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Cerebral outcomes in patients undergoing transcatheter aortic valve implantation

Vlastra, W.

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Citation for published version (APA):Vlastra, W. (2019). Cerebral outcomes in patients undergoing transcatheter aortic valve implantation.

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Download date: 24 Jul 2020

Chapter 1AThe current status of antiplatelet therapy in patients undergoing transcatheter aortic valve implantation.

J Thorac Dis. 2017 Oct 9(10);3652-3655

W. Vlastra, J.J. Piek, R. Delewi

24 Chapter 1

Comment on: Aspirin versus aspirin plus clopidogrel as antithrombotic treatment following transcatheter aortic valve replacement with a balloon expandable valve: The ARTE (aspirin versus aspirin + clopidogrel following transcatheter aortic valve implantation) randomized clinical trial.

Transcatheter aortic valve implantation (TAVI) is a minimally invasive and life-saving treatment in patients with aortic valve stenosis. As a consequence of increased operator experience and the refinement of valve technology, the target population of TAVI has rapidly expanded from inoperable patients to individuals with an intermediate risk score (1-3). This evolution of TAVI in the last decade has resulted in an improvement of better quality of life for the majority of the patients (4). Nevertheless, thromboembolic events and bleeding complications associated with TAVI remain an important complication associated with a high morbidity and mortality. In the recent PARTNER trial studying TAVI in intermediate risk patients, the incidence of myocardial infarction at 30 days was 1% and the incidence of neurological events 6%, including 3% disabling stroke (2). These rates were similar in patients undergoing surgical aortic valve replacement. This is in strong contrast with the early days of TAVI. In the pivotal PARTNER-B trial, stroke rates at 1 year follow-up were fivefold higher in patients undergoing TAVI compared to patients treated conservatively (1). As a result of these concerning outcomes, guidelines recommend anti-coagulation both during the procedure as well as an antithrombotic regimen after TAVI by means of several months of dual antiplatelet therapy (DAPT) (5). Nevertheless, in the absence of randomized data, the current guidelines are based upon empirical information rather than evidence based data. In the current editorial we discuss the latest evidence on antiplatelet therapy in patients undergoing TAVI and provide an outlook on future trials.

The present expert-opinion based guidelines of DAPT are not in accordance with combined evidence of current available studies. A pooled analysis of individual patient data by Hassell et al. included 435 patients from 4 studies (2 randomized controlled trials and 2 matched cohorts) (6). It was concluded that addition of clopidogrel versus treatment with aspirin alone did not reduce stroke or mortality rates during the first month after TAVI. Additionally, there was a trend towards less life-threatening and major bleedings in patients treated with single antiplatelet therapy (SAPT, OR 0.56, 95% CI: 0.28–1.11, P=0.09).

Continuing the quest for the optimal antiplatelet therapy after TAVI, the ARTE trial (aspirin versus aspirin plus clopidogrel as antithrombotic treatment following transcatheter aortic valve implantation) is an open-label pilot-trial in patients

25Cerebral outcomes in patients undergoing TAVI

undergoing TAVI with a balloon expandable valve, evaluating the risk/benefit ration of DAPT vs. SAPT (7). We congratulate the authors of the ARTE trial for conducting a very relevant and well-presented investigator-initiated trial. This multicentre trial by Rodés-Cabau et al. included 222 patients between 2012 and 2017 and was prematurely stopped at 74% of the intended population, due to slow enrolment. Patients were randomized to receive SAPT (N=111, aspirin or acetylsalicylic acid 80–100 mg/day for at least 6 months) or DAPT (N=111, aspirin or acetylsalicylic acid 80–100 mg/day for at least 6 months plus clopidogrel 75 mg for 3 months). Surprisingly, outcomes at 30 days showed a trend towards higher event rates in the DAPT arm compared to treatment with SAPT regarding both myocardial infarction [OR 4.13 (0.45–37.60), P=0.18] as well as neurological events [OR 3.11 (0.32–30.43), P=0.31]. Nevertheless, these outcomes should be interpreted with caution given the combination of relatively low event rates (3 patients with neurological events in the DAPT group vs. 1 in the SAPT group) and the modest sample size of the current study. This stroke rate (1.8% of the study population) is considerably lower than the stroke rates of the earlier discussed large scale prospective trials, despite comparable patient characteristics. A more compelling result is the threefold higher incidence of major or life-threatening bleeding events [OR 3.22 (1.01–10.34), P=0.04] in in the DAPT group. No new thromboembolic events and major bleedings happened between 30 days and 3 months in either of the groups. These major bleedings are of concern since they are identified as a strong independent predictor of mortality in the medium-term follow-up (adjusted hazard ratio: 3.91, 95% CI: 2.67–5.71, P<0.001) (8).

