- Email: [email protected]
Transcatheter Aortic Valve Implantation in Intermediate Surgical Risk Patients With Severe Aortic Stenosis: A Systematic Review and Meta-Analysis
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ORIGINAL ARTICLE
Heart, Lung and Circulation (2017) xx, 1–8 1443-9506/04/$36.00 http://dx.doi.org/10.1016/j.hlc.2017.02.032
Transcatheter Aortic Valve Implantation in Intermediate Surgical Risk Patients with Severe Aortic Stenosis: A Systematic Review and Meta-Analysis
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Kuljit Singh, MBBS, FRACP, PhD a,b*, Kristin Carson, PhD a, Mohammed K. Rashid, MD Candidate c[,10_TD$IF] Rohan Jayasinghe, MBBS, PhD a, Abdulrahman AlQahtani, MD c, Alexander Dick, MD c, Christopher Glover, MD c, Marino Labinaz, MD c a
University of Adelaide, Adelaide, SA, Australia Gold Coast University Hospital, Brisbane, Qld, Australia c University of Ottawa Heart Institute, Ottawa, Ontario, Canada b
Received 26 May 2016; received in revised form 15 November 2016; accepted 28 February 2017; online published-ahead-of-print xxx
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[13_TD$IF]Background
Recent data from randomised and observational studies have reported non-inferior outcomes for transcatheter aortic valve implantation (TAVI) compared to surgical aortic valve replacement (SAVR) in intermediate-risk patients. We performed a systematic review to evaluate the mortality of TAVI compared to SAVR in intermediate-risk patients.
Methods
A comprehensive search of four major databases (EMBASE, Ovid MEDLINE, PubMed, and Google Scholar) was performed from their inception to 29 April 2016. We included original research studies reporting data on TAVI and SAVR in intermediate-risk patients. We compared the outcomes of TAVI to SAVR.
Results
A total of 2,375 and 2,377 intermediate-risk patients underwent TAVI and SAVR respectively. The 30-day all-cause (p = 0.07), 30-day cardiac (p = 0.53), and 12-month all-cause mortality (p = 0.34) was similar between two groups. However, TAVI through transfemoral access had a significantly lower mortality than SAVR (OR 0.58, p = 0.006). The incidence of [14_TD$IF]moderate aortic incompetence (p [15_TD$IF]< 0.00001) and pacemaker implantation (p [16_TD$IF]< 0.0001) was higher in the TAVI group.
Conclusions
In the intermediate-risk patients, the 30-day and 12-month mortality are similar between TAVI and SAVR. Increased operator experience and improved device technology have led to a significant reduction in mortality in intermediate-risk patients undergoing TAVI.
Keywords
Transcatheter aortic valve implantation Transcatheter aortic valve replacement Intermediate-risk Low-risk High-risk
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Transcatheter aortic valve implantation (TAVI) has become the default approach for patients with severe aortic stenosis (AS) who are either inoperable or at high-risk for surgical aortic valve replacement (SAVR). Evidence relating to the
superiority of TAVI over medical therapy comes from the PARTNER Cohort B trial where mortality at one-year in patients undergoing TAVI was significantly reduced compared to medical treatment [1]. Similar results were shown by
*Corresponding author at: Interventional Cardiologist, Gold Coast University Hospital, Southport QLD 4215, & Senior Lecturer, University of Adelaide, Adelaide, South Australia, [12_TD$IF]5000, Australia. Phone +61 433 698 945, Fax: +61 4312 4919., Email: [email protected] © 2017 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Singh K, et al. Transcatheter Aortic Valve Implantation in Intermediate Surgical Risk Patients with Severe Aortic Stenosis: A Systematic Review and Meta-Analysis. Heart, Lung and Circulation (2017), http://dx.doi.org/ 10.1016/j.hlc.2017.02.032
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the Core Valve United States Pivotal Trial Extreme-Risk study, a prospective single-arm study comparing the Medtronic Core Valve to a prespecified goal [2]. Current guidelines recommend SAVR for severe AS in patients with low or intermediate surgical risk. The surgical risk in a patient with severe AS is defined using the Society of Thoracic Surgeons Risk Calculator (STS) and EuroSCORE. However, these risk scores do not take into consideration multiple factors that may increase the risk related to surgery. Patient frailty, cognitive impairment, the risk of delirium, anatomical characteristics, such as a porcelain aorta and social support postdischarge, are some of the factors that are not evaluated in the traditional risk scores. Hence, many patients who are in the intermediate-risk for SAVR are offered TAVI procedure. This issue is complicated, and the Heart Team, which consists of cardiologists and surgeons, makes decisions in such cases in consensus. Furthermore, developments in technology, such as, smaller sheath sizes, and repositionable TAVI valves, have led to a reduction in the rate of complications associated with TAVI [3–5]. In the randomised NOTION trial, no significant difference between TAVI and SAVR was found for the composite rate of death from any cause, stroke, or MI after one year [6]. While randomised trials have started enrolling low to intermediate risk patients for TAVI, there are already multiple observational studies that have assessed TAVI in the intermediate and low-risk groups using propensity-based analyses [7,8]. Using the currently available literature, we performed a systematic review and a meta-analysis to compare TAVI with SAVR in the intermediate risk patients with severe AS to compare 30-day and 12-[17_TD$IF]month mortality.
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Methods
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This systematic review and meta-analysis are reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement guidelines [9].
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Study Eligibility
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We performed a search for studies looking at outcomes of intermediate risk patients undergoing TAVI or SAVR. We included all studies that compared outcomes of TAVI to SAVR in the intermediate risk group. We included studies using STS and/or Logistic EuroSCORE to define surgical risk in AS patients. Low-risk, intermediate-risk, and high risk was defined as STS score of <4%, 4–8%, and >8%, respectively. Similarly, low, intermediate, and high risk were defined as logistic EuroSCORE of <10%, 10–20%, and >20%, respectively. Device success was defined according to the Valve Academic Research Consortium-2 (VARC-2) definition as the absence of procedural mortality and correct positioning of a single prosthetic heart valve into the proper anatomical location and intended performance of the prosthetic heart valve (no prosthesis-patient mismatch and mean aortic valve gradient <20 mmHg or peak velocity <3 m/s, and no moderate or severe prosthetic valve regurgitation) [10].
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62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77
We included comparative studies of any design (randomised control trials, cohort, case-control, and cross-sectional). However, in the case of observational studies, only data from propensity score matched cohort was obtained. Observational studies where no matching was performed between the SAVR and TAVI groups for basic characteristics were excluded from the analysis. This was done to reduce the bias between the TAVI and surgical groups. Eligible studies had to provide documentation of the essential features of patients in the TAVI and SAVR groups and mean or median risk scores for the two groups. Included studies also had to report significant complications following both procedures. Studies had to report one or more of the following outcomes: mortality, stroke rate, post-procedure aortic regurgitation, the rate of post-procedure permanent pacemaker implantation, post-procedure myocardial infarction, and rate of acute kidney injury. Furthermore, only studies with 10 patients were considered eligible. Inclusion was restricted to publications in the English language or when the translation of the foreign language publications was provided. When data were reported from overlapping study samples (e.g., multiple publications from the same group), the most recent study or the one with the highest number of patients was included in the analysis. Single case reports and previous systematic reviews on TAVI were not included.
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Data Sources and Search Strategy
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A comprehensive search strategy was designed before commencing the search. A thorough computer-based search was performed using Ovid MEDLINE, EMBASE, Google Scholar, and PubMed databases. Search terms included [18_TD$IF] (‘transcatheter aorta valve implantation[19_TD$IF]’ OR ‘transcatheter aortic valve replacement[20_TD$IF]’ OR ‘tavi’ OR tavr AND (‘low risk’ OR ‘intermediate risk[21_TD$IF]’)) and (Mortality or Mortalit* or Death*or Fatalit* or Incidence* or Prevalence* or Statistic*). No limit to the start date was applied, and the search was conducted up to 29 April 2016. We hand-searched references cited in the previous reviews and relevant articles on TAVI.
