Meta-Analysis of Usefulness of Cerebral Embolic Protection During Transcatheter Aortic Valve Implantation

Abstract

One of the most feared complications of transcatheter aortic valve implantation (TAVI) is stroke, with increased mortality and disability observed in patients suffering a stroke after TAVI. There has been no significant decline in stroke rates seen over the last 5 years; attention has therefore been given to strategies for cerebral embolic protection. With the emergence of new randomized trial data, we sought to perform an updated systematic review and meta-analysis to examine the effect of cerebral embolic protection during TAVI both on clinical outcomes and on neuroimaging parameters. We performed a random-effects meta-analysis of randomized clinical trials of cerebral embolic protection during TAVI. The primary end point was the risk of stroke. The risk of stroke was not significantly different with the use of cerebral embolic protection: relative risk (RR) 0.88, 95% confidence interval (CI) 0.57 to 1.36, p = 0.566. Nor was there a significant reduction in the risk of disabling stroke, non-disabling stroke or death. There was no significant difference in total lesion volume on MRI with cerebral embolic protection: mean difference -74.94, 95% CI -174.31 to 24.4, p = 0.139. There was also not a significant difference in the number of new ischemic lesions on MRI: mean difference -2.15, 95% -5.25 to 0.96, p = 0.176, although there was significant heterogeneity for the neuroimaging outcomes. In conclusion, cerebral embolic protection during TAVI is safe but there is no evidence of a statistically significant benefit on clinical outcomes or neuroimaging parameters. One of the most feared complications of transcatheter aortic valve implantation (TAVI) is stroke, with increased mortality and disability observed in patients suffering a stroke after TAVI. There has been no significant decline in stroke rates seen over the last 5 years; attention has therefore been given to strategies for cerebral embolic protection. With the emergence of new randomized trial data, we sought to perform an updated systematic review and meta-analysis to examine the effect of cerebral embolic protection during TAVI both on clinical outcomes and on neuroimaging parameters. We performed a random-effects meta-analysis of randomized clinical trials of cerebral embolic protection during TAVI. The primary end point was the risk of stroke. The risk of stroke was not significantly different with the use of cerebral embolic protection: relative risk (RR) 0.88, 95% confidence interval (CI) 0.57 to 1.36, p = 0.566. Nor was there a significant reduction in the risk of disabling stroke, non-disabling stroke or death. There was no significant difference in total lesion volume on MRI with cerebral embolic protection: mean difference -74.94, 95% CI -174.31 to 24.4, p = 0.139. There was also not a significant difference in the number of new ischemic lesions on MRI: mean difference -2.15, 95% -5.25 to 0.96, p = 0.176, although there was significant heterogeneity for the neuroimaging outcomes. In conclusion, cerebral embolic protection during TAVI is safe but there is no evidence of a statistically significant benefit on clinical outcomes or neuroimaging parameters. The clinical trial evidence base for transcatheter aortic valve implantation (TAVI) is as compared with surgical aortic valve replacement (SAVR) has now been established across the spectrum of surgical risk.1Kapadia SR Leon MB Makkar RR Tuzcu EM Svensson LG Kodali S Webb JG Mack MJ Douglas PS Thourani VH Babaliaros VC Herrmann HC Szeto WY Pichard AD Williams MR Fontana GP Miller DC Anderson WN Akin JJ Davidson MJ Smith CR PARTNER trial investigators. 5-year outcomes of transcatheter aortic valve replacement compared with standard treatment for patients with inoperable aortic stenosis (PARTNER 1): a randomised controlled trial.Lancet. 