Rodés-Cabau et al. hypothesize that the absent benefit of several months of DAPT may be explained by the time course of the development of these thromboembolic events. Indeed, 2 out of 3 strokes in the first year after TAVI occur within the first 30 days. Approximately a quarter of all strokes at 30 days is observed in the first 24 hours (1, 9) and more than half between days 1 to 5 (1). Accordingly, it is likely, that the increased thromboembolic risk for the largest part is more or less directly associated to the TAVI procedure itself. This is in accordance with the first PARTNER trial, where stroke rates between 30 days and 1 year were comparable in patients undergoing TAVI and patients treated conservatively (1). After the peri-procedural period, the risk of stroke seems predominantly influenced by the preexisting predisposition of a TAVI population composed of octogenarians with a typically concomitant adverse cardiovascular risk profile. In contrast, in a subgroup, the risk of stroke may be enhanced by new onset atrial fibrillation after TAVI. However in an observational study on this subgroup of patients, concomitant antiplatelet therapy use did not reduce the incidence of thromboembolic events after TAVI, while it did significantly increase the risk on major bleedings.

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To better understand this early peak of stroke and in order to examine potential therapeutic possibilities we have to look in more detail to the underlying pathophysiology of thromboembolic events (Figure 1). During TAVI, the use of large-sized delivery systems and catheters and, balloon valvuloplasty, positioning and implantation of the new valve and post-dilation manipulates the calcified native valves and the aortic wall. Consequently, potential dislodgement and embolization of aortic debris and crushed calcified native valves can take place. Moreover, the thrombophilic state induced by the devices used during TAVI may stimulate thrombus formation through platelet aggregation and subsequent activation of the coagulation pathway. This is confirmed by studies that quantified the etiology of embolization during TAVI by extracting debris from cerebral protection filters (10-12). Frequently found types of debris consisted of arterial wall tissue (52–94%), native valve tissue (20–60%), calcifications (50–73%) and surprisingly foreign material, detached from the percutaneous devices (10–36%). Interestingly, histopathologic debris was found in nearly all cerebral protective devices. The bulk of the debris extracted from the filters contained acute thrombi, implying inappropriate antithrombotic measures, only a few organizing thrombi were captured (6–33%), indicating it was already attached to the native valve or aortic wall prior to the TAVI.

It can be hypothesized that in order to prevent this peak of serious thromboembolic complications, the focus should be on the peri-procedural phase rather than the months after the procedure. Therapeutic options currently explored are the use of cerebral protection devices and antithrombotic measures peri-procedural. Diverse cerebral protection devices have been developed to reduce cerebrovascular events after TAVI. These devices work through deflection or filtering of the embolism and are in different stages of testing. So far, the use of two devices (Sentinel Cerebral Protection System, Claret Medical Inc. and TriGuard, Keystone Heart) has proven to be feasible during TAVI (10, 13). Improved versions of the current devices are under development and studies examining efficacy are ongoing. Also addressing the peri-procedural period, the BRAVO-3 trial randomized patients to TAVI with either bivalirudin or unfractionated heparin (control), cardiovascular events, bleeding rates and cerebral embolism on MRI scans were comparable in both groups (14, 15).

