Management of patient outcomes after TAVI

Transcatheter aortic valve implantation (TAVI), first performed in 2002 by Alain Cribier, is a standard of care among inoperable and mostly the first choice therapy for patients with severe aortic stenosis (AS) and at high risk in surgical aortic valve replacement (SAVR).^1,2 The number of TAVIs performed reached approximately 150,000 worldwide by the end of 2014.^1,2 After over a decade of experience, the efficacy of TAVI is well established. The very first studies, such as the Placement of Aortic Transcatheter Valves (PARTNER) randomised trial, and the OBSERVANT study and registries, confirmed TAVI’s comparability to classic SAVR in early and long-term prognosis improvement.^3–5 Current studies such as the US CoreValve Pivotal trial indicated TAVI’s superiority over SAVR in terms of periprocedural and late mortality as well as major cardiovascular and cerebrovascular events.^6–11

 

The procedural complications are rare but most of them are severe. They frequently require conversion to open surgery and are considered the main predictors of periprocedural mortality.^6–12 Procedural complications such as annular and left ventricle rupture, aortic dissection and coronary artery occlusion are potentially fatal. The sub-analysis of Edwards SAPIEN Aortic Bioprosthesis European Outcome (SOURCE) registry proved that although emergency cardiac surgery is required in only 1.2% of TAVI procedures, the immediate and 30-day mortality in the case of this complication exceeds 37% and 50%, respectively. The leading causes of an open surgery were prosthesis malpositioning (33%) and aortic injury (26%).¹² Annular rupture and aortic injury were related to total mortality, while the life-saving effect of the surgery was observed in patients with acute aortic regurgitation.¹² Similarly, periprocedural coronary obstruction might be a life-threatening complication. Although the most recent VIV International Data (VIVID) registry reported that this complication is relatively rare in the case of TAVI in native valves, it occurs 3- to 4-fold more commonly after valve-in-valve procedures and is associated with a high mortality rate.¹³ The procedural complications and their prevalence are presented in Table 1.

 

Despite the indisputable advantages, TAVI is still a high risk procedure related to a high rate of early, post-procedural complications, summarised by the second consensus of the Valve Academic Research Consortium.^2,6 The substantial prevalence of early complications appears to result from the technical complexity of the procedure and the patient’s unique characteristics.¹¹ Although the rate of the adverse events have been diminished by growing experience, the smaller delivery systems and the use of new generation devices, the identification of futile population and specific TAVI risk scores is still a top issue.^14,15

 

Early post-procedural complications are the primary limitations of TAVI and the main predictors of 30-day mortality (Table 1). The most detrimental for early prognosis are stroke, bleeding and vascular complications (VC) and related blood transfusions.^1–16

 

 

Cerebrovascular events (CVE) (a stroke or a transient ischaemic attack after TAVI) are uncommon and occur particularly during the first two post-procedural days. Early CVE appears to be mainly procedure-related ischaemic events resulting from mechanical injury of atherosclerotic plaques in ascending aorta and access site arteries.^15,16 The main predictors of CVE are routine elements of TAVI such as transfemoral approach, and pre-dilatation of native valves, prosthesis post-dilatation and its reposition, massive valve calcification.^15,16 Although the risk of CVE is reducible by cerebrovascular protection devices for example, Claret Montage™ Dual Filter System, TriGuard™ or the Embrella Embolic Deflector System,^16,17 approximately 68–90% of TAVI patients have proven to have clinically silent multifocal cerebral microembolism with an unknown cognitive and prognostic impact.

 

The most common adverse events after TAVI are early bleeding, vascular complications and related blood transfusion.^3–12 Since the very beginning of its clinical introduction, TAVI has been burdened with a high rate of bleeding and vascular complications. Previous analyses reported that post-procedural bleeding affected between 30–70% of TAVI patients.^{3–6,19–21} A high proportion of late bleeding was also observed two years after the procedure (14.7–28.6%).^3,18–20 Vascular complications were reported in 10–50% of the procedures.^{3–6,22–24} The high prevalence of vascular complications was claimed to be procedure-related due to mechanical injury of access arteries, learning curve, large sizes of delivery systems, as well as the ambiguous definition of these events. 

