Giuseppe Gargiulo, MD (*); Anna Sannino, MD (*); Davide Capodanno, MD, PhD; Marco Barbanti, MD; Sergio Buccheri, MD; Cinzia Perrino, MD, PhD; Piera Capranzano, MD; Ciro Indolfi, MD, PhD; Bruno Trimarco, MD; Corrado Tamburino, MD, PhD; Giovanni Esposito, MD, PhD
Grant Support: The authors are funded by their academic institutions.
Disclosures: Dr. Gargiulo reports grants from the CardioPath PhD Program, Federico II University of Naples, and from the European Association of Percutaneous Coronary Interventions, outside the submitted work. Dr. Barbanti is a consultant for Edwards Lifesciences. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M16-0060.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that she has no financial relationships or interests to disclose. Darren B. Taichman, MD, PhD, Executive Deputy Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer.
Reproducible Research Statement:Study protocol: See Supplement 1. Statistical code and data set: Available from Dr. Gargiulo (e-mail, firstname.lastname@example.org or email@example.com).
Requests for Single Reprints: Giovanni Esposito, MD, PhD, Division of Cardiology, Department of Advanced Biomedical Sciences, Federico II University of Naples, Via Pansini 5, 80131 Naples, Italy; e-mail, firstname.lastname@example.org.
Current Author Addresses: Dr. Gargiulo, Dr. Perrino, Prof. Trimarco, and Prof. Esposito: Division of Cardiology, Department of Advanced Biomedical Sciences, Federico II University of Naples, Via Pansini 5, 80131 Naples, Italy.
Dr. Sannino: Baylor Research Institute, Baylor Heart and Vascular Hospital, 621 North Hall Street, Dallas, TX 75226.
Prof. Capodanno; Drs. Barbanti, Buccheri, and Capranzano; and Prof. Tamburino: Department of General Surgery and Medical–Surgical Specialties, University of Catania, c/o Ospedale Ferrarotto, Via Salvatore Citelli 31, 95124 Catania, Italy.
Prof. Indolfi: Department of Medical and Surgical Sciences and URT Consiglio Nazionale delle Ricerche, Magna Graecia University, Viale Europa, Catanzaro 88100, Italy.
Author Contributions: Conception and design: G. Gargiulo, A. Sannino, D. Capodanno, G. Esposito.
Analysis and interpretation of the data: G. Gargiulo, A. Sannino, D. Capodanno, S. Buccheri, C. Perrino, P. Capranzano, B. Trimarco, C. Tamburino, G. Esposito.
Drafting of the article: G. Gargiulo, A. Sannino.
Critical revision for important intellectual content: G. Gargiulo, D. Capodanno, S. Buccheri, P. Capranzano, C. Indolfi, B. Trimarco, C. Tamburino.
Final approval of the article: G. Gargiulo, A. Sannino, D. Capodanno, M. Barbanti, S. Buccheri, C. Perrino, P. Capranzano, C. Indolfi, B. Trimarco, C. Tamburino, G. Esposito.
Statistical expertise: G. Gargiulo, D. Capodanno.
Collection and assembly of data: G. Gargiulo, A. Sannino.
The comparative benefits and harms of transcatheter aortic valve implantation (TAVI) and surgical aortic valve replacement (SAVR) for patients with aortic stenosis are unclear.
To compare clinical outcomes, including early (≤30-day) and midterm (≤1-year) mortality, in adults with severe aortic stenosis undergoing either TAVI or SAVR.
MEDLINE, Cochrane, and Scopus databases (without language restrictions) from April 2002 to 5 April 2016; multiple registries and Web sites; scientific meeting presentations.
Five randomized trials and 31 observational matched studies comparing mortality outcomes after TAVI or SAVR.
Two investigators independently extracted study data and rated risk of bias.
16 638 patients were analyzed. Overall, there was no statistically significant difference between TAVI and SAVR in early (odds ratio [OR], 1.01 [95% CI, 0.81 to 1.26]) or midterm (OR, 0.96 [CI, 0.81 to 1.14]) all-cause mortality. Analyses restricted to trials (early: OR, 0.80 [CI, 0.51 to 1.25]; midterm: OR, 0.90 [CI, 0.64 to 1.26]) were inconclusive, with wide CIs, whereas analyses of matched studies were similar to the overall results. Transfemoral TAVI provided mortality benefits over SAVR in trials. Analyses restricted to studies of patients at low to intermediate risk showed statistically nonsignificant reductions in early (OR, 0.67 [CI, 0.42 to 1.07]) and midterm (OR, 0.91 [CI, 0.67 to 1.23]) mortality with TAVI. Incidence of periprocedural myocardial infarction, major bleeding, acute kidney injury, and new-onset atrial fibrillation was lower with TAVI, but risk for pacemaker implantation, vascular complications, and paravalvular leak increased. Overall, there was a statistically nonsignificant increased risk in long-term (2- to 5-year) all-cause mortality with TAVI (OR, 1.28 [CI, 0.97 to 1.69]), whereas long-term mortality outcomes in patients at low to intermediate risk were inconclusive, with wide CIs (OR, 1.06 [CI, 0.59 to 1.91]).