So what will the (near) future bring us? Under the hypothesis that thrombin is a key-player in the pathophysiology of thromboembolic events the GALILEO study (clinicaltrials.gov, NCT02556203) is currently randomizing 1520 patients to receive either rivaroxaban and acetylsalicylic acid or standard therapy with DAPT. In addition, the POPular TAVI trial is a large randomized trial (clinicaltrials.gov, NCT02247128), continuing

27Cerebral outcomes in patients undergoing TAVI

on the path of monotherapy. This study is divided into two cohorts including more than 1,000 patients, in cohort A, patients without anticoagulation are randomized to receive SAPT or DAPT. In cohort B, patients on oral anticoagulation are randomized to receive additional clopidogrel or no additional antiplatelet therapy. If the POPular TAVI trial will confirm SAPT is non-inferior to DAPT, and associated with lower rates of bleedings, the initiation of (national) prospective randomized clinical registries could be the next step in the determination of personalized optimal antiplatelet therapy after TAVI.

In conclusion, the ARTE-trial provides important hypothesis-generating information on the significantly higher bleeding rates associated with DAPT after TAVI. However, it does not (yet) provide a reliable conclusion regarding the potential advantages reducing myocardial infarction and stroke, due to the limited sample size in combination with relatively low event rates. Nevertheless, the current study is probably the first step, followed by large-scale randomized studies and a change in daily clinical practice as the end result.

AcknowledgementsWe would like to acknowledge and thank Michael R. Jenkins for creating the illustration for the current editorial.

Conflicts of InterestThe authors have no conflicts of interest to declare.

Figure 1.

Schematic representation of potential mechanisms of thromboembolic events during transcatheter aortic valve implantation.

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REFERENCES1. 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. N Engl J Med. 2010;363(17):1597-607.

2. Leon MB, Smith CR, Mack MJ, Makkar RR, Svensson LG, Kodali SK, et al. Transcatheter or Surgical Aortic-Valve Replacement in Intermediate-Risk Patients. N Engl J Med. 2016;374(17):1609-20.

3. Reardon MJ, Van Mieghem NM, Popma JJ, Kleiman NS, Sondergaard L, Mumtaz M, et al. Surgical or Transcatheter Aortic-Valve Replacement in Intermediate-Risk Patients. N Engl J Med. 2017.

4. Baron SJ, Arnold SV, Wang K, Magnuson EA, Chinnakondepali K, Makkar R, et al. Health Status Benefits of Transcatheter vs Surgical Aortic Valve Replacement in Patients With Severe Aortic Stenosis at Intermediate Surgical Risk: Results From the PARTNER 2 Randomized Clinical Trial. JAMA cardiology. 2017.

5. Holmes DR, Jr., Mack MJ, Kaul S, Agnihotri A, Alexander KP, Bailey SR, et al. 2012 ACCF/AATS/SCAI/STS expert consensus document on transcatheter aortic valve replacement. J Am Coll Cardiol. 2012;59(13):1200-54.

6. Hassell ME, Hildick-Smith D, Durand E, Kikkert WJ, Wiegerinck EM, Stabile E, et al. Antiplatelet therapy following transcatheter aortic valve implantation. Heart. 2015;101(14):1118-25.

7. Rodes-Cabau J, Masson JB, Welsh RC, Garcia Del Blanco B, Pelletier M, Webb JG, et al. Aspirin Versus Aspirin Plus Clopidogrel as Antithrombotic Treatment Following Transcatheter Aortic Valve Replacement With a Balloon-Expandable Valve: The ARTE (Aspirin Versus Aspirin + Clopidogrel Following Transcatheter Aortic Valve Implantation) Randomized Clinical Trial. JACC Cardiovasc Interv. 2017;10(13):1357-65.

8. Genereux P, Cohen DJ, Mack M, Rodes-Cabau J, Yadav M, Xu K, et al. Incidence, predictors, and prognostic impact of late bleeding complications after transcatheter aortic valve replacement. J Am Coll Cardiol. 2014;64(24):2605-15.