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Study Selection and Data Extraction
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Two reviewers (KS and AQ) screened all titles and abstracts independently. This was followed by the full-text review of the selected articles by the same two reviewers. One reviewer (KS) extracted data independently from selected studies using a standardised, pilot-tested, extraction template. The following data were extracted: study characteristics (author, country, study design, study population, number of participants, and objective of the study); participant characteristics (age and gender); and clinical characteristics (in-hospital mortality, rate of post-procedure myocardial infarction, moderate to severe aortic regurgitation, rate of permanent pacemaker implantation, stroke and acute kidney injury).
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Quality Assessment
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We assessed publication bias by visual inspection of funnel plots and by calculation of the p value (one-sided) for Egger’s
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Please cite this article in press as: Singh K, et al. Transcatheter Aortic Valve Implantation in Intermediate Surgical Risk Patients with Severe Aortic Stenosis: A Systematic Review and Meta-Analysis. Heart, Lung and Circulation (2017), http://dx.doi.org/ 10.1016/j.hlc.2017.02.032
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105 106 107 108 109 110 111 112 113 114
117 118 119 120 121 122 123 124 125 126 127
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intercept. Two independent reviewers (KC and MR) assessed the quality of included studies. In the case of studies with randomised design we used six quality domains relevant to a meta-analysis. In the case of observational studies, quality of included studies was analysed using a sub-set of the Tooth et al., manuscript titled ‘Quality of Reporting of Observational Longitudinal Research’[2_TD$IF]1 [11], including only the 23 quality domains relevant to a meta-analysis of observational studies. We assessed biases using classifications of ‘‘low risk of bias” when data for the criterion were reported, ‘‘high risk of bias” when data were not reported, and ‘‘unclear risk of bias” when the criterion was not relevant to the study design. Review Manager (RevMan, Computer program, Version 5.2, Copenhagen, The Nordic Cochrane Centre, The Cochrane Collaboration, 2012), was used to generate the risk of bias graph. Disagreements between reviewers for classifications were resolved by either consensus or inclusion of a third party.
was assessed by a combination of the I2 statistic, Cochran[23_TD$IF]’ s Q test, and observation of the data for each outcome. The random effect model was used in case of significant heterogeneity (I2 40) and the fixed effect model was used when heterogeneity was low (I2 < 40). If formal meta-analysis was not possible because of a skewed distribution of the number of patients between each study, we disregarded the individual studies and used data as if obtained from a single study. Studies with missing data were excluded from meta-analyses and details extrapolated in the quality and risk of bias assessments. Significant interaction between variables was considered when p < 0.05. All calculations were performed using Review Manager software, version 5.2.
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Results
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Literature Identification
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Statistical Analysis
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Continuous variables are reported as mean SD, whereas skewed data are described as median interquartile range. The measure for estimating the common effect across the included studies was the odds ratio (OR) for binary outcomes and the mean difference for continuous outcomes. Categorical variables are reported using odds ratios (ORs) with 95% confidence intervals (CIs). Heterogeneity between studies
The literature search yielded 7759 citations on TAVI, of which 171 citations were from studies involving TAVI performance in low and intermediate risk groups ([1_TD$IF]Figure 1). Full text was reviewed for 171 shortlisted citations, and 66 articles were chosen for inclusion and exclusion criteria. Of the 66 full-text manuscripts considered for eligibility, eight studies reported comparative data on outcomes of TAVI and SAVR in the intermediate risk group [6–8,12–16].
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[1_TD$IF]Figure 1 Flow chart of search strategy. Abbreviations: TAVI, Transcatheter Aortic Valve Implantation; SAVR, Surgical Aortic Valve Replacement; STS, Society of Thoracic Surgeons; OR, Odds Ratio; MD, Mean Difference; CI, Confidence Interval
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172 173 174 175 176 177 178
Clinical Characteristics
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Other than the PARTNER IIA trial, which enrolled patients from the United States and Canada, all remaining studies included were from Europe and published in the last four years (2012–2016). Three included studies had a randomised design [6,12,16] and the rest were observational in nature. Among the observational studies, we only analysed the propensity score matched data to reduce bias. Among the eight included studies, a total of 34,040 patients who underwent either TAVI or SAVR were evaluated for inclusion/exclusion, and 7221 patients were incorporated in the analysis. After exclusion of the participants who were not matched, we included 4752 intermediate surgical risk patients in the current systematic review, of which 2375 underwent TAVI procedure, and 2377 underwent SAVR. The average age, gender distribution, mean EuroSCORE and STS score are shown in Table 1. Three studies utilised a transfemoral approach exclusively [6,7,15], one study used a transapical approach [12], and the remaining three studies [8,13,14,16] utilised both transfemoral and transapical access. Both balloon-expandable and self-expandable TAVI valves were used in five studies [7,8,13–15], while two studies [12,16] utilised only balloon-expandable, and one study [6] employed only a selfexpandable valve. There was no difference between the TAVI and SAVR groups with regards to the presence of NYHA II symptoms (86% vs. 86%), previous history of hypertension (74% vs. 72%), diabetes (31% vs. 29%), stroke (25% vs. 24%), and myocardial infarction (16% vs. 16%), (Table 2). Similarly,
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Please cite this article in press as: Singh K, et al. Transcatheter Aortic Valve Implantation in Intermediate Surgical Risk Patients with Severe Aortic Stenosis: A Systematic Review and Meta-Analysis. Heart, Lung and Circulation (2017), http://dx.doi.org/ 10.1016/j.hlc.2017.02.032
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NA
5.8 1.9
3.4 1.2
NA
Abbreviations: TAVI, Transcatheter Aortic Valve Implantation; SAVR, Surgical Aortic Valve Replacement; STS, Society of Thoracic Surgeons; USA, United States of America.
5.8 2.1
NA 8.8 2.8
NA NA
8.7 2.7 111 (51.4) 101 (46.3)
548 (54.2)
78.2 4.6
81.7 6.7
78.3 5.2 216 216 432
2032
Germany 2015
2016
USA/Canada
1011
1021
81.5 6.7
560 (54.8)
NA
3.1 1.5 10.3 5.8
13.2 2.8 13 2.4
9.4 3.1 12 (33.3)
230 (48.9)
9 (26.5)
230 (48.9)
82 4.4
78.6 5.4
80 3.6
77.2 6.2
36 34
470
70
940
Denmark 2012
2015
Germany
470
NA
3.1 1.7
4.6 2.63 4.57 2.28
NA 9.4 10.4
24.4 13.4 23.2 15.1
8.8 9.5 80 (60.1)
49 (44.1)
83 (62.4)
49 (44.1)
78.8 6.9
79.4 3
79.4 7.4
80.5 6.9
133
111
133
111
266
[5_TD$IF]3–8%
2.9 1.6 8.9 5.5 8.4 4 71 (52.6) 78 (53.8)
99 (38.8)
79 4.7
80.6 5.7
135
79.2 4.9
79.7 4.9
SAVR EuroSCORE
TAVI
145
222
Schymik et al.
258
Leon et al.
257
7
255 256
8
254
Nielsen et al.
253
Bestehorn et al.
252
5
251
6
250
by meta-analysis there was no difference in the EuroSCORE between the TAVI and SAVR groups (MD 0.21, 95% CI 0.48–0.05, I2 = 0%, p = 0.12) (Figure 2).
Mortality
Italy
249
2012
248
Latib et al.
247
4
246
Netherlands Italy
245
2012
244
D’Errigo et al.
243
3
242
510
240 241
280
239
Denmark/Sweden
238
Switzerland/Germany/
237
2015
236
Thyregod et al.
235
Piazza et al.
234
1
233
2
232
SAVR
231
TAVI
230
SAVR
229
TAVI
228
SAVR
227
TAVI
226
Men (%)
224 225
Age SD
223
Number
222
Total
221
Country
220
Year
219
Author
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Table 1 Basic characteristic of the studies included in the first part of the review comparing outcomes between TAVI and SAVR.
