significantly alter the result.
      We performed a meta-regression analysis for all-cause mortality. Female gender (slope 0.011, p = 0.19), age (slope 0.015, p = 0.67) and maximum follow-up duration (slope 0.014, p = 0.28) did not significantly affect the relative risk (i.e. HR) of all-cause mortality (Fig. 3). These results imply that these clinical factors did not significantly affect the HR of all-cause mortality.
      Figure thumbnail gr3
      Fig. 3Meta-regression of proportion of female (%), mean age (years), and maximum length of follow-up duration (years), with the area of each circle inversely proportional to the variance of the log hazard ratio.
      Visual assessment of funnel plot showed asymmetry on visual assessment for all-cause mortality. Egger's regression test showed significant asymmetry (p = 0.008). Trim and fill method was applied. A total of five studies were filled in but the result remained consistent with worse all-cause mortality in DM patients (HR 1.15, 95%CI 1.04–1.27) (Fig. 4).
      Figure thumbnail gr4
      Fig. 4Funnel plot corrected with the trim-and-fill method. Five hypothetical studies are incorporated (black circles and rhombus) represent imputed studies and corrected hazard ratio. Open circles and an open rhombus represent identified studies and their summary measure, respectively. Closed circles and a closed rhombus denote estimated missing studies after adjustment for funnel plot asymmetry and the summary measure incorporating the hypothetical studies, respectively.

      Discussion

      This is one of the first meta-analyses to assess the impact of DM on clinical outcomes after TAVI. Although DM is an established risk factor for increased mortality following coronary artery diseases, its effect on aortic stenosis patients following aortic valve replacement has not been well studied. With the recent dramatic increase in TAVI, it is clinically significantly important to assess the impact of DM on clinical outcomes. The major findings of this meta-analysis were 1: DM increased the risk of all-cause mortality by statistically significant 15% during the mid-term follow-up who received TAVI for severe symptomatic AS; 2: The incidence of perioperative complications (myocardial infarction, bleeding, major vascular complication, stroke, and new onset atrial fibrillation) was similar between DM and non-DM patients; 3: Sex, age, and follow-up duration did not significantly affect the mortality during follow-up.
      DM increased the risk of all-cause mortality by statistically significant 15% during the mid-term follow-up in patients who received TAVI for severe symptomatic AS. There may be several reasons to explain the negative effect of DM in post TAVI cohorts. According to a study by Xiong et al., the top three causes of death beyond 30 days post-TAVI were infection/sepsis (14.3%), heart failure (14.1%), and sudden death (10.8%) [
      • Xiong T.Y.
      • Liao Y.B.
      • Zhao Z.G.
      • Xu Y.N.
      • Wei X.
      • Zuo Z.L.
      • Li Y.J.
      • Cao J.Y.
      • Tang H.
      • Jilaihawi H.
      • Feng Y.
      • Chen M.
      Causes of death following transcatheter aortic valve replacement: a systematic review and meta-analysis.
      ]. DM patients are susceptible to these conditions and may account for increased mortality [
      • Peleg A.Y.
      • Weerarathna T.
      • McCarthy J.S.
      • Davis T.M.
      Common infections in diabetes: pathogenesis, management and relationship to glycaemic control.
      ,
      • Johansson I.
      • Dahlström U.
      • Edner M.
      • Näsman P.
      • Rydén L.
      • Norhammar A.
      Risk factors, treatment and prognosis in men and women with heart failure with and without diabetes.
      ,
      • Jouven X.
      • Lemaître R.N.
      • Rea T.D.
      • Sotoodehnia N.
      • Empana J.P.
      • Siscovick D.S.
      Diabetes, glucose level, and risk of sudden cardiac death.
      ]. In addition, Regueiro et al. reported DM as a risk of infective endocarditis, which resulted in higher 2-year mortality post TAVI [
      • Regueiro A.
      • Linke A.
      • Latib A.
      • Ihlemann N.
      • Urena M.
      • Walther T.
      • Husser O.
      • Herrmann H.C.
      • Nombela-Franco L.
      • Cheema A.N.
      • Le Breton H.
      • Stortecky S.
      • Kapadia S.
      • Bartorelli A.L.
      • Sinning J.M.
      • et al.
      Association between transcatheter aortic valve replacement and subsequent infective endocarditis and in-hospital death.
      ]. Roughly, half of the deaths after TAVI were related to cardiovascular disease, which relationship with DM is well established [
      • Sarwar N.