9. Rodes-Cabau J, Webb JG, Cheung A, Ye J, Dumont E, Feindel CM, et al. Transcatheter aortic valve implantation for the treatment of severe symptomatic aortic stenosis in patients at very high or prohibitive surgical risk: acute and late outcomes of the multicenter Canadian experience. J Am Coll Cardiol. 2010;55(11):1080-90.

10. Kapadia SR, Kodali S, Makkar R, Mehran R, Lazar RM, Zivadinov R, et al. Protection Against Cerebral Embolism During Transcatheter Aortic Valve Replacement. J Am Coll Cardiol. 2017;69(4):367-77.

11. Schmidt T, Schluter M, Alessandrini H, Akdag O, Schewel D, Schewel J, et al. Histology of debris captured by a cerebral protection system during transcatheter valve-in-valve implantation. Heart. 2016;102(19):1573-80.

12. Van Mieghem NM, Schipper ME, Ladich E, Faqiri E, van der Boon R, Randjgari A, et al. Histopathology of embolic debris captured during transcatheter aortic valve replacement. Circulation. 2013;127(22):2194-201.

13. Lansky AJ, Schofer J, Tchetche D, Stella P, Pietras CG, Parise H, et al. 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(31):2070-8.

14. Dangas GD, Lefevre T, Kupatt C, Tchetche D, Schafer U, Dumonteil N, et al. Bivalirudin Versus Heparin Anticoagulation in Transcatheter Aortic Valve Replacement: The Randomized BRAVO-3 Trial. J Am Coll Cardiol. 2015;66(25):2860-8.

15. Van Belle E, Hengstenberg C, Lefevre T, Kupatt C, Debry N, Husser O, et al. Cerebral Embolism During Transcatheter Aortic Valve Replacement: The BRAVO-3 MRI Study. J Am Coll Cardiol. 2016;68(6):589-99.

29Cerebral outcomes in patients undergoing TAVI

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Chapter 1BAntiplatelet strategies in patients undergoing transcatheter aortic valve implantation – Data sharing is caring

Rev Esp Cardiol. 2018 Apr;71(4):240-242.

W. Vlastra, R. Delewi

32 Chapter 1

Comment on: Dual Versus Single Antiplatelet Regimen With or Without Anticoagulation in Transcatheter Aortic Valve Replacement: Indirect Comparison and Meta-analysis.

Fortunately, in modern western cardiovascular medicine, serious complications after clinical interventions are relatively rare. From an epidemiological point of view, these low event rates are perhaps less convenient. For researchers, large investments are needed to conduct adequately powered clinical trials. Consequently, in the ongoing quest for evidence-based strategies, alternative methodological strategies have been developed with the aim of tackling these low event rates and increasing power. The first approach is to alter a primary clinical endpoint to a surrogate endpoint. Surrogate endpoints are frequently used in hypothesis-generating exploratory studies. It is hypothesized that if a specific treatment strategy positively influences a cardiovascular risk factor (eg, blood pressure, or a certain biomarker), this may reduce clinical events (death, stroke, myocardial infarction).

A second common strategy is the use of a combined endpoint as the primary outcome. The main advantage of these endpoints is statistical efficacy (smaller sample sizes, earlier availability of the study results); additionally, a summary measure for efficacy can be defined. One of the limitations of composite endpoints is that a negative separate outcome can be camouflaged. These first 2 options make statistical comparisons possible by increasing the absolute incidence of events.

A third convenient option is to expand the total population size by combining the available evidence. Achieving a higher purpose by combining data fits the current trend of sharing and collectivism among research communities. Cooperation between study centers may strongly be encouraged since it increases the sample size and also the validity of individual study results. In this editorial we will evaluate the current combined evidence on antiplatelet strategies after transcatheter aortic valve implantation (TAVI), from registries to data from randomized controlled trials (RCTs).