215
255
214
255
213
2013
212
17.62 11.7
STS Score
211
17.29 9.1
210
TAVI
SAVR
209
104 (40.8)
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At 30 days, there were 84 (3.5%) deaths in the TAVI group and 109 (4.6%) deaths in the SAVR group. The numbers of cardiac deaths were lower in the TAVI (2.5%, 41/1650) group compared to the SAVR group (2.8%, 47/1652). Looking at studies reporting 12-month mortality, more than 11% of patients had died in both groups by 12 months (TAVR 173/1501 vs. SAVR 183/1445). The 30-day all-cause mortality was lower in patients undergoing TAVI compared to SAVR, but this did not reach a statistically significant level (OR 0.76, 95% CI 0.57–1.02, I2[1_TD$IF] = 25%, p = 0.07) ([1_TD$IF]Figure 3a). However, when ‘‘trans-femoral TAVI” outcomes were compared to SAVR, the all-cause 30-day mortality was significantly lower in the TAVI group (OR 0.58, 95% CI 0.38–0.85, I2 = 0%, p = 0.006) (Figure 4). However, there was no difference in 30-day cardiac mortality (OR 0.87, 95% CI 0.57–1.33, I2[1_TD$IF] = 0%, p = 0.53) (supplementary file) and 12-month all-cause mortality (OR 0.90, 95% CI 0.72–1.12, I2 = 0%, p = 0.34) (Figure 3b) between the two groups. Also, there was no difference in the 12-month cardiac mortality (OR 0.92, 95% CI 0.40–2.12, I2[1_TD$IF] = 49%, p = 0.85).
Complications There was no significant difference in the stroke events between the two groups [(TAVI 68/1650, 4.1% vs. SAVR 79/1652, 4.8%), (OR 0.86, 95% CI 0.62–1.20, I2 = 0%, p = 0.37)](supplementary file). Post-procedure, any form of aortic incompetence was significantly higher in the TAVI group (464/1434, 32%) as compared to the SAVR group (69/1436, 4.8%), (OR 11.88, 95% CI 6.33–22.30, I2 = 73%, p < 0.00001) (supplementary file). Similarly, the presence of moderate to severe aortic incompetence in the TAVI group (73/1650, 4.4%) was significantly higher than the SAVR group (10/1652, 0.6%), (OR 6.61, 95% CI 3.46–12.65, I2 = 0%, p < 0.0001) (supplementary file). New pacemaker implantation rate was significantly higher in the TAVI group (192/1650, 11.6% vs. 85/1652, 5.1%) (OR 4.85, 95% CI 1.68–14.00, I2 = 60%, p < 0.00001) (supplementary file).
[24_TD$IF]Quality Assessment Risk of bias assessment among the randomised studies showed low risk of bias in all studies. Among observational studies, study quality was quite good with 14 out of the 26 criteria having at least 75% of all studies reporting a low risk of bias for bias. Criteria not well reported were, justification of the number of included participants, reasons for noninclusion of subjects, accounting for cofounders in the analyses, accounting for missing data in the analyses, impact of bias assessed qualitatively and impact of bias assessed quantitatively (supplementary file).
Please cite this article in press as: Singh K, et al. Transcatheter Aortic Valve Implantation in Intermediate Surgical Risk Patients with Severe Aortic Stenosis: A Systematic Review and Meta-Analysis. Heart, Lung and Circulation (2017), http://dx.doi.org/ 10.1016/j.hlc.2017.02.032
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Table 2 There was no difference in the traditional risk factors between the TAVI and SAVR groups on meta-analysis. TAVI (Total No.) %
SAVR (Total No.) %
Odds Ratio
p Value
Symptoms (NYHA II) Diabetes
840 (981) 86% 670 (2159) 31%
833 (971) 86% 637 (2161) 29%
0.98 (0.75–1.27) 1.08 [6_TD$IF](0.95–1.23)
0.87 0.25
Hypertension
379 (511) 74%
363 (501) 72%
1.09 [7_TD$IF](0.83–1.44)
0.54
Prior Stroke
392 (1556) 25%
377 (1558) 24%
1.06 [8_TD$IF](0.90–1.26)
0.48
Prior MI
223 (1400) 16%
217 (1400) 16%
1.04 [9_TD$IF](0.85–1.28)
0.70
Abbreviations: TAVI, Transcatheter Aortic Valve Implantation; SAVR, Surgical Aortic Valve Replacement; NYHA, New York Heart Association; MI, Myocardial infarction.
259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284
[25_TD$IF]Discussion In the current systematic review, we assessed the role of TAVI in the intermediate risk patients with severe AS using a meta-analytic approach. We included three randomised and five observational studies with propensity-matched data in this review. We found that the all-cause 30-day mortality was lower in intermediate-risk patients undergoing TAVI (3.5%) compared to SAVR (4.8%) with a trend towards significance (p = 0.07). When comparison of patients group undergoing TAVI via transfemoral access was performed with SAVR, the all-cause 30-day mortality was significantly lower with TAVI compared to surgery. The mortality at 12 months, was more than 11% in each group, and similar between the two approaches. Post-procedure stroke rate was slightly lower with TAVI (4.1%) compared to SAVR (4.8%), without any statistical difference. The rate of post-procedural aortic incompetence and requirement of a pacemaker was significantly greater in the TAVI cohort. In intermediate-risk patients undergoing TAVI, the allcause 30-day mortality was lower than the SAVR group, with a trend towards significance (p = 0.07). This group of TAVI patients underwent TAVI through transapical, transfemoral and other arterial accesses such as, transaortic and subclavian. When we compared data of transfemoral access TAVI alone with SAVR, TAVI was found to have a significant
reduction in the 30-day all-cause mortality. We know that the transapical approach is associated with a higher risk of complications; therefore, the inclusion of studies utilising transapical access can affect the results. The high risk of complications related to transapical access has been previously demonstrated and [12], once again, confirmed in the PARTNER IIA and PARTNER SAPIEN 3 trial [12,16]. Our study confirms the findings that transfemoral access improves short-term TAVI outcomes against SAVR. The difference in mortality between the two approaches was similar at 12 months despite a lower mortality in the TAVI arm at 30 days. Non-cardiac comorbidities are usually the underlying cause of higher early mortality in patients undergoing SAVR. Previous studies have reported a similar 30-day mortality post-aortic valve surgery, in particular, in the STS database, the 30-day mortality for low-risk patients undergoing SAVR was 4% and this increased to more than 6% when SAVR was performed along with coronary bypass surgery [17]. This trend of high early mortality has also been reported in other studies of SAVR [18]. Underlying comorbidities, in particular, diabetes, renal failure, peripheral vascular disease, immunosuppression, and stroke are the main causes of higher 30-day mortality in patients undergoing SAVR. The results of our study highlight that a significant advantage of TAVI over SAVR is the reduction of the rate of early mortality for the intermediate-risk group especially if TAVI is performed using transfemoral access. Similar
Figure 2 Meta-analysis of EuroSCORE between the TAVI and SAVR. Abbreviations: TAVITranscatheter Aortic Valve Implantation; SAVRSurgical Aortic Valve Replacement; STSSociety of Thoracic Surgeons; OROdds Ratio; MDMean Difference; CIConfidence Interval Please cite this article in press as: Singh K, et al. Transcatheter Aortic Valve Implantation in Intermediate Surgical Risk Patients with Severe Aortic Stenosis: A Systematic Review and Meta-Analysis. Heart, Lung and Circulation (2017), http://dx.doi.org/ 10.1016/j.hlc.2017.02.032
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Figure 3 a and b: Meta-analysis showing all-cause a) 30-day mortality and b) 12 month mortality between the TAVI and SAVR. Abbreviations: TAVI, Transcatheter Aortic Valve Implantation; SAVR, Surgical Aortic Valve Replacement; STS, Society of Thoracic Surgeons; OR, Odds Ratio; MD, Mean Difference; CI, Confidence Interval
findings have been observed by PARTNER trial investigators in a sub-study looking at the cause of death in patients undergoing TAVI and SAVR [19]. Observational studies, such as those included in the current review, allow for the inclusion of a broader population of patients than is possible in randomised control studies. Hence, the mortality reported in the real-world population is somewhat higher. In the recent studies, mortality in the intermediate risk patients undergoing TAVI is very low. There is considerable interest, now, to find the most appropriate group of patients for TAVI, who will achieve the maximum benefit. This is particularly important when we
are expanding the indication of TAVI to low and intermediate risk groups in the current environment of financial constraints. Transaortic valve implantation is currently a more expensive option than surgery due to the cost of valves, but as demand for TAVI grows and as new vendors enter the market and increase competition, costs are expected to decline. The incidence of aortic incompetence and the need for permanent pacemaker post-TAVI was significantly higher compared to SAVR. In our study, the incidence of moderate to severe aortic incompetence post-TAVI was 4.4%, which is very close to the incidence noted in the recently published