      • Gao P.
      • Seshasai S.R.
      • Gobin R.
      • Kaptoge S.
      • Di Angelantonio E.
      • Ingelsson E.
      • Lawlor D.A.
      • Selvin E.
      • Stampfer M.
      • Stehouwer C.D.
      • Lewington S.
      • Pennells L.
      • Thompson A.
      • et al.
      Emerging Risk Factors Collaboration
      Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies.
      ,
      • Xiong T.Y.
      • Liao Y.B.
      • Zhao Z.G.
      • Xu Y.N.
      • Wei X.
      • Zuo Z.L.
      • Li Y.J.
      • Cao J.Y.
      • Tang H.
      • Jilaihawi H.
      • Feng Y.
      • Chen M.
      Causes of death following transcatheter aortic valve replacement: a systematic review and meta-analysis.
      ]. Nakamura et al. reported that DM was associated with impaired left ventricular mass regression after either TAVI or SAVR after 1-year follow-up [
      • Nakamura T.
      • Toda K.
      • Kuratani T.
      • Miyagawa S.
      • Yoshikawa Y.
      • Fukushima S.
      • Saito S.
      • Yoshioka D.
      • Kashiyama N.
      • Daimon T.
      • Sawa Y.
      Diabetes mellitus impairs left ventricular mass regression after surgical or transcatheter aortic valve replacement for severe aortic stenosis.
      ]. Patients with greater regression of left ventricular mass post TAVI had a similar rate of all-cause mortality but had half the rate of re-hospitalization for heart failure [
      • Lindman B.R.
      • Stewart W.J.
      • Pibarot P.
      • Hahn R.T.
      • Otto C.M.
      • Xu K.
      • Devereux R.B.
      • Weissman N.J.
      • Enriquez-Sarano M.
      • Szeto W.Y.
      • Makkar R.
      • Miller D.C.
      • Lerakis S.
      • Kapadia S.
      • Bowers B.
      • et al.
      Early regression of severe left ventricular hypertrophy after transcatheter aortic valve replacement is associated with decreased hospitalizations.
      ]. On the other hand, residual left ventricular hypertrophy has been reported with reduced long-term mortality after SAVR [
      • Beach J.M.
      • Mihaljevic T.
      • Rajeswaran J.
      • Marwick T.
      • Edwards S.T.
      • Nowicki E.R.
      • Thomas J.
      • Svensson L.G.
      • Griffin B.
      • Gillinov A.M.
      • Blackstone E.H.
      Ventricular hypertrophy and left atrial dilatation persist and are associated with reduced survival after valve replacement for aortic stenosis.
      ]. These data support that DM patients after TAVI may have worse cardiovascular mortality but the study included in our meta-analysis showed no difference in cardiovascular mortality [
      • Conrotto F.
      • D’Ascenzo F.
      • Giordana F.
      • Salizzoni S.
      • Tamburino C.
      • Tarantini G.
      • Presbitero P.
      • Barbanti M.
      • Gasparetto V.
      • Mennuni M.
      • Napodano M.
      • Rossi M.L.
      • La Torre M.
      • Ferraro G.
      • Omedè P.
      • et al.
      Impact of diabetes mellitus on early and midterm outcomes after transcatheter aortic valve implantation (from a multicenter registry).
      ]. However, because there is limited evidence, further study is warranted to determine whether DM patients have increased risk of cardiovascular death after TAVI (Table 1).
      Table 1Summary of included studies.
      StudyStudy designNumber (total)Age (year)Men (%)DM (%)IDDM (%)BMI (kg/m2)Surgical risk scoreMaximum follow-up
      Abramowitz
      • Abramowitz Y.
      • Jilaihawi H.
      • Chakravarty T.
      • Mangat G.
      • Maeno Y.
      • Kazuno Y.
      • Takahashi N.
      • Kawamori H.
      • Cheng W.
      • Makkar R.R.
      Impact of diabetes mellitus on outcomes after transcatheter aortic valve implantation.
      CP80282.0 ± 8.860.031.79.626.8 ± 5.88.1 ± 5.0
      Society of Thoracic Surgery score.
      2 years
      Berkovitch
      • Berkovitch A.
      • Segev A.
      • Barbash I.
      • Grossman Y.
      • Maor E.
      • Erez A.
      • Regev E.
      • Fink N.
      • Mazin I.
      • Hamdan A.