Following the trend of modern medicine, TAVI is nowadays a relatively safe intervention, with low rates of serious complications. However, these rare serious outcomes are associated with increased morbidity and mortality and therefore deserve appropriate treatment strategies. Two of the most feared complications associated with TAVI are thromboembolic and bleeding events. Myocardial infarction occurs in 1% of all patients in the first 30 days after TAVI. Stroke after TAVI, including transient ischemic attack (TIA), is more frequently reported (5%-6%) (1). These clinical strokes seem to be the tip of the iceberg of the real cerebral

33Cerebral outcomes in patients undergoing TAVI

embolization burden associated with the TAVI procedure. Cerebral diffusion-weighted magnetic resonance imaging scans performed within a week after TAVI show new ischemic lesions in three-quarters of patients undergoing TAVI, with an average of 4 lesions per patient, dispersed through all brain regions (2) .Nevertheless, their clinical relevance remains unclear (3). Stroke in this frail elderly TAVI population is associated with a 3.5-fold increase in mortality in the first 30 days after the procedure (4). To reduce these thromboembolic events, current expert-based guidelines recommend 3 to 6 months of dual antiplatelet therapy (DAPT) after TAVI. The underlying motivation for periprocedural DAPT was mainly derived from the common practice of percutaneous coronary interventions, to support the incorporation process of the device. Additionally, in the early days of TAVI, it was feared that hemodynamic support using extracorporeal circulation induced platelet activation and consumption (5).

However, nowadays extracorporeal hemodynamic support is barely used during TAVI. Moreover, the use of large catheters and delivery systems in combination with antithrombotic drugs during TAVI is associated with a considerable risk of bleeding complications. Bleedings were reported in 41% of the patients after TAVI, most of them being defined as major (22%) or life threatening (16%) (6). The majority of these bleedings are related to the procedure; nevertheless, bleeding complications after the periprocedural phase occur in 6% of all patients and are strongly correlated with mortality in the first year after TAVI (adjusted hazard ratio, 3.91; 95% confidence interval [95%CI], 2.67-5.71; P < 0.001) (7). In conclusion, both thromboembolic and bleeding complications after TAVI are associated with poor outcomes, compromising quality of life and increasing health care costs. Therefore, data on antithrombotic strategies aimed at lowering these events in TAVI patients are more than welcome.

As described in their article recently published in Revista Española de Cardiología, Verdoia et al. performed a meta-analysis combining the current available evidence on antithrombotic therapy in patients undergoing TAVI (8). We congratulate the authors for conducting a well-executed meta-analysis on such an important matter. Tackling the problem of relatively low event rates, the meta-analysis included 5 studies comparing DAPT with single antiplatelet therapy (SAPT) and 4 studies comparing DAPT with SAPT plus oral anticoagulation (OAC). In total, approximately 8000 patients were included. The authors conclude that overall mortality was significantly reduced in patients treated with DAPT vs SAPT (with or without OAC) (odds ratio [OR], 0.81; 95%CI, 0.70-0.93; P = 0.003). This effect was similar when selecting the studies comparing DAPT vs SAPT without OAC (OR, 0.80; 95%CI,

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0.69-0.93; P =0.004), and was not significant in the studies comparing DAPT vs SAPT with OAC (OR, 0.86; 95%CI, 0.55-1.35; P = 0.51). Moreover, there was a non-significant trend toward lower stroke rates in patients treated with DAPT vs SAPT with or without OAC (OR, 0.83; 95%CI, 0.63-1.10, P = 0.20). Additionally, the authors conclude that bleeding rates were similar in patients treated with DAPT compared with patients treated with SAPT with or without OAC (OR, 1.69; 95%CI, 0.86-3.31; P = 0.13). The authors conclude that treatment with DAPT was associated with a significant reduction in mortality, without a significant increase of major bleedings, and therefore support the current strategy recommended by the guidelines.