The number of trials was limited, and study designs and patient characteristics were heterogeneous.
Compared with SAVR, TAVI may have similar or better early and midterm outcomes for adults with aortic stenosis, including those at low to intermediate risk.
Table. Characteristics of the Randomized Trials*
Forest plot for early all-cause mortality in the overall population.
Knapp–Hartung random-effects OR and 95% CI for 30-day all-cause mortality stratified by study design. NOTION = Nordic Aortic Valve Intervention; OR = odds ratio; PARTNER = Placement of Aortic Transcatheter Valves; SAVR = surgical aortic valve replacement; STACCATO = A Prospective, Randomised Trial of Transapical Transcatheter Aortic Valve Implantation Versus Surgical Aortic Valve Replacement in Operable Elderly Patients With Aortic Stenosis; TAVI = transcatheter aortic valve implantation.
* Percentages do not sum to 18.3% and 81.7% for randomized and matched studies, respectively, because of rounding.
Forest plot for midterm all-cause mortality in the overall population.
Knapp–Hartung random-effects OR and 95% CI for midterm all-cause mortality stratified by study design. NOTION = Nordic Aortic Valve Intervention; OR = odds ratio; PARTNER = Placement of Aortic Transcatheter Valves; SAVR = surgical aortic valve replacement; STACCATO = A Prospective, Randomised Trial of Transapical Transcatheter Aortic Valve Implantation Versus Surgical Aortic Valve Replacement in Operable Elderly Patients With Aortic Stenosis; TAVI = transcatheter aortic valve implantation.
Forest plots for all-cause mortality in the low- to intermediate-risk population.
Knapp–Hartung random-effects OR and 95% CI for 30-day (top), midterm (middle), and long-term (bottom) all-cause mortality in patients at low to intermediate risk. NOTION = Nordic Aortic Valve Intervention; OR = odds ratio; PARTNER = Placement of Aortic Transcatheter Valves; SAVR = surgical aortic valve replacement; TAVI = transcatheter aortic valve implantation.
* Percentages do not sum to 100% for early all-cause mortality because of rounding.
Forest plot for all outcomes of the meta-analysis.
Summary of Knapp–Hartung random-effects OR and 95% CI for all end points, including forest plots and details of studies and participants. AKI = acute kidney injury; CV = cardiovascular; MI = myocardial infarction; NOAF = new-onset atrial fibrillation; OR = odds ratio; Pint = interaction P value; PM = pacemaker; SAVR = surgical aortic valve replacement; TAVI = transcatheter aortic valve implantation.
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Author Insight Video - Giovanni Esposito, MD, PhD
Xinlin Zhang, Biao Xu
Affiliated Drum Tower Hospital, Nanjing University School of Medicine
August 14, 2016
Transcatheter Aortic Valve Implantation Versus Surgical Aortic Valve Replacement
The meta-analysis by Gargiulo and colleagues recently published in the Journal compared transcatheter aortic valve implantation (TAVI) with surgical aortic valve replacement (SAVR) in both low-to-intermediate-risk and high-risk patients with severe aortic stenosis . The authors conclude that the early and midterm all-cause mortality was similar between TAVI and SAVR, but TAVI was associated with a statistically nonsignificant increased risk of long-term mortality. Their conclusion on long-term mortality was questionable because the overall result was mainly driven by data from observational studies, which causes significant heterogeneity and shows significant subgroup interaction between randomized trials and observational studies. Although all observational studies included were matched studies, residual confounding that cannot be removed without a randomized design still exist. Therefore, analyses should be separately performed and conclusions be separately made. Also in the analyses of patients at low to intermediate risk, the authors did not perform separate analysis for randomized trials and observational studies. These results should be interpreted with caution.Meanwhile, for the long-term analysis, unlike short-term outcome with similar period of follow-up, there was considerable variability in the length of follow-up for each of these trials. Therefore, the analysis of long-term outcomes should incorporate the duration of the trials, which however, was not performed in the analysis by Gargiulo and colleagues. Rates (for instance the rate of outcomes per 1000 person years), rather than number of events, may be more appropriate. Also, given the lack of data on the predictors of long-term outcomes at this point of time, we would like to know the metaregression results of long-term mortality.A number of cohort studies  and a patient-level meta-analysis  suggested that female sex was independently associated with improved survival (reduced mortality) at midterm