Figure 4 Meta-analysis showing 30-day cardiac mortality between the TAVI and SAVR cohort for studies where TAVI was performed with transfemoral access. Abbreviations: TAVI, Transcatheter Aortic Valve Implantation; SAVR, Surgical Aortic Valve Replacement; STS, Society of Thoracic Surgeons; OR, Odds Ratio; MD, Mean Difference; CI, Confidence Interval
Please cite this article in press as: Singh K, et al. Transcatheter Aortic Valve Implantation in Intermediate Surgical Risk Patients with Severe Aortic Stenosis: A Systematic Review and Meta-Analysis. Heart, Lung and Circulation (2017), http://dx.doi.org/ 10.1016/j.hlc.2017.02.032
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Q9
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Q10
PARTNER II A trial [16]. The rate of new pacemaker requirement was nearly double with TAVI (11.6%) when compared to SAVR (5.6%). This incidence is higher than that observed in the TAVI arm (8.5%) of PARTNER IIA trial, but roughly similar to the surgical arm (6.9%). The discrepancy in the incidence rate of the pacemaker requirement post-TAVI in our study and PARTNER IIA trial could be due to the fact that we included studies utilising both the Medtronic Core Valve and Edwards SAPIEN Valve. There is considerable evidence that the Medtronic Core Valve is associated with a higher incidence of pacemaker requirements when compared to the Edwards SAPIEN Valve. The rate of pacemaker implantation in the NOTION study, a core valve randomised study of intermediate-risk patients, was as high as 34% [6]. Similar incidence of pacemaker requirement has been reported in the real world UK Core Valve Collaborative Registry [20]. Newer generation valves have made the TAVI process simpler specifically through the advances related to smaller flexible sheaths and development of repositionable valves. However, the advantages related to the requirement for a pacemaker have shown mixed results. The rate of pacemaker requirement with the SAPIEN 3 valve is low [21], but the only completely repositionable valve, LOTUS , is associated with high rate of pacemaker implantation [22]. It is also important to understand that, although patients in the intermediate risk groups represent a lower risk category than TAVI cohorts in previous high-risk studies, these patients are still among the highest-risk quintile of patients with AS who routinely undergo open-heart surgery [23]. A high 12-month mortality with both approaches indicates that patients labelled as intermediate risk on traditional risk calculators are actually ‘‘high-risk operable” patients. This highlights the deficiency of the current surgical risk calculators that do not take into account the frailty, malnutrition, risk of infections, cognitive impairment, the risk of delirium, anatomical characteristics, such as a porcelain aorta and social support post-discharge. This also emphasises the importance of the Heart Team, especially at a time when TAVI is going through a rapid growth and many small centres are planning on starting a TAVI program in Australia. The results of our study are in agreement with the results of two recent randomised studies, which have demonstrated the TAVI procedure to be non-inferior to SAVR in intermediate-risk patients with severe AS [6,16]. However, the current systematic review has some limitations. First of all, the publication bias can affect the results. We included observational and randomised studies together in the meta-analysis. We tried to reduce bias by only including propensity score matched data in the first part of the study. Secondly, we did not have patient-level data and not all of the studies reported transapical and transfemoral results separately for us to perform the sub-group analysis. Also, we combined the results for Edwards SAPIEN and Medtronic Core Valve together for analysis. Combining the two different types of valves may or may not affect the overall mortality, but could influence the individual complications such as aortic
incompetence and pacemaker implantation rates. Most importantly, in our study we did not assess the long-term follow-up to confirm if the TAVI is as effective as SAVR. Long-term data that is critical for TAVI indication has to be broadened to include lower-risk groups of patients. The impact of mild aortic incompetence and high pacemaker rate on the survival of TAVI patients needs to be assessed before broadening TAVI indications. Our study demonstrates that TAVI procedure can be performed successfully in lower to intermediate risk patients with similar 30-day and 12-month mortality to SAVR. In no way do we recommend TAVI to replace SAVR for routine AS patients, given that the intermediate risk patients in our analysis represent a relatively high-risk quintile of patients with AS who routinely undergo open-heart surgery. Instead, our systematic review consolidates the evidence of PARTNER IIA and NOTION trials that TAVI can be performed successfully with similar survival to SAVR in a select group of patients who are intermediate-risk for surgery.
393
Conflict of Interest
412
On behalf of all authors, the corresponding author states that there is no conflict of interest.
413
394 395 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411
414
[26_TD$IF]Acknowledgements
415
None[27_TD$IF].
416 417
Appendix A. Supplementary data
418
Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.hlc. 2017.02.032.
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References [1] Leon MB, Smith CR, Mack M, Miller DC, Moses JW, Svensson LG, et al. Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery. The New England Journal of Medicine 2010;363:1597–607. [2] Popma JJ, Adams DH, Reardon MJ, Yakubov SJ, Kleiman NS, Heimansohn D, et al. Transcatheter aortic valve replacement using a self-expanding bioprosthesis in patients with severe aortic stenosis at extreme risk for surgery. Journal of the American College of Cardiology 2014;63:1972–81. [3] Binder RK, Stortecky S, Heg D, Tueller D, Jeger R, Toggweiler S, et al. Procedural results and clinical outcomes of transcatheter aortic valve implantation in Switzerland: An observational cohort study of Sapien 3 versus Sapien XT transcatheter heart valves. Circulation Cardiovascular Interventions 2015;8. [4] Sinning JM, Werner N, Nickenig G, Grube E. Medtronic corevalve evolut valve. EuroIntervention: journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology 2012;8(Suppl Q):Q94–6. [5] Meredith IT, Walters DL, Dumonteil N, Worthley SG, Tchetche D, Manoharan G, et al. 1-year outcomes with the fully repositionable and retrievable lotus transcatheter aortic replacement valve in 120 high-risk surgical
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8
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patients with severe aortic stenosis: Results of the REPRISE II study. JACC Cardiovascular Interventions 2016;9:376–84. Thyregod HG, Steinbruchel DA, Ihlemann N, Nissen H, Kjeldsen BJ, Petursson P, et al. Transcatheter versus surgical aortic valve replacement in patients with severe aortic valve stenosis: 1-year results from the all-comers notion randomized clinical trial. Journal of the American College of Cardiology 2015;65:2184–94. Latib A, Maisano F, Bertoldi L, Giacomini A, Shannon J, Cioni M, et al. Transcatheter vs surgical aortic valve replacement in intermediate-surgical-risk patients with aortic stenosis: A propensity score-matched casecontrol study. American Heart Journal 2012;164:910–7. Piazza N, Kalesan B, van Mieghem N, Head S, Wenaweser P, Carrel TP, et al. A 3-center comparison of 1-year mortality outcomes between transcatheter aortic valve implantation and surgical aortic valve replacement on the basis of propensity score matching among intermediate-risk surgical patients. JACC Cardiovascular Interventions 2013;6:443–51. Moher D, Liberati A, Tetzlaff J, Altman DG, Group P. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. Int J Surg 2010;8:336–41. Kappetein AP, Head SJ, Genereux P, Piazza N, van Mieghem NM, Blackstone EH, et al. Updated standardized endpoint definitions for transcatheter aortic valve implantation: The valve academic research Consortium-2 consensus document. The Journal of Thoracic and Cardiovascular Surgery 2013;145:6–23. Tooth L, Ware R, Bain C, Purdie DM, Dobson A. Quality of reporting of observational longitudinal research. American Journal of Epidemiology 2005;161:280–8. Nielsen HH, Klaaborg KE, Nissen H, Terp K, Mortensen PE, Kjeldsen BJ, et al. A prospective, randomised trial of transapical transcatheter aortic valve implantation vs. surgical aortic valve replacement in operable elderly patients with aortic stenosis: The STACCATO trial. EuroIntervention: journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology 2012;8:383–9. D’Errigo P, Barbanti M, Ranucci M, Onorati F, Covello RD, Rosato S, et al. Transcatheter aortic valve implantation versus surgical aortic valve replacement for severe aortic stenosis: Results from an intermediate risk propensity-matched population of the Italian observant study. International Journal of Cardiology 2013;167:1945–52. Schymik G, Heimeshoff M, Bramlage P, Herbinger T, Wurth A, Pilz L, et al. A comparison of transcatheter aortic valve implantation and