The results from the meta-analysis are interesting and stand in contrast to the outcomes of the current available (combined) RCTs (9). The largest RCT to date (n = 222) on the same topic was published simultaneously with the meta-analysis by Verdoia et al. (10) Consequently, there are currently a total of 3 RCTs assessing DAPT vs SAPT in patients undergoing TAVI, with 421 patients in total. At 30-days’ follow-up, mortality was comparable in patients treated with DAPT vs SAPT (13 vs 10 patients). Similarly, the occurrence of stroke/TIA was equal in both treatment groups (n = 5) (10-12). Absolute numbers of bleedings were reported in only 2 of the trials (n = 301): life-threatening and major bleedings were more than 2-fold higher in patients treated with DAPT (n = 16) vs patients treated with SAPT (n = 7) and this difference was statistically significant in the ARTE trial (P = 0.038) (10, 12). Currently, there are no randomized data comparing DAPT with OAC. The POPular TAVI trial (NCT02247128) is enrolling and randomizing patients on OAC to receive additional clopidogrel or no additional antiplatelet therapy. In summary, the currently available RCTs seem to suggest that SAPT is non-inferior to DAPT regarding mortality or stroke and is additionally associated with less serious bleedings.

How can this discrepancy between the recent meta-analysis and the current available randomized data be explained? Well-conducted, large-scale RCTs are considered the gold standard. However, it is not uncommon for meta-analyses and subsequent large RCTs to reach different conclusions. Approximately one-third of the outcomes of large RCTs was not predicted accurately by previously published meta-analyses on the same topic (13). A partial explanation may be the heterogeneity of studies included in meta-analyses. The meta-analysis by Verdoia et al. included 5 studies evaluating SAPT vs DAPT. Among these studies (2 small RCTs, 2 small observational studies, and 1 large registry), considerable divergence was evident regarding the odds ratios of both mortality and stroke. The 4 small studies adopted positions on both sides of the no-difference line, without reaching individual statistical

35Cerebral outcomes in patients undergoing TAVI

significance due to the low number of total event rates (mortality rates = 3-12; stroke rates = 1-3) (12,12,14,15). In contrast, the fifth study, a large US registry, presented at the Transcatheter Cardiovascular Therapeutics conference in 2015, contained 4132 patients and also a high number of events (mortality, n = 550; stroke, n = 140) (16). Consequently, the conclusion of the meta-analysis (comparing DAPT vs SAPT, without OAC) was for more than 90% driven by the results from a single large registry. Potentially, in this case, the summarizing of results from different types of studies into 1 odds ratio may oversimplify a complex matter.

How, then, should we interpret this meta-analysis? The challenge is that currently the only other available evidence-based alternative is composed of a series of small RCTs. Clinicians should realize that the meta-analysis by Verdoia et al. and the series of small RCTs perhaps both answer different questions and are complementary. We speculate from our own experience that participants consenting to randomized controlled TAVI studies are often younger and have fewer comorbidities compared with those refusing to participate. This may limit the generalizability of RCTs to the total TAVI population and may also result in relatively low event rates, as reported in the previously discussed trials. Alternatively, despite being severely confounded, a large-scale registry such as that included in the meta-analysis provides real-life data on antiplatelet strategies tailored per patient. It is likely that low-risk patients for thromboembolism in the registry received SAPT rather than DAPT. Consequently, it could be postulated that this tailor-made strategy prevented increased rates of bleeding complications. Therefore, both study methods have their advantages and pitfalls. Clinicians may consider combining both when searching for answers. We believe that pooling individual subject data, despite being time-consuming and requiring extensive cooperation, may enhance statistical power and at the same time allow comparison of outcomes across different study and site settings. Additionally, the variation in study patients in pooled datasets may be used for subgroup analysis and interaction testing.

The current meta-analysis underlines the need for more data on this important topic. We encourage the initiation of both large-scale randomized trials, as well as registries containing real-life data. Sharing these data between researchers and clinicians in open-access databases seems to be the way forward. Clinicians and patients will benefit from the diversity of trial types in the decision-making process regarding the optimal antithrombotic strategy after TAVI.

Conflicts of interestBoth authors have no conflicts of interest to declare.