follow-up of 1 year following TAVI. However, in this study by Gargiulo and colleagues , metaregression analysis showed that male sex was associated with an improved midterm treatment effect of TAVI. Can the authors provide a possible explanation for these opposite findings? Finally, the authors found that transfemoral TAVI provided mortality benefits over SAVR in randomized trials, but did not provide any data from observational studies. It would be interesting to know whether this observation is concordant in observational studies, which always have larger sample size and are important complements to randomized trials.References: Gargiulo G, Sannino A, Capodanno D, Barbanti M, Buccheri S, Perrino C, et al. Transcatheter aortic valve implantation versus surgical aortic valve replacement: a systematic review and meta-analysis. Ann Intern Med. 2016. [PMID: 27272666] doi:10.7326/M16-0060 Kodali S, Williams MR, Doshi D, Hahn RT, Humphries KH, Nkomo VT, et al. Sex-specific differences at presentation and outcomes among patients undergoing transcatheter aortic valve replacement: a cohort study. Ann Intern Med. 2016;164:377-84. [PMID: 26903039] doi: 10.7326/M15-0121 O'Connor SA, Morice MC, Gilard M, Leon MB, Webb JG, Dvir D, Rodés-Cabau J, et al. Revisiting sex equality with transcatheter aortic valve replacement outcomes: a collaborative, patient-level meta-analysis of 11,310 patients. J Am Coll Cardiol. 2015;66:221-8. [PMID: 26184614] doi: 10.1016/j.jacc.2015.05.024
Marat Fudim MD, Gerald S. Bloomfield MD, Zainab Samad MD
Duke University Medical Center, Department of Cardiology
September 30, 2016
Transcatheter Aortic Valve Implantation versus Surgical Aortic Valve Replacement
TO THE EDITOR: We commend Gargiulo and colleagues for the systematic review and meta-analysis of the literature on transcatheter aortic valve implantation (TAVI) and surgical aortic valve replacement (SAVR) (1). The authors compare short and long-term clinical outcomes as well as harms of both therapies. Despite limited number of eligible studies, their findings suggest that TAVI tends to perform as well as SAVR in the general population. The authors report that TAVI use trends towards better short (≤30 days) and midterm (≤1 year) outcomes in low to intermediate risk patients. These findings have been most recently supported by the PARTNER 2 trial, which was included in this analysis (2). The comparable hemodynamic profile of prosthetic valves and effects on postoperative left ventricular function and remodeling also supports the equivalent effectiveness of TAVI and SAVR. In a review of more than 67 studies, Kim and colleagues (3) found that TAVI is at least equivalent if not superior over SAVR in regards to hemodynamic performance of the valve as measured by post-operative trans-aortic valve gradients decrease. Further, TAVI was less likely to result in prosthesis-patient mismatch, a known driver of perioperative and postoperative mortality (4). There was no difference in effects on left ventricular function but SAVR appeared to regress the left ventricular mass more so than TAVI. It remains unclear to what extent hemodynamic and functional differences between TAVI and SAVR contribute to the observed differences in clinical outcomes. The growing extension of TAVI towards low and lower risk patients, lends greater impetus towards understanding this relationship. Future studies need to link hemodynamic/functional data directly to outcomes in order to understand potential mechanisms of clinical outcomes. To do so, will require public-private partnerships with unrestricted data sharing between institutions and companies and groups of investigators working together with access to patient level data from multiple studies (5). References1. Gargiulo G, Sannino A, Capodanno D et al. Transcatheter Aortic Valve Implantation Versus Surgical Aortic Valve Replacement: A Systematic Review and Meta-analysis. Annals of internal medicine 2016;165:334-44.2. Leon MB, Smith CR, Mack MJ et al. Transcatheter or Surgical Aortic-Valve Replacement in Intermediate-Risk Patients. The New England journal of medicine 2016;374:1609-20.3. Kim SJ, Samad Z, Bloomfield GS, Douglas PS. A critical review of hemodynamic changes and left ventricular remodeling after surgical aortic valve replacement and percutaneous aortic valve replacement. American heart journal 2014;168:150-9 e1-7.4. Dayan V, Vignolo G, Soca G, Paganini JJ, Brusich D, Pibarot P. Predictors and Outcomes of Prosthesis-Patient Mismatch After Aortic Valve Replacement. JACC Cardiovascular imaging 2016;9:924-33.5. Academic Research Organization Consortium for Continuing Evaluation of Scientific S-C, Patel MR, Armstrong PW et al. Sharing Data from Cardiovascular Clinical Trials--A Proposal. The New England journal of medicine 2016;375:407-9.