2015; 385: 2485-2491Abstract Full Text Full Text PDF PubMed Scopus (554) Google Scholar, 2Leon MB Smith CR Mack MJ Makkar RR Svensson LG Kodali SK Thourani VH Tuzcu EM Miller DC Herrmann HC Doshi D Cohen DJ Pichard AD Kapadia S Dewey T Babaliaros V Szeto WY Williams MR Kereiakes D Zajarias A Greason KL Whisenant BK Hodson RW Moses JW Trento A Brown DL Fearon WF Pibarot P Hahn RT Jaber WA Anderson WN Alu MC Webb JG PARTNER 2 investigators. Transcatheter or surgical aortic-valve replacement in intermediate-risk patients.N Engl J Med. 2016; 374: 1609-1620Crossref PubMed Scopus (2703) Google Scholar, 3Mack MJ Leon MB Thourani VH Makkar R Kodali SK Russo M Kapadia SR Malaisrie SC Cohen DJ Pibarot P Leipsic J Hahn RT Blanke P Williams MR McCabe JM Brown DL Babaliaros V Goldman S Szeto WY Genereux P Pershad A Pocock SJ Alu MC Webb JG Smith CR PARTNER 3 investigators. Transcatheter aortic-valve replacement with a balloon-expandable valve in low-risk patients.N Engl J Med. 2019; 380: 1695-1705Crossref PubMed Scopus (1689) Google Scholar, 4Gleason TG Reardon MJ Popma JJ Deeb GM Yakubov SJ Lee JS Kleiman NS Chetcuti S Hermiller JB Heiser J Merhi W Zorn GL Tadros P Robinson N Petrossian G Hughes GC Harrison JK Conte JV Mumtaz M Oh JK Huang J Adams DH. 5-year outcomes of self-expanding transcatheter versus surgical aortic valve replacement in high-risk patients.J Am Coll Cardiol. 2018; 72: 2687-2696Crossref PubMed Scopus (148) Google Scholar, 5Popma JJ Deeb GM Yakubov SJ Mumtaz M Gada H O'Hair D Bajwa T Heiser JC Merhi W Kleiman NS Askew J Sorajja P Rovin J Chetcuti SJ Adams DH Teirstein PS Zorn GL Forrest JK Tchétché D Resar J Walton A Piazza N Ramlawi B Robinson N Petrossian G Gleason TG Oh JK Boulware MJ Qiao H Mugglin AS Reardon MJ Transcatheter aortic-valve replacement with a self-expanding valve in low-risk patients.N Engl J Med. 2019; 380: 1706-1715Crossref PubMed Scopus (1321) Google Scholar, 6Reardon MJ Van Mieghem NM Popma JJ Kleiman NS Søndergaard L Mumtaz M Adams DH Deeb GM Maini B Gada H Chetcuti S Gleason T Heiser J Lange R Merhi W Oh JK Olsen PS Piazza N Williams M Windecker S Yakubov SJ Grube E Makkar R Lee JS Conte J Vang E Nguyen H Chang Y Mugglin AS Serruys PWJC Kappetein AP Investigators SURTAVI Surgical or Transcatheter aortic-valve replacement in intermediate-risk patients.N Engl J Med. 2017; 376: 1321-1331Crossref PubMed Scopus (1452) Google Scholar One of the most feared complications of TAVI is stroke, with increased mortality and disability observed in patients suffering a stroke after TAVI.7Adams DH Popma JJ Reardon MJ Yakubov SJ Coselli JS Deeb GM Gleason TG Buchbinder M Hermiller J Kleiman NS Chetcuti S Heiser J Merhi W Zorn G Tadros P Robinson N Petrossian G Hughes GC Harrison JK Conte J Maini B Mumtaz M Chenoweth S Oh JK. Transcatheter aortic-valve replacement with a self-expanding prosthesis.N Engl J Med. 2014; 370: 1790-1798Crossref PubMed Scopus (1829) Google Scholar Furthermore, it is not known whether silent cerebral lesions may lead to deterioration in neurocognitive function in the longer-term. Despite advances in TAVI technology and technique, in-hospital stroke rates are still in the order of 2%. Attention has therefore been given to strategies for cerebral embolic protection, where devices can be employed to either filter or deflect debris during TAVI. Embolic protection devices have thus far been tested in relatively small randomized clinical trials (RCTs) only; with the emergence of new randomized trial data, we sought to perform an updated systematic review and meta-analysis to examine the effect of cerebral embolic protection during TAVI both on clinical outcomes and on neuroimaging parameters. The present analysis was performed according to published PRISMA guidance.8Moher D Liberati A Tetzlaff J Altman DG Group PRISMA Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.Ann Intern Med. 2009; 151 (W64): 264-269Crossref PubMed Scopus (14931) Google Scholar We prospectively registered the analysis at the PROSPERO international prospective register of systematic reviews (CRD42020214106). Ethical approval was not applicable in this case. We performed a systematic search of the MEDLINE, Cochrane Central Register of Controlled Trials, and Embase databases from December 2010 through October 2020 for all randomized trials comparing cerebral embolic protection to control during TAVI. Our search strings included (“severe aortic stenosis” OR “severe symptomatic aortic stenosis”) AND (“transcatheter aortic valve implantation” OR “transcatheter aortic valve replacement”) AND (“embolic protection”) OR (“cerebral protection”). We hand-searched the bibliographies of selected studies and meta-analyses to identify further eligible studies. There were no language restrictions. We also reviewed abstracts presented at conferences. Abstracts were reviewed for suitability and articles accordingly retrieved. Two