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surgical aortic valve replacement in 1,141 patients with severe symptomatic aortic stenosis and less than high risk. Catheterization and Cardiovascular Interventions: official journal of the Society for Cardiac Angiography & Interventions 2015;86:738–44. Bestehorn K, Bestehorn M, Fleck E. Influence of different approaches of aortic valve replacement on the incidence of post-operative delirium in intermediate risk patients – a matched pair analysis. Current Medical Research and Opinion 2015;31:2157–63. Leon MB, Smith CR, Mack MJ, Makkar RR, Svensson LG, Kodali SK, et al. Transcatheter or surgical aortic-valve replacement in intermediate-risk Q11 patients. New England Journal of Medicine 2016;374(17):1609–20. Edwards FH, Peterson ED, Coombs LP, DeLong ER, Jamieson WR, Shroyer ALW, et al. Prediction of operative mortality after valve replacement surgery. Journal of the American College of Cardiology 2001;37:885–92. Blackstone EH, Kirklin JW. Death and other time-related events after valve replacement. Circulation 1985;72:753–67. Svensson LG, Blackstone EH, Rajeswaran J, Brozzi N, Leon MB, Smith CR, et al. Comprehensive analysis of mortality among patients undergoing TAVR: Results of the PARTNER trial. Journal of the American College of Cardiology 2014;64:158–68. Khawaja MZ, Rajani R, Cook A, Khavandi A, Moynagh A, Chowdhary S, et al. Permanent pacemaker insertion after corevalve transcatheter aortic valve implantation: Incidence and contributing factors (the UK CoreValve Collaborative). Circulation 2011;123:951–60. Binder RK, Rode´s-Cabau J, Wood DA, Mok M, Leipsic J, De Larochellie`re R, et al. Transcatheter aortic valve replacement with the Sapien 3a new balloon-expandable transcatheter heart valve. JACC Cardiovascular Q12 Interventions 2013;6:293–300. Meredith Am IT, Walters DL, Dumonteil N, Worthley SG, Tchetche D, Manoharan G, et al. Transcatheter aortic valve replacement for severe symptomatic aortic stenosis using a repositionable valve system: 30-day primary endpoint results from the REPRISE II study. Journal of the American College of Cardiology 2014;64:1339–48. Mohr FW, Holzhey D, Mollmann H, Beckmann A, Veit C, Figulla HR, et al. The German aortic valve registry: 1-year results from 13,680 patients with aortic valve disease. European Journal of Cardio-Thoracic Surgery: official journal of the European Association for Cardio-thoracic Surgery 2014;46:808–16.
Please cite this article in press as: Singh K, et al. Transcatheter Aortic Valve Implantation in Intermediate Surgical Risk Patients with Severe Aortic Stenosis: A Systematic Review and Meta-Analysis. Heart, Lung and Circulation (2017), http://dx.doi.org/ 10.1016/j.hlc.2017.02.032
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ORIGINAL ARTICLE
Heart, Lung and Circulation (2017) xx, 1–8 1443-9506/04/$36.00 http://dx.doi.org/10.1016/j.hlc.2017.02.032
Transcatheter Aortic Valve Implantation in Intermediate Surgical Risk Patients with Severe Aortic Stenosis: A Systematic Review and Meta-Analysis
1 2 3 4 5
6
Q1
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Q2 Q3
Kuljit Singh, MBBS, FRACP, PhD a,b*, Kristin Carson, PhD a, Mohammed K. Rashid, MD Candidate c[,10_TD$IF] Rohan Jayasinghe, MBBS, PhD a, Abdulrahman AlQahtani, MD c, Alexander Dick, MD c, Christopher Glover, MD c, Marino Labinaz, MD c a
University of Adelaide, Adelaide, SA, Australia Gold Coast University Hospital, Brisbane, Qld, Australia c University of Ottawa Heart Institute, Ottawa, Ontario, Canada b
Received 26 May 2016; received in revised form 15 November 2016; accepted 28 February 2017; online published-ahead-of-print xxx
Q4
[13_TD$IF]Background
Recent data from randomised and observational studies have reported non-inferior outcomes for transcatheter aortic valve implantation (TAVI) compared to surgical aortic valve replacement (SAVR) in intermediate-risk patients. We performed a systematic review to evaluate the mortality of TAVI compared to SAVR in intermediate-risk patients.
Methods
A comprehensive search of four major databases (EMBASE, Ovid MEDLINE, PubMed, and Google Scholar) was performed from their inception to 29 April 2016. We included original research studies reporting data on TAVI and SAVR in intermediate-risk patients. We compared the outcomes of TAVI to SAVR.
Results
A total of 2,375 and 2,377 intermediate-risk patients underwent TAVI and SAVR respectively. The 30-day all-cause (p = 0.07), 30-day cardiac (p = 0.53), and 12-month all-cause mortality (p = 0.34) was similar between two groups. However, TAVI through transfemoral access had a significantly lower mortality than SAVR (OR 0.58, p = 0.006). The incidence of [14_TD$IF]moderate aortic incompetence (p [15_TD$IF]< 0.00001) and pacemaker implantation (p [16_TD$IF]< 0.0001) was higher in the TAVI group.
Conclusions
In the intermediate-risk patients, the 30-day and 12-month mortality are similar between TAVI and SAVR. Increased operator experience and improved device technology have led to a significant reduction in mortality in intermediate-risk patients undergoing TAVI.
Keywords
Transcatheter aortic valve implantation Transcatheter aortic valve replacement Intermediate-risk Low-risk High-risk
15 16 17 18 19 20
Q5
Transcatheter aortic valve implantation (TAVI) has become the default approach for patients with severe aortic stenosis (AS) who are either inoperable or at high-risk for surgical aortic valve replacement (SAVR). Evidence relating to the
superiority of TAVI over medical therapy comes from the PARTNER Cohort B trial where mortality at one-year in patients undergoing TAVI was significantly reduced compared to medical treatment [1]. Similar results were shown by
*Corresponding author at: Interventional Cardiologist, Gold Coast University Hospital, Southport QLD 4215, & Senior Lecturer, University of Adelaide, Adelaide, South Australia, [12_TD$IF]5000, Australia. Phone +61 433 698 945, Fax: +61 4312 4919., Email: [email protected] © 2017 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Singh K, et al. Transcatheter Aortic Valve Implantation in Intermediate Surgical Risk Patients with Severe Aortic Stenosis: A Systematic Review and Meta-Analysis. Heart, Lung and Circulation (2017), http://dx.doi.org/ 10.1016/j.hlc.2017.02.032
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22 23 Q7 24
HLC 2348 1–8
2
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K. Singh et al.
the Core Valve United States Pivotal Trial Extreme-Risk study, a prospective single-arm study comparing the Medtronic Core Valve to a prespecified goal [2]. Current guidelines recommend SAVR for severe AS in patients with low or intermediate surgical risk. The surgical risk in a patient with severe AS is defined using the Society of Thoracic Surgeons Risk Calculator (STS) and EuroSCORE. However, these risk scores do not take into consideration multiple factors that may increase the risk related to surgery. Patient frailty, cognitive impairment, the risk of delirium, anatomical characteristics, such as a porcelain aorta and social support postdischarge, are some of the factors that are not evaluated in the traditional risk scores. Hence, many patients who are in the intermediate-risk for SAVR are offered TAVI procedure. This issue is complicated, and the Heart Team, which consists of cardiologists and surgeons, makes decisions in such cases in consensus. Furthermore, developments in technology, such as, smaller sheath sizes, and repositionable TAVI valves, have led to a reduction in the rate of complications associated with TAVI [3–5]. In the randomised NOTION trial, no significant difference between TAVI and SAVR was found for the composite rate of death from any cause, stroke, or MI after one year [6]. While randomised trials have started enrolling low to intermediate risk patients for TAVI, there are already multiple observational studies that have assessed TAVI in the intermediate and low-risk groups using propensity-based analyses [7,8]. Using the currently available literature, we performed a systematic review and a meta-analysis to compare TAVI with SAVR in the intermediate risk patients with severe AS to compare 30-day and 12-[17_TD$IF]month mortality.