 

Although the decade of experience and procedure improvements decreased their prevalence, early bleeding and vascular complications still have been the main safety limitations of TAVI (Table 1). The high prevalence of bleeding and VC appears to result from the unique patient characteristics and suboptimal antithrombotic prophylaxis. Numerous single-centre analyses confirmed that the TAVI populations due to advanced age, baseline anaemia, renal failure, general atherosclerosis, diabetes and low body mass are initially subjected to high risk for bleeding.^20,21 Vascular complications are predicted by arterial morphology and the procedure related risk factors such as severe calcification, small dimensions of access site arteries, small ratio between arterial–delivery systems diameters and the use of percutaneous closure devices.^22–24

 

The majority of reported bleeding is related with the access route complications and periprocedural blood loss.^19–21,25 Yet, a number of studies indicate that early bleeding is not only procedure related incidents.^19,21 Depending on the analyses, the percentage of bleeding resulted from distant organ haemorrhage and periprocedural blood loss range from 8% to nearly 30%.^19,21

 

In previous analyses, between 40–80% of the subjects required blood transfusion after TAVI.^19,25 Currently, Nuis et al. in a multicentre observational study reported that about 40% of TAVI participants underwent blood transfusion in the early post-procedural period.²⁶ The most frequent indication is operative blood loss and access site complications.^26,27 Seiffert et al. proved that the independent predictors of blood transfusion were low body mass index, combined antithrombotic/antiplatelet therapy and baseline anaemia.²⁷ Although blood transfusion is the consequence of bleeding, vascular complications and pre-procedural anaemia, they have a separate, significant adverse impact on early and late mortality after TAVI.^26–28

 

The complications described above seem to have much in common with antithrombotic/antiplatelet therapy. The current guidelines recommended dual antiplatelet therapy (DAPT) with acetylsalicylic acid (ASA) and clopidogrel as a thromboembolic prophylaxis for three to six months after TAVI.^1,29 This recommendation was empirically transferred from percutaneous coronary intervention (PCI), and time of prophylaxis was based on histological findings of CV prosthesis incorporation and endothelialisation over a period of three months after implantation.³⁰ The safety and efficacy of DAPT prophylaxis after TAVI is not evidence-based. Moreover, due to concomitant atrial fibrillation (AF), combined therapy with oral vitamin K antagonists (OAC) is commonly required. 

 

This translates into the individualisation of the therapy and a large discrepancy between the guidelines and real-life antithrombotic prophylaxis after TAVI.^21,31 Although the impact of anticoagulation on bleeding is difficult to investigate, four single centre studies, and current meta-analysis compared regimens of DAPT versus ASA in TAVI prophylaxis.^21,32 ASA reduced 30-day and six-month risk for bleeding and vascular complications with the comparable efficacy profile to DAPT. The beneficial effect of ASA discredits the justification of DAPT prophylaxis.³² Thus, after TAVI, analogously as after surgical bioprosthesis implantation, three months of antiplatelet monotherapy or OAC appears to be reasonable.¹ We hope that the benefit–risk balance of low-dose aspirin prophylaxis in TAVI elderly in comparison to DAPT will be defined by ongoing, prospective, randomised ARTE trial.³³

 

The concern of the safety of prophylaxis after TAVI may pave the way for non vitamin K oral anticoagulants (NOACs). These drugs turned out to be safer than OAC.³⁴ Therefore, they are recommended in elderly patients with non-valvular atrial fibrillation.³⁴ Yet, the safety and efficacy of NOACs in TAVI population is unknown. Although, patients with chronic NOACs therapy subjected to PCI can receive NOACs in combination with antiplatelet agents, these drugs are not recommended in TAVI.³⁵

 

The majority of bleeding, vascular complications and blood transfusion occur during TAVI or early after the procedure. Thus, pre-procedural anticoagulation also appears to be relevant for these events.²¹ Emphasising the impact of pre-procedural therapy, we showed that clopidogrel used in combined therapy before TAVI is an independent bleeding risk factor. Notably, the use of clopidogrel before TAVI is related to preceding PCI, performed as the preparation for a valve implantation.²¹ It is related to current position of ESC, which state that the diagnosis and treatment of coronary artery disease should be performed before TAVI.¹

 

However, the term of prior PCI, the type of stents and the duration of combined therapy before TAVI remain undefined. Current ESC/EACTS guidelines recommend clopidogrel discontinuation before a coronary bypass surgery.³⁵ Similarly in TAVI candidates PCI should rather be performed early enough to finish combined therapy with clopidogrel before valve implantation. Our proposal for periprocedural antithrombotic therapy in TAVI population is presented in Table 2. 

 

 

Additional frequent TAVI complications are conduction disturbances. These abnormalities appear predominantly in early post-procedural period and end up with permanent pacemaker implantation (PPI) significantly more common than SAVR (6–40% versus 2–10%). Anatomical proximity of the aortic valve complex to the AV node, His bundle and its branches may explain the observed increase in conduction disturbances after TAVI.^36–38

 

The main patient-related predictors for PPI are age, male gender, thickness of the intraventricular septum and aortic annulus/left ventricle outflow track (LVOT) asymmetry. Predisposing conduction disturbances are pre-procedural left anterior fascicular block, right bundle branch block, first-degree atrioventricular block, as well as intra-procedural atrioventricular blocks, and new left bundle branch block.^36–38 Invariably big differences in PPI between CV and ES prostheses are reported. 