Giuseppe Gargiulo, MD, Davide Capodanno, MD, PhD, Corrado Tamburino, MD, PhD, Bruno Trimarco, MD, PhD, Giovanni Esposito, MD, PhD.
Federico II University, Ferrarotto Hospital
February 17, 2017
We thank Xinlin Zhang and Biao Xu, and Marat Fudim and colleagues for their interest in our meta-analysis.(1) We agree with Zhang and Xu that long-term outcomes represent the most awaited information from future studies comparing TAVI and SAVR. Indeed, our study sets long-term mortality as a secondary exploratory endpoint to refrain from over-interpretation, and our conclusions are focused on early and mid-term follow-up considerations. Zhang and Xu should note in our paper the statement that the effects of TAVI on long-term mortality remain unclear and may reflect the individual underlying risk and the TAVI approach used. Our study is transparent in reporting that the observed nonsignificant increase in long-term mortality with TAVI was solely driven by matched studies with significant heterogeneity related to study design. Indeed, randomized trials did not show significant differences in long-term mortality, and TAVI proved better than SAVR when transfemoral procedures were considered,(1) which is consistent with another recent meta-analysis.(2) We used the longest follow-up from available studies to depict the most comprehensive description of currently available mortality data. Risk measures were used to account for the heterogeneity in follow-up availability. Notably, when analyzing rates per patient/year as suggested, findings remained consistent (Poisson regression incidence rate ratio: 1.17 [0.97-1.42]; p=0.10; interaction p between randomized and matched studies=0.006). Zhang and Xu should consider anyway that this kind of analysis has relevant limitations when data are aggregated at the study level, being more suitable for individual patient-level data.(3)The subanalysis of low-to-intermediate risk patients was exploratory and consistent with the main analysis, which we believe may be informative for current and future daily practice. Indeed, only two of the 8 studies were randomized and stratification by trial design did not display significant subgroup heterogeneity (interaction p=0.26 and 0.83 for early and midterm mortality, respectively). We respectfully disagree with the comments of Zhang and Xu regarding meta-regression analyses, sharing the methodological concerns broadly discussed elsewhere.(4,5) Our study-level data are not best suited for exploring predictors of long-term mortality or the impact of gender. We limited our observation to potential effect modifiers that could explain heterogeneity findings. Meta-regressions are useful to identify potential sources of inconsistency but should not be over-interpreted.(4,5) Subgroups of randomized trials did not show gender-by-treatment effect interactions, and future larger analyses of patient-level data are necessary to better study this interaction, if any.We share with Fudim and Marat the opinion that the relationship between the hemodynamic profiles of the prosthetic surgical or percutaneous valves on one hand, and subsequent clinical outcomes on the other hand, is of paramount importance and warrants further mechanistic investigation. References1. Gargiulo G, Sannino A, Capodanno D et al. Transcatheter Aortic Valve Implantation Versus Surgical Aortic Valve Replacement: A Systematic Review and Meta-analysis. Annals of internal medicine 2016;165:334-44.2. Siontis GC, Praz F, Pilgrim T, et al. Transcatheter aortic valve implantation vs. surgical aortic valve replacement for treatment of severe aortic stenosis: a meta-analysis of randomized trials. Eur Heart J. 2016 Jul 7. pii: ehw225. [Epub ahead of print]3. Stewart LA, Clarke M, Rovers M, et al. PRISMA-IPD Development Group. Preferred Reporting Items for Systematic Review and Meta-Analyses of individual participant data: the PRISMA-IPD Statement. JAMA. 2015 Apr 28;313(16):1657-65.4. Thompson SG, Higgins JP. How should meta-regression analyses be undertaken and interpreted? Stat Med. 2002 Jun 15;21(11):1559-73.5. Thompson SG, Higgins JP. Treating individuals 4: can meta-analysis help target interventions at individuals most likely to benefit? Lancet. 2005 Jan 22-28;365(9456):341-6.
Gargiulo G, Sannino A, Capodanno D, Barbanti M, Buccheri S, Perrino C, et al. Transcatheter Aortic Valve Implantation Versus Surgical Aortic Valve Replacement: A Systematic Review and Meta-analysis. Ann Intern Med. 2016;165:334-344. doi: 10.7326/M16-0060
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Published: Ann Intern Med. 2016;165(5):334-344.
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