56
Methods
57 59
This systematic review and meta-analysis are reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement guidelines [9].
60
Study Eligibility
61
We performed a search for studies looking at outcomes of intermediate risk patients undergoing TAVI or SAVR. We included all studies that compared outcomes of TAVI to SAVR in the intermediate risk group. We included studies using STS and/or Logistic EuroSCORE to define surgical risk in AS patients. Low-risk, intermediate-risk, and high risk was defined as STS score of <4%, 4–8%, and >8%, respectively. Similarly, low, intermediate, and high risk were defined as logistic EuroSCORE of <10%, 10–20%, and >20%, respectively. Device success was defined according to the Valve Academic Research Consortium-2 (VARC-2) definition as the absence of procedural mortality and correct positioning of a single prosthetic heart valve into the proper anatomical location and intended performance of the prosthetic heart valve (no prosthesis-patient mismatch and mean aortic valve gradient <20 mmHg or peak velocity <3 m/s, and no moderate or severe prosthetic valve regurgitation) [10].
58
62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77
We included comparative studies of any design (randomised control trials, cohort, case-control, and cross-sectional). However, in the case of observational studies, only data from propensity score matched cohort was obtained. Observational studies where no matching was performed between the SAVR and TAVI groups for basic characteristics were excluded from the analysis. This was done to reduce the bias between the TAVI and surgical groups. Eligible studies had to provide documentation of the essential features of patients in the TAVI and SAVR groups and mean or median risk scores for the two groups. Included studies also had to report significant complications following both procedures. Studies had to report one or more of the following outcomes: mortality, stroke rate, post-procedure aortic regurgitation, the rate of post-procedure permanent pacemaker implantation, post-procedure myocardial infarction, and rate of acute kidney injury. Furthermore, only studies with 10 patients were considered eligible. Inclusion was restricted to publications in the English language or when the translation of the foreign language publications was provided. When data were reported from overlapping study samples (e.g., multiple publications from the same group), the most recent study or the one with the highest number of patients was included in the analysis. Single case reports and previous systematic reviews on TAVI were not included.
78
Data Sources and Search Strategy
103
A comprehensive search strategy was designed before commencing the search. A thorough computer-based search was performed using Ovid MEDLINE, EMBASE, Google Scholar, and PubMed databases. Search terms included [18_TD$IF] (‘transcatheter aorta valve implantation[19_TD$IF]’ OR ‘transcatheter aortic valve replacement[20_TD$IF]’ OR ‘tavi’ OR tavr AND (‘low risk’ OR ‘intermediate risk[21_TD$IF]’)) and (Mortality or Mortalit* or Death*or Fatalit* or Incidence* or Prevalence* or Statistic*). No limit to the start date was applied, and the search was conducted up to 29 April 2016. We hand-searched references cited in the previous reviews and relevant articles on TAVI.
104
Study Selection and Data Extraction
115
Two reviewers (KS and AQ) screened all titles and abstracts independently. This was followed by the full-text review of the selected articles by the same two reviewers. One reviewer (KS) extracted data independently from selected studies using a standardised, pilot-tested, extraction template. The following data were extracted: study characteristics (author, country, study design, study population, number of participants, and objective of the study); participant characteristics (age and gender); and clinical characteristics (in-hospital mortality, rate of post-procedure myocardial infarction, moderate to severe aortic regurgitation, rate of permanent pacemaker implantation, stroke and acute kidney injury).
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Quality Assessment
128
We assessed publication bias by visual inspection of funnel plots and by calculation of the p value (one-sided) for Egger’s
129 130
Please cite this article in press as: Singh K, et al. Transcatheter Aortic Valve Implantation in Intermediate Surgical Risk Patients with Severe Aortic Stenosis: A Systematic Review and Meta-Analysis. Heart, Lung and Circulation (2017), http://dx.doi.org/ 10.1016/j.hlc.2017.02.032
79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102
105 106 107 108 109 110 111 112 113 114
117 118 119 120 121 122 123 124 125 126 127
HLC 2348 1–8
3
TAVI in Intermediate Risk Patients
intercept. Two independent reviewers (KC and MR) assessed the quality of included studies. In the case of studies with randomised design we used six quality domains relevant to a meta-analysis. In the case of observational studies, quality of included studies was analysed using a sub-set of the Tooth et al., manuscript titled ‘Quality of Reporting of Observational Longitudinal Research’[2_TD$IF]1 [11], including only the 23 quality domains relevant to a meta-analysis of observational studies. We assessed biases using classifications of ‘‘low risk of bias” when data for the criterion were reported, ‘‘high risk of bias” when data were not reported, and ‘‘unclear risk of bias” when the criterion was not relevant to the study design. Review Manager (RevMan, Computer program, Version 5.2, Copenhagen, The Nordic Cochrane Centre, The Cochrane Collaboration, 2012), was used to generate the risk of bias graph. Disagreements between reviewers for classifications were resolved by either consensus or inclusion of a third party.
was assessed by a combination of the I2 statistic, Cochran[23_TD$IF]’ s Q test, and observation of the data for each outcome. The random effect model was used in case of significant heterogeneity (I2 40) and the fixed effect model was used when heterogeneity was low (I2 < 40). If formal meta-analysis was not possible because of a skewed distribution of the number of patients between each study, we disregarded the individual studies and used data as if obtained from a single study. Studies with missing data were excluded from meta-analyses and details extrapolated in the quality and risk of bias assessments. Significant interaction between variables was considered when p < 0.05. All calculations were performed using Review Manager software, version 5.2.
157
Results
170
Literature Identification
171
149
Statistical Analysis
150
Continuous variables are reported as mean SD, whereas skewed data are described as median interquartile range. The measure for estimating the common effect across the included studies was the odds ratio (OR) for binary outcomes and the mean difference for continuous outcomes. Categorical variables are reported using odds ratios (ORs) with 95% confidence intervals (CIs). Heterogeneity between studies
The literature search yielded 7759 citations on TAVI, of which 171 citations were from studies involving TAVI performance in low and intermediate risk groups ([1_TD$IF]Figure 1). Full text was reviewed for 171 shortlisted citations, and 66 articles were chosen for inclusion and exclusion criteria. Of the 66 full-text manuscripts considered for eligibility, eight studies reported comparative data on outcomes of TAVI and SAVR in the intermediate risk group [6–8,12–16].
131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148
151 152 153 154 155 156
[1_TD$IF]Figure 1 Flow chart of search strategy. Abbreviations: TAVI, Transcatheter Aortic Valve Implantation; SAVR, Surgical Aortic Valve Replacement; STS, Society of Thoracic Surgeons; OR, Odds Ratio; MD, Mean Difference; CI, Confidence Interval
158 159 160 161 162 163 164 165 166 167 168 169
172 173 174 175 176 177 178
Clinical Characteristics
179
Other than the PARTNER IIA trial, which enrolled patients from the United States and Canada, all remaining studies included were from Europe and published in the last four years (2012–2016). Three included studies had a randomised design [6,12,16] and the rest were observational in nature. Among the observational studies, we only analysed the propensity score matched data to reduce bias. Among the eight included studies, a total of 34,040 patients who underwent either TAVI or SAVR were evaluated for inclusion/exclusion, and 7221 patients were incorporated in the analysis. After exclusion of the participants who were not matched, we included 4752 intermediate surgical risk patients in the current systematic review, of which 2375 underwent TAVI procedure, and 2377 underwent SAVR. The average age, gender distribution, mean EuroSCORE and STS score are shown in Table 1. Three studies utilised a transfemoral approach exclusively [6,7,15], one study used a transapical approach [12], and the remaining three studies [8,13,14,16] utilised both transfemoral and transapical access. Both balloon-expandable and self-expandable TAVI valves were used in five studies [7,8,13–15], while two studies [12,16] utilised only balloon-expandable, and one study [6] employed only a selfexpandable valve. There was no difference between the TAVI and SAVR groups with regards to the presence of NYHA II symptoms (86% vs. 86%), previous history of hypertension (74% vs. 72%), diabetes (31% vs. 29%), stroke (25% vs. 24%), and myocardial infarction (16% vs. 16%), (Table 2). Similarly,
180 181
Please cite this article in press as: Singh K, et al. Transcatheter Aortic Valve Implantation in Intermediate Surgical Risk Patients with Severe Aortic Stenosis: A Systematic Review and Meta-Analysis. Heart, Lung and Circulation (2017), http://dx.doi.org/ 10.1016/j.hlc.2017.02.032
182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207
HLC 2348 1–8
4
NA
5.8 1.9
3.4 1.2
NA
Abbreviations: TAVI, Transcatheter Aortic Valve Implantation; SAVR, Surgical Aortic Valve Replacement; STS, Society of Thoracic Surgeons; USA, United States of America.