 

According to current meta-analyses CV implantation relates to 2.5-fold higher risk for PPI than ES implantation.³⁸ Similarly, the first randomised comparison between CV and ES indicated a significantly higher rate of PPI in case of the former one (37.6% versus 17.3%; p=0.001).9 This results from the greater length of CV prosthesis, the depth of its implantation in LVOT and continuous radial force exerted by CV in this area.⁹ Other established procedure-related risk factors for PPI are a bigger balloon and a greater number of native valve pre- and post-dilatations and prosthesis–aortic annulus mismatch.^36,37

 

Although PPI after TAVI does not deteriorate the prognosis; it has a substantial haemodynamic impact. As Biner et al. proved, PPI attenuates the improvement in left ventricle ejection fraction and stroke volume, and showed smaller reduction in systolic pulmonary artery pressure and deterioration of right ventricular index.³⁸

 

Subsequent TAVI complication – moderate or severe paravalvular regurgitation (PVR) – impairs survival.^39,40 The prevalence of more than mild PVR after TAVI varies widely among the studies. In the latest meta-analysis by Athappan et al., the pooled estimation for overall incidence of serious PVR was 11.7%.³⁹ Irrespective of the reported differences in its occurrence, PVR is mainly moderate and invariably greater in case of CV versus ES (2–42.5% versus 0.6–22%).^9,39,40 PVR results mostly from aortic annulus–prosthesis diameter mismatch, severe and asymmetric calcification of the aortic valvular complex and incomplete device expansion. 

 

Severe PVR frequently required several balloon post-dilatations and valve in valve implantation.³⁹ Numerous studies, starting with PARTNER trial, indicated that severe PVR is associated with increased 30-day and late mortality.^{8–10,16,39,40} Although some of the recent data have suggested a reduction in PVR over time,^6,7 other outcomes like the ones from the CHOICE study did not observe it up to 30 days after the procedure.⁹ The next generation of bioprostheses might potentially minimise PVR, as the results of the REPRISE II trial for the LotusValve™ System described.¹⁷

 

Another threat for the TAVI population is post-procedural acute kidney injury (AKI), which complicated nearly one fifth of the procedures.^41,42 Although the majority of post-procedural AKI is mild (stage 1), previous and up-to-date reports confirmed its adverse impact on early and long-term prognosis. The risk of AKI results potentially from high prevalence of baseline renal failure, the haemodynamic changes during the procedure, the use of contrast agents, female sex, general anaesthesia, blood transfusion, peripheral vascular disease and history of heart failure.^41,42 Additionally, the strong correlation of AKI with early post-procedural bleeding and VC due to renal hypoperfusion was noted.⁴¹

 

Interestingly, a few analyses reported the global substantial improvement in renal function after TAVI. The prevalence of this phenomenon significantly exceeded that of AKI.⁴¹

 

High risk in patients and a great number of TAVI complications translates into prolonged hospitalisation. In SENTINEL registry the mean time of hospitalisation was 9.3±8.1days with over 10 days of hospital stay in >40% of patients after a transapical valve implantation.¹¹ In the FRENCH registry, hospital stay was even longer with a mean value of 11.1±8.0 days and 13.3±7.8 days of hospitalisation for patients after transapical procedure, including at least 4.9±4.8 days of an intensive care unit stay.⁸ Nevertheless, TAVI turned out to be a cost effective intervention in comparison to medical management, as well as to SAVR in high-risk elderly patients with severe AS.^43,44

 

Although the two-year PARTNER trial observation of bioprostheses durability is promising,¹⁸ there still has been the paucity of long-term follow-up data, which could clearly confirm long-term advantages of TAVI. The durability of modern bioprostheses implanted surgically exceeds 15–20 years. 

 

We can only speculate that the durability of TAVI bioprostheses is similar to the ones implanted surgically since the US CoreValve Pivotal trial demonstrated comparable changes in the mean aortic valve gradient and effective orifice area one year after TAVI and SAVR.⁶ Although TAVI prostheses undergo the same preservation and decalcification processes, the crimping or stretching during the implantation might alter their 5–10 year durability. 

 

This knowledge seems to be essential in face of common extension of TAVI indications to lower risk patient population.^4,8,10 We can expect that the US CoreValve Pivotal trial results translate into a more liberal recommendation for patients with intermediate surgical risk. Despite the lack of thorough data on prosthesis long-term durability, this trend has been already observed in the FRENCH 2 registry and OBSERVANT study.^4,8

 

These changes will happen in the near future since in FRENCH 2 registry patients choice in favour of TAVI increased significantly (from 14.4 to 17.1%; p=0.04).⁸ Similarly, in the GARY registry, 13% of patients have currently opted for TAVI rather than conventional SAVR.¹⁰

 

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