      • Goldenberg I.
      • Hay I.
      • Spiegelstien D.
      • Guetta V.
      • Fefer P.
      Clinical impact of diabetes mellitus in patients undergoing transcatheter aortic valve replacement.
      CP44381.3 ± 7.646.535.79.9NR5.5 ± 3.8
      Society of Thoracic Surgery score.
      2 years
      Bouleti
      • Bouleti C.
      • Himbert D.
      • Iung B.
      • Alos B.
      • Kerneis C.
      • Ghodbane W.
      • Messika-Zeitoun D.
      • Brochet E.
      • Fassa A.A.
      • Depoix J.P.
      • Ou P.
      • Nataf P.
      • Vahanian A.
      Long-term outcome after transcatheter aortic valve implantation.
      CO12381.5 ± 8.456.123.65.725.7 ± 4.77.1 ± 4.7
      Society of Thoracic Surgery score.
      6 years
      Chorin
      • Chorin E.
      • Finkelstein A.
      • Banai S.
      • Aviram G.
      • Barkagan M.
      • Barak L.
      • Keren G.
      • Steinvil A.
      Impact of diabetes mellitus and hemoglobin A1C on outcome after transcatheter aortic valve implantation.
      CP58682.6 ± 6.042.340.6NRNR4.2 ± 2.5
      Society of Thoracic Surgery score.
      4 years
      Codner
      • Codner P.
      • Orvin K.
      • Assali A.
      • Sharony R.
      • Vaknin-Assa H.
      • Shapira Y.
      • Schwartzenberg S.
      • Bental T.
      • Sagie A.
      • Kornowski R.
      Long-term outcomes for patients with severe symptomatic aortic stenosis treated with transcatheter aortic valve implantation.
      CO36082.1 ± 6.943.634NR26.2 ± 5.17.5 ± 4.7
      Society of Thoracic Surgery score.
      5 years
      Conrotto
      • Conrotto F.
      • D’Ascenzo F.
      • Giordana F.
      • Salizzoni S.
      • Tamburino C.
      • Tarantini G.
      • Presbitero P.
      • Barbanti M.
      • Gasparetto V.
      • Mennuni M.
      • Napodano M.
      • Rossi M.L.
      • La Torre M.
      • Ferraro G.
      • Omedè P.
      • et al.
      Impact of diabetes mellitus on early and midterm outcomes after transcatheter aortic valve implantation (from a multicenter registry).
      CP51181.8 ± 2.150.429.414.1NR10.0 ± 3.0
      Society of Thoracic Surgery score.
      2 years
      D’Ascenzo
      • D’Ascenzo F.
      • Conrotto F.
      • Salizzoni S.
      • Rossi M.L.
      • Nijhoff F.
      • Gasparetto V.
      • Barbanti M.
      • Mennuni M.
      • Omedè P.
      • Grosso Marra W.
      • Quadri G.
      • Giordana F.
      • Tamburino C.
      • Tarantini G.
      • Presbitero P.
      • et al.
      Incidence, predictors, and impact on prognosis of systolic pulmonary artery pressure and its improvement after transcatheter aortic valve implantation: a multicenter registry.
      CO67481.5 ± 5.665.937.89.9NR9.1 ± 7.7
      Society of Thoracic Surgery score.
      760 days
      D’Onofrio
      • D’Onofrio A.
      • Salizzoni S.
      • Agrifoglio M.
      • Lucchetti V.
      • Musumeci F.
      • Esposito G.
      • Magagna P.
      • Aiello M.
      • Savini C.
      • Cassese M.
      • Glauber M.
      • Punta G.
      • Alfieri O.
      • Gabbieri D.
      • Mangino D.
      • et al.
      When does transapical aortic valve replacement become a futile procedure? An analysis from a national registry.
      CO64581.2 ± 6.44227.37.9NR10 ± 7.91 year
      Escarcega
      • Escárcega R.O.
      • Baker N.C.
      • Lipinski M.J.
      • Koifman E.
      • Kiramijyan S.
      • Magalhaes M.A.
      • Gai J.
      • Torguson R.
      • Satler L.F.
      • Pichard A.D.
      • Waksman R.
      Clinical profiles and correlates of mortality in nonagenarians with severe aortic stenosis undergoing transcatheter aortic valve replacement.
      CO65482 ± 74933NRNRNR1 year
      Gulino
      • Gulino S.
      • Barbanti M.