5.8 2.1
NA 8.8 2.8
NA NA
8.7 2.7 111 (51.4) 101 (46.3)
548 (54.2)
78.2 4.6
81.7 6.7
78.3 5.2 216 216 432
2032
Germany 2015
2016
USA/Canada
1011
1021
81.5 6.7
560 (54.8)
NA
3.1 1.5 10.3 5.8
13.2 2.8 13 2.4
9.4 3.1 12 (33.3)
230 (48.9)
9 (26.5)
230 (48.9)
82 4.4
78.6 5.4
80 3.6
77.2 6.2
36 34
470
70
940
Denmark 2012
2015
Germany
470
NA
3.1 1.7
4.6 2.63 4.57 2.28
NA 9.4 10.4
24.4 13.4 23.2 15.1
8.8 9.5 80 (60.1)
49 (44.1)
83 (62.4)
49 (44.1)
78.8 6.9
79.4 3
79.4 7.4
80.5 6.9
133
111
133
111
266
[5_TD$IF]3–8%
2.9 1.6 8.9 5.5 8.4 4 71 (52.6) 78 (53.8)
99 (38.8)
79 4.7
80.6 5.7
135
79.2 4.9
79.7 4.9
SAVR EuroSCORE
TAVI
145
222
Schymik et al.
258
Leon et al.
257
7
255 256
8
254
Nielsen et al.
253
Bestehorn et al.
252
5
251
6
250
by meta-analysis there was no difference in the EuroSCORE between the TAVI and SAVR groups (MD 0.21, 95% CI 0.48–0.05, I2 = 0%, p = 0.12) (Figure 2).
Mortality
Italy
249
2012
248
Latib et al.
247
4
246
Netherlands Italy
245
2012
244
D’Errigo et al.
243
3
242
510
240 241
280
239
Denmark/Sweden
238
Switzerland/Germany/
237
2015
236
Thyregod et al.
235
Piazza et al.
234
1
233
2
232
SAVR
231
TAVI
230
SAVR
229
TAVI
228
SAVR
227
TAVI
226
Men (%)
224 225
Age SD
223
Number
222
Total
221
Country
220
Year
219
Author
218
Q1
216 217
Table 1 Basic characteristic of the studies included in the first part of the review comparing outcomes between TAVI and SAVR.
215
255
214
255
213
2013
212
17.62 11.7
STS Score
211
17.29 9.1
210
TAVI
SAVR
209
104 (40.8)
208
3–8%
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At 30 days, there were 84 (3.5%) deaths in the TAVI group and 109 (4.6%) deaths in the SAVR group. The numbers of cardiac deaths were lower in the TAVI (2.5%, 41/1650) group compared to the SAVR group (2.8%, 47/1652). Looking at studies reporting 12-month mortality, more than 11% of patients had died in both groups by 12 months (TAVR 173/1501 vs. SAVR 183/1445). The 30-day all-cause mortality was lower in patients undergoing TAVI compared to SAVR, but this did not reach a statistically significant level (OR 0.76, 95% CI 0.57–1.02, I2[1_TD$IF] = 25%, p = 0.07) ([1_TD$IF]Figure 3a). However, when ‘‘trans-femoral TAVI” outcomes were compared to SAVR, the all-cause 30-day mortality was significantly lower in the TAVI group (OR 0.58, 95% CI 0.38–0.85, I2 = 0%, p = 0.006) (Figure 4). However, there was no difference in 30-day cardiac mortality (OR 0.87, 95% CI 0.57–1.33, I2[1_TD$IF] = 0%, p = 0.53) (supplementary file) and 12-month all-cause mortality (OR 0.90, 95% CI 0.72–1.12, I2 = 0%, p = 0.34) (Figure 3b) between the two groups. Also, there was no difference in the 12-month cardiac mortality (OR 0.92, 95% CI 0.40–2.12, I2[1_TD$IF] = 49%, p = 0.85).
Complications There was no significant difference in the stroke events between the two groups [(TAVI 68/1650, 4.1% vs. SAVR 79/1652, 4.8%), (OR 0.86, 95% CI 0.62–1.20, I2 = 0%, p = 0.37)](supplementary file). Post-procedure, any form of aortic incompetence was significantly higher in the TAVI group (464/1434, 32%) as compared to the SAVR group (69/1436, 4.8%), (OR 11.88, 95% CI 6.33–22.30, I2 = 73%, p < 0.00001) (supplementary file). Similarly, the presence of moderate to severe aortic incompetence in the TAVI group (73/1650, 4.4%) was significantly higher than the SAVR group (10/1652, 0.6%), (OR 6.61, 95% CI 3.46–12.65, I2 = 0%, p < 0.0001) (supplementary file). New pacemaker implantation rate was significantly higher in the TAVI group (192/1650, 11.6% vs. 85/1652, 5.1%) (OR 4.85, 95% CI 1.68–14.00, I2 = 60%, p < 0.00001) (supplementary file).
[24_TD$IF]Quality Assessment Risk of bias assessment among the randomised studies showed low risk of bias in all studies. Among observational studies, study quality was quite good with 14 out of the 26 criteria having at least 75% of all studies reporting a low risk of bias for bias. Criteria not well reported were, justification of the number of included participants, reasons for noninclusion of subjects, accounting for cofounders in the analyses, accounting for missing data in the analyses, impact of bias assessed qualitatively and impact of bias assessed quantitatively (supplementary file).
Please cite this article in press as: Singh K, et al. Transcatheter Aortic Valve Implantation in Intermediate Surgical Risk Patients with Severe Aortic Stenosis: A Systematic Review and Meta-Analysis. Heart, Lung and Circulation (2017), http://dx.doi.org/ 10.1016/j.hlc.2017.02.032
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Table 2 There was no difference in the traditional risk factors between the TAVI and SAVR groups on meta-analysis. TAVI (Total No.) %
SAVR (Total No.) %
Odds Ratio
p Value
Symptoms (NYHA II) Diabetes
840 (981) 86% 670 (2159) 31%
833 (971) 86% 637 (2161) 29%
0.98 (0.75–1.27) 1.08 [6_TD$IF](0.95–1.23)
0.87 0.25
Hypertension
379 (511) 74%
363 (501) 72%
1.09 [7_TD$IF](0.83–1.44)
0.54
Prior Stroke
392 (1556) 25%
377 (1558) 24%
1.06 [8_TD$IF](0.90–1.26)
0.48
Prior MI
223 (1400) 16%
217 (1400) 16%
1.04 [9_TD$IF](0.85–1.28)
0.70
Abbreviations: TAVI, Transcatheter Aortic Valve Implantation; SAVR, Surgical Aortic Valve Replacement; NYHA, New York Heart Association; MI, Myocardial infarction.