independent authors performed the search and literature screening (YA and JH), with disputes resolved by consensus. Only RCTs comparing cerebral embolic protection to control were included. We did not consider observational studies The primary end point was the risk of stroke. Other clinical end points included risk of death, disabling stroke, non-disabling stroke, all bleeding, life-threatening or disabling bleeding, major vascular complications, and acute kidney injury. Neuroimaging endpoints were total lesion volume on MRI, new ischemic lesions on MRI, and the number of patients with new ischemic lesions on MRI. Two authors (YA and JH) independently abstracted the data from included trials, with disputes resolved by consensus. Tests for publication bias would only be performed in the event of 10 or more trials being suitable for inclusion.9Anon The Cochrane Collarobation. Cochrane handbook for systematic reviews of interventions - 10.4.3.1 recommendations on testing for funnel plot asymmetry.The Cochrane Collaboration. 2011; : 24-25Google Scholar Included studies were assessed using the Cochrane Risk of Bias tool.10Higgins JPT Altman DG Gøtzsche PC Jüni P Moher D Oxman AD Savovic J Schulz KF Weeks L Sterne JAC Cochrane Bias Methods Group, Cochrane Statistical Methods GroupThe Cochrane Collaboration's tool for assessing risk of bias in randomised trials.BMJ. 2011; 343: d5928Crossref PubMed Scopus (14347) Google Scholar Intention-to-treat analyses were used, with the longest follow-up time available. For clinical outcomes, we extracted event counts to calculate relative risks (RR) and performed random-effects meta-analyses using the restricted maximum likelihood estimator, with fixed effect as a sensitivity analysis. For imaging end points, we performed a random-effects meta-analysis using the mean difference in effect sizes and their associated standard errors using the restricted maximum likelihood (REML) estimator. The standard errors for the trials were calculated by dividing the difference between the upper and lower 95% confidence intervals by 2 × the appropriate normal score (1.96). Interactions between important characteristics that varied across trials were assessed by performing a mixed-effects meta-analysis with the characteristic as a moderator. We performed the same analyses with standardized mean differences as a sensitivity analysis. Medians and interquartile ranges were converted to means and standard errors using published methodology.11Hozo SP Djulbegovic B Hozo I. Estimating the mean and variance from the median, range, and the size of a sample.BMC Med Res Methodol. 2005; 5: 13Crossref PubMed Scopus (4515) Google Scholar The I2 statistic was used to assess heterogeneity.12Higgins JPT Thompson SG. Quantifying heterogeneity in a meta-analysis.Stat Med. 2002; 21: 1539-1558Crossref PubMed Scopus (18639) Google Scholar Low heterogeneity was defined as 0-25%; moderate heterogeneity was defined as 25% to 50%; and significant heterogeneity was defined as >50%. Mean values are expressed as mean ± SD unless otherwise stated. Statistical significance was set at p <0.05. The statistical programming environment R13 with the metafor package13AnonConducting meta-analyses in R with the metafor package | viechtbauer.J Statistical Software. 2017; (Available at https://www.jstatsoft.org/article/view/v036i03. Accessed October 23, 2020): 1-48PubMed Google Scholar was used for all statistical analyses. Six trials14Moses Jeffrey W. A randomized evaluation of the TriGUARD3 cerebral embolic protection device to reduce the impact of cerebral embolic lesions after transcatheter aortic valve implantation: the REFLECT II trial.Presented at: TCT. 15. 2020: 2020Google Scholar, 15Van Mieghem NM van Gils L Ahmad H van Kesteren F der Werf HW van Brueren G Storm M Lenzen M Daemen J den Heuvel AFM van Tonino P Baan J Koudstaal PJ Schipper MEI der Lugt A van Jaegere PPT de. Filter-based cerebral embolic protection with transcatheter aortic valve implantation: the randomised MISTRAL-C trial.EuroIntervention. 2016; 12: 499-507Crossref PubMed Scopus (103) Google Scholar, 16Kapadia SR Kodali S Makkar R Mehran R Lazar RM Zivadinov R Dwyer MG Jilaihawi H Virmani R Anwaruddin S Thourani VH Nazif T Mangner N Woitek F Krishnaswamy A Mick S Chakravarty T Nakamura M McCabe JM Satler L Zajarias A Szeto WY Svensson L Alu MC White RM Kraemer C Parhizgar A Leon MB Linke A Makkar R Al-Jilaihawi H Kapadia S Krishnaswamy A Tuzcu EM Mick S Kodali S Nazif T Thourani V Babaliaros V Devireddy C Mavromatis K Waksman R Satler L Pichard A Szeto W Anwaruddin S Vallabhajosyula P Giri J Herrmann H Zajarias A et al.Protection against cerebral embolism during transcatheter aortic valve replacement.J Am Coll Cardiol. 