      • Deste W.
      • Immè S.
      • Aruta P.
      • Bottari V.
      • Benvenuto E.
      • Tamburino C.
      • Di Landro A.
      • Liberto D.
      • Santonoceto L.
      • Sicuso R.
      • Di Stefano D.
      • Todaro D.
      • Di Simone E.
      • et al.
      Four-year durability of clinical and haemodynamic outcomes of transcatheter aortic valve implantation with the self-expanding CoreValve.
      CO12581.1 ± 4.740.028.0NR26.7 ± 5.36.1 ± 3.5
      Society of Thoracic Surgery score.
      4 years
      Johansson
      • Johansson M.
      • Nozohoor S.
      • Bjursten H.
      • Ragnarsson S.
      • Götberg M.
      • Kimblad P.O.
      • Zindovic I.
      • Sjögren J.
      Late survival and heart failure after transcatheter aortic valve implantation.
      CO16680 ± 95124NR27 ± 523 ± 155 years
      Kobrin
      • Kobrin D.M.
      • McCarthy F.H.
      • Herrmann H.C.
      • Anwaruddin S.
      • Kobrin S.
      • Szeto W.Y.
      • Bavaria J.E.
      • Groeneveld P.W.
      • Desai N.D.
      Transcatheter and surgical aortic valve replacement in dialysis patients: a propensity-matched comparison.
      CO500583.8 ± 7.65148NRNRNR1 year
      Linke
      • Linke A.
      • Wenaweser P.
      • Gerckens U.
      • Tamburino C.
      • Bosmans J.
      • Bleiziffer S.
      • Blackman D.
      • Schäfer U.
      • Müller R.
      • Sievert H.
      • Søndergaard L.
      • Klugmann S.
      • Hoffmann R.
      • Tchétché D.
      • Colombo A.
      • et al.
      Treatment of aortic stenosis with a self-expanding transcatheter valve: the International Multi-centre ADVANCE Study.
      CO101581.1 ± 6.44931.3NRNR5.3 ± 3.1
      Society of Thoracic Surgery score.
      1 year
      Munoz-Garcia
      • Muñoz-García A.J.
      • del Valle R.
      • Trillo-Nouche R.
      • Elízaga J.
      • Gimeno F.
      • Hernández-Antolín R.
      • Teles R.
      • de Gama Ribeiro V.
      • Molina E.
      • Cequier A.
      • Urbano-Carrillo C.
      • Cruz-González I.
      • Payaslian M.
      • Patricio L.
      Ibero-American registry investigators. The Ibero-American transcatheter aortic valve implantation registry with the CoreValve prosthesis. Early and long-term results.
      CO122080.7 ± 6.345.331.2NRNR17.3 ± 132 years
      O’Connor
      • O’Connor S.A.
      • Morice M.C.
      • Gilard M.
      • Leon M.B.
      • Webb J.G.
      • Dvir D.
      • Rodés-Cabau J.
      • Tamburino C.
      • Capodanno D.
      • D’Ascenzo F.
      • Garot P.
      • Chevalier B.
      • Mikhail G.W.
      • Ludman P.F.
      Revisiting sex equality with transcatheter aortic valve replacement outcomes: a collaborative, patient-level meta-analysis of 11,310 patients.
      CO1131082.4 ± 7.951.427.2NR26.5 ± 5.523.1 ± 14.7
      Logistic EuroSCORE.
      5 years
      Puls
      • Puls M.
      • Sobisiak B.
      • Bleckmann A.
      • Jacobshagen C.
      • Danner B.C.
      • Hünlich M.
      • Beißbarth T.
      • Schöndube F.
      • Hasenfuß G.
      • Seipelt R.
      • Schillinger W.
      Impact of frailty on short- and long-term morbidity and mortality after transcatheter aortic valve implantation: risk assessment by Katz Index of activities of daily living.
      CO30082.1 ± 5.33434NR26.5 ± 4.77.3 ± 5.43.3 years
      Ruparelia
      • Ruparelia N.
      • Latib A.
      • Buzzatti N.
      • Giannini F.
      • Figini F.
      • Mangieri A.
      • Regazzoli D.
      • Stella S.
      • Sticchi A.
      • Kawamoto H.
      • Tanaka A.
      • Agricola E.
      • Monaco F.
      • Castiglioni A.
      • Ancona M.
      • et al.
      Long-term outcomes after transcatheter aortic valve implantation from a singlehigh-volume center (The Milan Experience).