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REFERENCES1. Leon MB, Smith CR, Mack MJ, et al. Transcatheter or Surgical Aortic-Valve Replacement

in Intermediate-Risk Patients. N Engl J Med. 2016;374:1609-1620.2. Pagnesi M, Martino EA, Chiarito M, et al. Silent cerebral injury after transcatheter aortic

valve implantation and the preventive role of embolic protection devices: A systematic review and meta-analysis. Int J Cardiol. 2016;221:97-106.

3. Hassell ME, Nijveldt R, Roos YB, et al. Silent cerebral infarcts associated with cardiac disease and procedures. Nat Rev Cardiol. 2013;10:696-706.

4. Eggebrecht H, Schmermund A, Voigtlander T, Kahlert P, Erbel R, Mehta RH. Risk of stroke after transcatheter aortic valve implantation (TAVI): a meta-analysis of 10,037 published patients. EuroIntervention. 2012;8:129-138.

5. Grube E, Laborde JC, Gerckens U, et al. Percutaneous implantation of the CoreValve self-expanding valve prosthesis in high-risk patients with aortic valve disease: the Siegburg first-in-man study. Circulation. 2006;114:1616-1624.

6. Genereux P, Head SJ, Van Mieghem NM, et al. Clinical outcomes after transcatheter aortic valve replacement using valve academic research consortium definitions: a weighted meta-analysis of 3,519 patients from 16 studies. J Am Coll Cardiol. 2012;59:2317-2326.

7. Genereux P, Cohen DJ, Mack M, et al. Incidence, predictors, and prognostic impact of late bleeding complications after transcatheter aortic valve replacement. J Am Coll Cardiol. 2014;64:2605-2615.

8. Verdoia M, Barbieri L, Nardin M, Suryapranata H, De Luca G. Dual Versus Single Antiplatelet Regimen With or Without Anticoagulation in Transcatheter Aortic Valve Replacement: Indirect Comparison and Meta-analysis. Rev Esp Cardiol. 2017. http://dx.doi.org/ 10.1016/j.rec.2017.06.012.

9. Hassell ME, Hildick-Smith D, Durand E, et al. Antiplatelet therapy following transcatheter aortic valve implantation. Heart. 2015;101:1118-1125.

10. Rodes-Cabau J, Masson JB, Welsh RC, et al. Aspirin Versus Aspirin Plus Clopidogrel as Antithrombotic Treatment Following Transcatheter Aortic Valve Replacement With a Balloon-Expandable Valve: The ARTE (Aspirin Versus Aspirin + Clopidogrel Following Transcatheter Aortic Valve Implantation) Randomized Clinical Trial. JACC Cardiovasc Interv. 2017;10:1357-1365.

11. Stabile E, Pucciarelli A, Cota L, et al. SAT-TAVI (single antiplatelet therapy for TAVI) study: a pilot randomized study comparing double to single antiplatelet therapy for transcatheter aortic valve implantation. Int J Cardiol. 2014;174:624-627.

12. Ussia GP, Scarabelli M, Mule M, et al. Dual antiplatelet therapy versus aspirin alone in patients undergoing transcatheter aortic valve implantation. Am J Cardiol. 2011;108:1772-1776.

13. LeLorier J, Gregoire G, Benhaddad A, Lapierre J, Derderian F. Discrepancies between meta-analyses and subsequent large randomized, controlled trials. N Engl J Med. 1997;337:536-542.

14. Durand E, Blanchard D, Chassaing S, et al. Comparison of two antiplatelet therapy strategies in patients undergoing transcatheter aortic valve implantation. Am J Cardiol. 2014;113:355-360.

15. Poliacikova P, Cockburn J, de Belder A, Trivedi U, Hildick-Smith D. Antiplatelet and antithrombotic treatment after transcatheter aortic valve implantation - comparison of regimes [abstract]. J Invasive Cardiol. 2013;25:544-548.

16. Sherwood MW, Vora AN, Vemulapalli S, et al. TCT-103 National variation in post-TAVR. Antithrombotic therapy utilization and associated outcomes: Insights from the STS/ACC TVT Registry [abstract]. J Am Coll Cardiol. 2015;66:B47-B48.