2017; 69: 367-377Crossref PubMed Scopus (253) Google Scholar, 17Haussig S Mangner N Dwyer MG Lehmkuhl L Lücke C Woitek F Holzhey DM Mohr FW Gutberlet M Zivadinov R Schuler G Linke A. Effect of a cerebral protection device on brain lesions following transcatheter aortic valve implantation in patients with severe aortic stenosis: The CLEAN-TAVI randomized clinical trial.JAMA. 2016; 316: 592Crossref PubMed Scopus (187) Google Scholar, 18Wendt D Kleinbongard P Knipp S Al-Rashid F Gedik N El Chilali K Schweter S Schlamann M Kahlert P Neuhäuser M Forsting M Erbel R Heusch G Jakob H Thielmann M Intraaortic protection from embolization in patients undergoing transaortic transcatheter aortic valve implantation.Ann Thorac Surg. 2015; 100: 686-691Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar, 19Lansky AJ Schofer J Tchetche D Stella P Pietras CG Parise H Abrams K Forrest JK Cleman M Reinöhl J Cuisset T Blackman D Bolotin G Spitzer S Kappert U Gilard M Modine T Hildick-Smith D Haude M Margolis P Brickman AM Voros S Baumbach A A prospective randomized evaluation of the TriGuard™ HDH embolic DEFLECTion device during transcatheter aortic valve implantation: results from the DEFLECT III trial.Eur Heart J. 2015; 36: 2070-2078Crossref PubMed Scopus (191) Google Scholar randomizing 856 patients were eligible for analysis. 488 patients were randomized to cerebral embolic protection and 368 patients were randomized to control. Baseline characteristics are shown in Table 1 of the Supplementary Appendix. The risk of bias assessment is shown in Table 2 of the Supplementary Appendix. The search strategy and results are shown in Figure 1 of the Supplementary Appendix. The risk of stroke was not significantly different with the use of cerebral embolic protection: RR 0.88, 95% CI 0.57 to 1.36, p = 0.566 (see Figure 1). There was no heterogeneity (I2 = 0.0%). There was also no significant difference in the risk of disabling stroke (RR 0.85, 95% CI 0.21 to 3.41, p = 0.818, Figure 2) or non-disabling stroke (RR 0.81, 95% CI 0.50 to 1.32, p = 0.396, Figure 3). Again, there was no heterogeneity for either of these outcomes (I2 = 0.0%). The risk of death was not significantly different with the use of cerebral embolic protection: RR 0.56, 95% CI 0.21 to 1.51, p = 0.255. There was no heterogeneity (I2 = 0.0%).Figure 3Effect of cerebral embolic protection on the risk of non-disabling stroke. REML = restricted maximum likelihood.View Large Image Figure ViewerDownload Hi-res image Download (PPT) The risk of all bleeding was not significantly different with the use of cerebral embolic protection (RR 0.84, 95% CI 0.55 to 1.29, p = 0.431). There was mild heterogeneity (I2=13.5%). The risk of life-threatening or disabling bleeding was also not significantly different with the use of cerebral embolic protection (RR 0.71, 95% CI 0.21 to 2.40, p = 0.587). There was mild heterogeneity (I2=14.4%). The risk of major vascular complications was not significantly different with the use of cerebral embolic protection: RR 1.04, 95% 0.62 to 1.74, p = 0.877. There was no heterogeneity (I2 = 0.0%). Nor was there any difference in the risk of acute kidney injury: RR 0.75, 95% CI 0.21 to 2.76, p = 0.668. There was mild heterogeneity (I2 = 6.2%). There was no significant difference in total lesion volume on MRI with cerebral embolic protection: mean difference -74.94, 95% CI -174.31 to 24.4, p = 0.139 (Figure 4). There was significant heterogeneity (I2 = 95.8%). There was also not a significant difference in the number of new ischemic lesions on MRI: mean difference -2.15, 95% -5.25 to 0.96, p = 0.176 (Figure 5). There was significant heterogeneity (I2 = 97.2%). There was no difference in the number of patients seen to have new ischemic lesions on MRI: RR 0.99, 95% CI 0.94 to 1.05, p = 0.794. There was no heterogeneity (I2 = 0.0%).Figure 5Effect of cerebral embolic protection on difference in new ischemic lesions. REML = restricted maximum likelihood.View Large Image Figure ViewerDownload Hi-res image Download (PPT) All results were consistent when analyzed by fixed