      CO70382.6 ± 8.241.630.4NRNR22.7 ± 16.8
      Logistic EuroSCORE.
      7 years
      Schymik
      • Schymik G.
      • Tzamalis P.
      • Bramlage P.
      • Heimeshoff M.
      • Würth A.
      • Wondraschek R.
      • Gonska B.D.
      • Posival H.
      • Schmitt C.
      • Schröfel H.
      • Luik A.
      Clinical impact of a new left bundle branch block following TAVI implantation: 1-year results of the TAVIK cohort.
      CO63482.0 ± 4.538.333.8NRNR21.7 ± 13.1
      Logistic EuroSCORE.
      1 year
      Seifert
      • Seiffert M.
      • Sinning J.M.
      • Meyer A.
      • Wilde S.
      • Conradi L.
      • Vasa-Nicotera M.
      • Ghanem A.
      • Kempfert J.
      • Hammerstingl C.
      • Ojeda F.M.
      • Kim W.K.
      • Koschyk D.H.
      • Schirmer J.
      • Baldus S.
      • Grube E.
      • et al.
      Development of a risk score for outcome after transcatheter aortic valve implantation.
      CO84580.9 ± 6.548.928.4NR26.3 ± 5.26.4 ± 7.4
      Society of Thoracic Surgery score.
      1 year
      Toggweiler
      • Toggweiler S.
      • Humphries K.H.
      • Lee M.
      • Binder R.K.
      • Moss R.R.
      • Freeman M.
      • Ye J.
      • Cheung A.
      • Wood D.A.
      • Webb J.G.
      5-year outcome after transcatheter aortic valve implantation.
      CO8883 ± 75325NRNR9.0 ± 5.0
      Society of Thoracic Surgery score.
      5 years
      Yoon
      • Yoon S.H.
      • Ahn J.M.
      • Hayashida K.
      • Watanabe Y.
      • Shirai S.
      • Kao H.L.
      • Yin W.H.
      • Lee M.K.
      • Tay E.
      • Araki M.
      • Yamanaka F.
      • Arai T.
      • Lin M.S.
      • Park J.B.
      • Park D.W.
      • et al.
      Clinical outcomes following transcatheter aortic valve replacement in Asian population.
      CO84881.8 ± 6.646.730.1NR23.0 ± 3.85.2 ± 3.8
      Society of Thoracic Surgery score.
      2 years
      Zahn
      • 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.
      German Transcatheter Aortic Valve Interventions-Registry Investigators. Predictors of one-year mortality after transcatheter aortic valve implantation for severe symptomatic aortic stenosis.
      CO131881.7 ± 6.141.534.0NR26.8 ± 10.420.3 ± 13.5
      Logistic EuroSCORE.
      1 year
      BMI, body mass index; CO, cohort study; CP, comparative study; DM, diabetes; IDDM, insulin dependent diabetes; NR, not reported. Continuous variables are expressed as mean ± standard deviation.
      a Society of Thoracic Surgery score.
      b Logistic EuroSCORE.
      The incidence of perioperative complications (myocardial infarction, bleeding, major vascular complications, stroke, and new onset atrial fibrillation) was similar between DM and non-DM patients. Past studies suggested that these perioperative complications were associated with worse prognosis [
      • Toggweiler S.
      • Humphries K.H.
      • Lee M.
      • Binder R.K.
      • Moss R.R.
      • Freeman M.
      • Ye J.
      • Cheung A.
      • Wood D.A.
      • Webb J.G.
      5-year outcome after transcatheter aortic valve implantation.
      ,
      • Tarantini G.
      • Mojoli M.
      • Windecker S.
      • Wendler O.
      • Lefèvre T.
      • Saia F.
      • Walther T.
      • Rubino P.
      • Bartorelli A.L.
      • Napodano M.
      • D’Onofrio A.
      • Gerosa G.
      • Iliceto S.
      • Vahanian A.
      Prevalence and impact of atrial fibrillation in patients with severe aortic stenosis undergoing transcatheter aortic valve replacement: an analysis from the SOURCE XT Prospective Multicenter Registry.
      ,
      • Muralidharan A.
      • Thiagarajan K.
      • Van Ham R.
      • Gleason T.G.
      • Mulukutla S.
      • Schindler J.T.
      • Jeevanantham V.
      • Thirumala P.D.