259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284
[25_TD$IF]Discussion In the current systematic review, we assessed the role of TAVI in the intermediate risk patients with severe AS using a meta-analytic approach. We included three randomised and five observational studies with propensity-matched data in this review. We found that the all-cause 30-day mortality was lower in intermediate-risk patients undergoing TAVI (3.5%) compared to SAVR (4.8%) with a trend towards significance (p = 0.07). When comparison of patients group undergoing TAVI via transfemoral access was performed with SAVR, the all-cause 30-day mortality was significantly lower with TAVI compared to surgery. The mortality at 12 months, was more than 11% in each group, and similar between the two approaches. Post-procedure stroke rate was slightly lower with TAVI (4.1%) compared to SAVR (4.8%), without any statistical difference. The rate of post-procedural aortic incompetence and requirement of a pacemaker was significantly greater in the TAVI cohort. In intermediate-risk patients undergoing TAVI, the allcause 30-day mortality was lower than the SAVR group, with a trend towards significance (p = 0.07). This group of TAVI patients underwent TAVI through transapical, transfemoral and other arterial accesses such as, transaortic and subclavian. When we compared data of transfemoral access TAVI alone with SAVR, TAVI was found to have a significant
reduction in the 30-day all-cause mortality. We know that the transapical approach is associated with a higher risk of complications; therefore, the inclusion of studies utilising transapical access can affect the results. The high risk of complications related to transapical access has been previously demonstrated and [12], once again, confirmed in the PARTNER IIA and PARTNER SAPIEN 3 trial [12,16]. Our study confirms the findings that transfemoral access improves short-term TAVI outcomes against SAVR. The difference in mortality between the two approaches was similar at 12 months despite a lower mortality in the TAVI arm at 30 days. Non-cardiac comorbidities are usually the underlying cause of higher early mortality in patients undergoing SAVR. Previous studies have reported a similar 30-day mortality post-aortic valve surgery, in particular, in the STS database, the 30-day mortality for low-risk patients undergoing SAVR was 4% and this increased to more than 6% when SAVR was performed along with coronary bypass surgery [17]. This trend of high early mortality has also been reported in other studies of SAVR [18]. Underlying comorbidities, in particular, diabetes, renal failure, peripheral vascular disease, immunosuppression, and stroke are the main causes of higher 30-day mortality in patients undergoing SAVR. The results of our study highlight that a significant advantage of TAVI over SAVR is the reduction of the rate of early mortality for the intermediate-risk group especially if TAVI is performed using transfemoral access. Similar
Figure 2 Meta-analysis of EuroSCORE between the TAVI and SAVR. Abbreviations: TAVITranscatheter Aortic Valve Implantation; SAVRSurgical Aortic Valve Replacement; STSSociety of Thoracic Surgeons; OROdds Ratio; MDMean Difference; CIConfidence Interval Please cite this article in press as: Singh K, et al. Transcatheter Aortic Valve Implantation in Intermediate Surgical Risk Patients with Severe Aortic Stenosis: A Systematic Review and Meta-Analysis. Heart, Lung and Circulation (2017), http://dx.doi.org/ 10.1016/j.hlc.2017.02.032
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Figure 3 a and b: Meta-analysis showing all-cause a) 30-day mortality and b) 12 month mortality between the TAVI and SAVR. Abbreviations: TAVI, Transcatheter Aortic Valve Implantation; SAVR, Surgical Aortic Valve Replacement; STS, Society of Thoracic Surgeons; OR, Odds Ratio; MD, Mean Difference; CI, Confidence Interval
findings have been observed by PARTNER trial investigators in a sub-study looking at the cause of death in patients undergoing TAVI and SAVR [19]. Observational studies, such as those included in the current review, allow for the inclusion of a broader population of patients than is possible in randomised control studies. Hence, the mortality reported in the real-world population is somewhat higher. In the recent studies, mortality in the intermediate risk patients undergoing TAVI is very low. There is considerable interest, now, to find the most appropriate group of patients for TAVI, who will achieve the maximum benefit. This is particularly important when we
are expanding the indication of TAVI to low and intermediate risk groups in the current environment of financial constraints. Transaortic valve implantation is currently a more expensive option than surgery due to the cost of valves, but as demand for TAVI grows and as new vendors enter the market and increase competition, costs are expected to decline. The incidence of aortic incompetence and the need for permanent pacemaker post-TAVI was significantly higher compared to SAVR. In our study, the incidence of moderate to severe aortic incompetence post-TAVI was 4.4%, which is very close to the incidence noted in the recently published
Figure 4 Meta-analysis showing 30-day cardiac mortality between the TAVI and SAVR cohort for studies where TAVI was performed with transfemoral access. Abbreviations: TAVI, Transcatheter Aortic Valve Implantation; SAVR, Surgical Aortic Valve Replacement; STS, Society of Thoracic Surgeons; OR, Odds Ratio; MD, Mean Difference; CI, Confidence Interval
Please cite this article in press as: Singh K, et al. Transcatheter Aortic Valve Implantation in Intermediate Surgical Risk Patients with Severe Aortic Stenosis: A Systematic Review and Meta-Analysis. Heart, Lung and Circulation (2017), http://dx.doi.org/ 10.1016/j.hlc.2017.02.032
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Q9
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Q10
PARTNER II A trial [16]. The rate of new pacemaker requirement was nearly double with TAVI (11.6%) when compared to SAVR (5.6%). This incidence is higher than that observed in the TAVI arm (8.5%) of PARTNER IIA trial, but roughly similar to the surgical arm (6.9%). The discrepancy in the incidence rate of the pacemaker requirement post-TAVI in our study and PARTNER IIA trial could be due to the fact that we included studies utilising both the Medtronic Core Valve and Edwards SAPIEN Valve. There is considerable evidence that the Medtronic Core Valve is associated with a higher incidence of pacemaker requirements when compared to the Edwards SAPIEN Valve. The rate of pacemaker implantation in the NOTION study, a core valve randomised study of intermediate-risk patients, was as high as 34% [6]. Similar incidence of pacemaker requirement has been reported in the real world UK Core Valve Collaborative Registry [20]. Newer generation valves have made the TAVI process simpler specifically through the advances related to smaller flexible sheaths and development of repositionable valves. However, the advantages related to the requirement for a pacemaker have shown mixed results. The rate of pacemaker requirement with the SAPIEN 3 valve is low [21], but the only completely repositionable valve, LOTUS , is associated with high rate of pacemaker implantation [22]. It is also important to understand that, although patients in the intermediate risk groups represent a lower risk category than TAVI cohorts in previous high-risk studies, these patients are still among the highest-risk quintile of patients with AS who routinely undergo open-heart surgery [23]. A high 12-month mortality with both approaches indicates that patients labelled as intermediate risk on traditional risk calculators are actually ‘‘high-risk operable” patients. This highlights the deficiency of the current surgical risk calculators that do not take into account the frailty, malnutrition, risk of infections, cognitive impairment, the risk of delirium, anatomical characteristics, such as a porcelain aorta and social support post-discharge. This also emphasises the importance of the Heart Team, especially at a time when TAVI is going through a rapid growth and many small centres are planning on starting a TAVI program in Australia. The results of our study are in agreement with the results of two recent randomised studies, which have demonstrated the TAVI procedure to be non-inferior to SAVR in intermediate-risk patients with severe AS [6,16]. However, the current systematic review has some limitations. First of all, the publication bias can affect the results. We included observational and randomised studies together in the meta-analysis. We tried to reduce bias by only including propensity score matched data in the first part of the study. Secondly, we did not have patient-level data and not all of the studies reported transapical and transfemoral results separately for us to perform the sub-group analysis. Also, we combined the results for Edwards SAPIEN and Medtronic Core Valve together for analysis. Combining the two different types of valves may or may not affect the overall mortality, but could influence the individual complications such as aortic
incompetence and pacemaker implantation rates. Most importantly, in our study we did not assess the long-term follow-up to confirm if the TAVI is as effective as SAVR. Long-term data that is critical for TAVI indication has to be broadened to include lower-risk groups of patients. The impact of mild aortic incompetence and high pacemaker rate on the survival of TAVI patients needs to be assessed before broadening TAVI indications. Our study demonstrates that TAVI procedure can be performed successfully in lower to intermediate risk patients with similar 30-day and 12-month mortality to SAVR. In no way do we recommend TAVI to replace SAVR for routine AS patients, given that the intermediate risk patients in our analysis represent a relatively high-risk quintile of patients with AS who routinely undergo open-heart surgery. Instead, our systematic review consolidates the evidence of PARTNER IIA and NOTION trials that TAVI can be performed successfully with similar survival to SAVR in a select group of patients who are intermediate-risk for surgery.
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Conflict of Interest
412
On behalf of all authors, the corresponding author states that there is no conflict of interest.
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414
[26_TD$IF]Acknowledgements
415
None[27_TD$IF].
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Appendix A. Supplementary data
418
Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.hlc. 2017.02.032.
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Please cite this article in press as: Singh K, et al. Transcatheter Aortic Valve Implantation in Intermediate Surgical Risk Patients with Severe Aortic Stenosis: A Systematic Review and Meta-Analysis. Heart, Lung and Circulation (2017), http://dx.doi.org/ 10.1016/j.hlc.2017.02.032
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