effect (see Supplementary Appendix). Neuroimaging end points were also analyzed using standardized mean difference, the results of which are shown in the Supplementary Appendix. In this study, encompassing the totality of the randomized trial data for cerebral embolic protection during TAVI, we have shown that there is currently not a detectible statistically significant benefit of cerebral protection in terms of clinical stroke, and nor is there a statistically significant reduction in terms of total lesion volume or new cerebral lesions on MRI. The use of cerebral embolic protection appears to be safe, with no significant increase in any adverse event. Despite significant advancements in TAVI technology and techniques, stroke rates have been largely static. The TVT registry has shown no significant decline for in-hospital strokes after TAVI between 2012 and 2019 with rates of roughly 2% per year. Stroke can have clinical as as a significant and patients consider stroke the most important clinical end Y S M J R T A M M R J A new of randomised control data to the a to end J Cardiol. 2015; Full Text Full Text PDF PubMed Scopus Google Scholar There has thus been significant in strategies to reduce the risk of stroke after TAVI. that cerebral embolic protection devices have been to stroke Stroke is a relatively and the total number of patients randomized in cerebral protection trials to is meta-analysis is appropriate to their In this analysis the risk of stroke was not significantly by the use of cerebral embolic protection, although it be that this analysis is to a significant effect on clinical stroke In to stroke, embolic protection may be to embolic debris to the brain which may have on neurocognitive The results of the present analysis not a significant reduction in total lesion volume or number of new lesions on MRI. may be to device for to cerebral during protection with is also that the of of devices in the aortic can lead to debris to the thus The results of this analysis are consistent with a presented analysis from the TVT DJ embolic protection and TAVI results from the TVT at: October Google Scholar observational study, using an included over patients and no significant reduction in stroke with the use of cerebral embolic protection. also that cerebral protection was used in of patients in and with in as time the end of of were using cerebral embolic protection in over of there being no clinical trial evidence of a benefit on clinical outcomes. There not to be a for using cerebral embolic protection, with no increased risk of major adverse seen in this analysis as vascular complications or acute kidney injury. there may be more significant to use of embolic of of patients randomized clinical trials to an effect on clinical outcomes cerebral embolic protection as of clinical to patients in order that a can be on the of cerebral embolic protection during TAVI. We only the data, and there are only trials randomizing a total of 856 The of device are not across trials, with devices being to debris and being is a of although there was or heterogeneity observed for clinical outcomes. trials are to a more on the of cerebral embolic protection during TAVI. to patients these the results of the clinical trials is this analysis the evidence in the is a we not whether there are of patients may benefit from embolic protection. is that there are which may lead to benefit with cerebral protection, as stroke, aortic or valve data meta-analysis may to of these We also did not perform analysis by of embolic protection device or of TAVI to the small number of trials and One of the included trials has not been the results significantly in the published we this analysis analysis only randomized trials which a spectrum of patients seen in clinical this can the of RCTs and meta-analysis of these trials, is the only to the and of the impact of bias from both and Our analysis is also consistent with a observational using to In conclusion, cerebral embolic protection during TAVI is safe but there is no evidence of a statistically significant benefit on clinical outcomes or neuroimaging parameters. The use of cerebral embolic protection during TAVI be restricted to randomized clinical trials, or in selected high-risk where clinical a The authors that have no known or that have to the in this Download with

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