      Meta-analysis of perioperative stroke and mortality in transcatheter aortic valve implantation.
      ,
      • Kochman J.
      • Rymuza B.
      • Huczek Z.
      • Kołtowski Ł.
      • Ścisło P.
      • Wilimski R.
      • Ścibisz A.
      • Stanecka P.
      • Filipiak K.J.
      • Opolski G.
      Incidence, predictors and impact of severe periprocedural bleeding according to VARC-2 criteria on 1-year clinical outcomes in patients after transcatheter aortic valve implantation.
      ,
      • Sannino A.
      • Gargiulo G.
      • Schiattarella G.G.
      • Perrino C.
      • Stabile E.
      • Losi M.A.
      • Galderisi M.
      • Izzo R.
      • de Simone G.
      • Trimarco B.
      • Esposito G.
      A meta-analysis of the impact of pre-existing and new-onset atrial fibrillation on clinical outcomes in patients undergoing transcatheter aortic valve implantation.
      ]. However, as previously discussed, our result suggested worse outcomes of TAVI in DM patients. We speculate that because there were only a few studies included for meta-analysis of perioperative complications, statistical power may not be adequate to reveal the difference of incidence of these complications. Furthermore, because of the inconsistency of the complications reported, we were not able to perform meta-analysis for some complications (i.e. acute kidney injury). Acute kidney injury is one of the frequently reported complications post TAVI associated with worse survival but DM was not a risk factor in the past studies [
      • Chatani K.
      • Abdel-Wahab M.
      • Wübken-Kleinfeld N.
      • Gordian K.
      • Pötzing K.
      • Mostafa A.E.
      • Kraatz E.G.
      • Richardt D.
      • El-Mawardy M.
      • Richardt G.
      Acute kidney injury after transcatheter aortic valve implantation: impact of contrast agents, predictive factors, and prognostic importance in 203 patients with long-term follow-up.
      ,
      • Aalaei-Andabili S.H.
      • Pourafshar N.
      • Bavry A.A.
      • Klodell C.T.
      • Anderson R.D.
      • Karimi A.
      • Petersen J.W.
      • Beaver T.M.
      Acute kidney injury after transcatheter aortic valve replacement.
      ]. Only Conrotto et al. assessed the adverse events during mid-term follow-up and reported that myocardial infarction was observed significantly more in the DM compared to non-DM patients (8.3% versus 1.4%, p < 0.01) [
      • Conrotto F.
      • D’Ascenzo F.
      • Giordana F.
      • Salizzoni S.
      • Tamburino C.
      • Tarantini G.
      • Presbitero P.
      • Barbanti M.
      • Gasparetto V.
      • Mennuni M.
      • Napodano M.
      • Rossi M.L.
      • La Torre M.
      • Ferraro G.
      • Omedè P.
      • et al.
      Impact of diabetes mellitus on early and midterm outcomes after transcatheter aortic valve implantation (from a multicenter registry).
      ]. Cardiovascular death and cerebrovascular events were similar between the two groups while all-cause mortality was significantly higher in DM patients [
      • Conrotto F.
      • D’Ascenzo F.
      • Giordana F.
      • Salizzoni S.
      • Tamburino C.
      • Tarantini G.
      • Presbitero P.
      • Barbanti M.
      • Gasparetto V.
      • Mennuni M.
      • Napodano M.
      • Rossi M.L.
      • La Torre M.
      • Ferraro G.
      • Omedè P.
      • et al.
      Impact of diabetes mellitus on early and midterm outcomes after transcatheter aortic valve implantation (from a multicenter registry).
      ]. This suggests that non-cardiovascular death was the main reason for increased mortality in DM cohorts. However, the study was limited in absolute event numbers and observational study design as mentioned. More data are needed to explain the cause (atherosclerotic disease versus non-atherosclerotic disease) of worse mortality in DM patients following TAVI.
      Sex, age, and follow-up duration did not significantly affect the relative risk (i.e. HR) of mortality during follow-up. Past studies have suggested that female sex was associated with favorable outcomes despite increased perioperative complications [
      • Aalaei-Andabili S.H.
      • Pourafshar N.
      • Bavry A.A.
      • Klodell C.T.
      • Anderson R.D.
      • Karimi A.
      • Petersen J.W.
      • Beaver T.M.
      Acute kidney injury after transcatheter aortic valve replacement.
      ]. Lower rates of paravalvular regurgitation and burden of comorbidities was considered as the cause, however, the exact mechanism remains unclear. The impact of age on post TAVI cohorts has been reported with conflicting results [
      • Kodali S.
      • Williams M.R.
      • Doshi D.
      • Hahn R.T.
      • Humphries K.H.
      • Nkomo V.T.
      • Cohen D.J.
      • Douglas P.S.
      • Mack M.
      • Xu K.
      • Svensson L.
      • Thourani V.H.
      • Tuzcu E.M.
      • Weissman N.J.
      • Leon M.
      • et al.
      Sex-specific differences at presentation and outcomes among patients undergoing transcatheter aortic valve replacement: a cohort study.
      ,
      • Thourani V.H.
      • Jensen H.A.
      • Babaliaros V.
      • Kodali S.K.
      • Rajeswaran J.
      • Ehrlinger J.
      • Blackstone E.H.
      • Suri R.M.
      • Don C.W.
      • Aldea G.
      • Williams M.R.
      • Makkar R.
      • Svensson L.G.
      • McCabe J.M.
      • Dean L.S.
      • et al.
      Outcomes in nonagenarians undergoing transcatheter aortic valve replacement in the PARTNER-I Trial.
      • Arsalan M.
      • Szerlip M.
      • Vemulapalli S.
      • Holper E.M.
      • Arnold S.V.
      • Li Z.
      • DiMaio M.J.
      • Rumsfeld J.S.
      • Brown D.L.
      • Mack M.J.
      Should transcatheter aortic valve replacement be performed in nonagenarians?: Insights from the STS/ACC TVT Registry.
      ]. Because the past studies were mainly observational studies, the definite impact of age has not been determined.
      We speculated that longer duration of follow-up would negatively affect the relative risk (i.e. HR) of mortality as DM patients are at increased risk for atherosclerotic diseases. However, our meta-regression result did not support this idea. The data on clinical events during follow-up beyond 30 days are scarce. Conrotto et al. reported no difference in all-cause and cardiovascular mortality although myocardial infarction was more frequent in DM cohorts [
      • Conrotto F.
      • D’Ascenzo F.
      • Giordana F.
      • Salizzoni S.
      • Tamburino C.
      • Tarantini G.
      • Presbitero P.
      • Barbanti M.
      • Gasparetto V.
      • Mennuni M.
      • Napodano M.
      • Rossi M.L.
      • La Torre M.
      • Ferraro G.
      • Omedè P.
      • et al.
      Impact of diabetes mellitus on early and midterm outcomes after transcatheter aortic valve implantation (from a multicenter registry).
      ].
      There are several limitations that require attention in assessing the presented data. First, the major limitation of this meta-analysis is that the included studies were non-randomized observational studies and therefore more subject to biases than meta-analysis of randomized clinical trials. Second, the variables used to report the adjusted HR were not consistent among studies and therefore subject to biases. The difference in study design (comparative versus cohort studies) may also affect the selection of variables to calculate the adjusted HR with multivariate analysis. For example, DM may not be selected for multivariate analysis when not significant in the univariate analysis in the cohort studies. Indeed, when meta-analysis was performed exclusively with comparative studies, it did not show significant worse association for mid-term all-cause mortality. However, only three studies were included with one reporting only the un-adjusted HR. Therefore, the result may be insufficient to conclude the association of DM and all-cause mortality after TAVI. Third, although the rigorous search was conducted to include all the available studies, we cannot totally exclude the possibilities of publication bias. Indeed, publication bias was observed with the Egger's test but after the trim and fill method, the result was consistent. Fourth, the meta-analysis of perioperative complications was assessed only from comparative cohort studies. Because the assessment of perioperative complications was not the primary purpose of our study, we did not include the studies that reported DM as a risk factor for certain perioperative complications. Lastly, since the severity of DM (i.e. duration of DM history, hemoglobin A1c) was not available in most studies, we were unable to assess the severity of DM on adverse events. This will limit the magnitude of the impact of DM on the prognosis after TAVI.

      Conclusions

      In this meta-analysis with more than 20,000 patients included, DM was not associated with increased risk for several perioperative complications. However, DM increased mortality after TAVI during mid-term (≥ one year) follow-up. More detailed investigation of causes of mortality during the follow-up in DM patients may lead to improved outcome in DM patients following TAVI.

      Funding source

      None.

      Disclosures

      All authors have no disclosures.

      Acknowledgments

      None.

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