Influence of Valve Type and Antiplatelet Regimen on Platelet Reactivity After TAVI: Subanalysis of the REAC-TAVI Trial

Abstract: Objectives. Ticagrelor has proven more effective than clopidogrel at attaining a maintained suppression of high platelet reactivity (HPR) in aortic stenosis patients undergoing transcatheter aortic valve implantation (TAVI). This study aims to assess the influence of implanted valve type on the degree of platelet reactivity (PR) after TAVI. Methods. This study is a prespecified analysis of REAC-TAVI, a prospective, multicenter study that included patients on dual-antiplatelet therapy with aspirin and clopidogrel before TAVI. Patients with HPR (n = 48) were randomized to aspirin and clopidogrel or aspirin and ticagrelor for 3 months, while those without HPR (n = 20) were continued on aspirin and clopidogrel. PR was measured 6 hours, 24 hours, 5 days, 30 days, and 90 days after TAVI with VerifyNow assay. Bioprosthetic valves were classified as balloon-expandable valve (BEV), self-expandable valve (SEV), or other. Results. Sixty-eight patients comprising 32 BEVs, 28 SEVs, and 8 other valves were included. Devices were larger and postdilation was more frequent in the SEV group. Follow-up PR was lower in patients treated with ticagrelor vs those treated with clopidogrel at all time points after TAVI, including patients without baseline HPR (P<.001). PR after TAVI was similar in the three groups. Major cardiovascular adverse events, stroke, and hemorrhagic complications were comparable across the different bioprosthesis groups at 4-month follow-up. Conclusions. The effect of valve type on PR after TAVI is similar across the spectrum of most transcatheter valves. In our sample, ticagrelor achieved a faster and more effective reduction in PR than clopidogrel in patients with HPR undergoing TAVI, irrespective of valve type. 

J INVASIVE CARDIOL 2020;32(12):446-452. Epub 2020 August 10. 

Key words: aortic stenosis, bioprosthetic valves, dual-antiplatelet therapy

Transcatheter aortic valve implantation (TAVI) is the treatment of choice for patients with severe aortic stenosis (AS) who are inoperable or at high surgical risk.^1,2 Recently, new evidence supporting non-inferiority of TAVI as compared with surgical aortic valve replacement in intermediate- and low-risk patients has emerged.^3-5 However, incidence of periprocedural thromboembolic and hemorrhagic adverse events after TAVI remains relevant and associates with higher morbidity and mortality.^6,7 Importantly, risk of thromboembolic events remains elevated at up to 6 months after the procedure, which implies a prothrombotic state in this population.⁸ Moreover, different degrees of subclinical valve thrombosis, which has been related to hemodynamic valve deterioration, are recognized in up to 15% of TAVI recipients by means of multislice computer tomography (MSCT).^9,10 Thus, identification of an optimal antithrombotic regimen after TAVI that adequately balances ischemic and bleeding hazards currently remains an important unanswered question.^11,12

In clinical practice, and based on American and European guidelines, dual-antiplatelet therapy (DAPT) with aspirin and clopidogrel for 1-6 months followed by lifelong aspirin is the most frequently employed antithrombotic regimen after TAVI,^13,14 despite a lack of compelling evidence.

However, individual response to clopidogrel is known to be highly variable, and high platelet reactivity (HPR) has been recognized in up to one-third of patients with ischemic heart disease,^15,16 resulting in worse clinical outcomes.¹⁷ Notwithstanding, data on platelet reactivity (PR) in AS patients undergoing TAVI are scarce and limited mostly to observational studies,^18-20 and the impact of HPR on outcomes after TAVI has not been evaluated to date. 

The previously published REAC-TAVI trial identified baseline HPR in over two-thirds of patients undergoing TAVI on previous DAPT with aspirin and clopidogrel.²¹ In this prespecified subanalysis of the REAC-TAVI trial, we aimed to assess the influence of transcatheter aortic valve type on PR after TAVI, according to the DAPT regimen employed.

Methods

The REAC-TAVI study design has been previously described. Briefly, it is a prospective, multicenter, randomized clinical trial that assessed PR following transfemoral TAVI in patients on DAPT with aspirin and clopidogrel. Patients with baseline HPR were randomized in a 1:1 fashion to aspirin and clopidogrel or aspirin and ticagrelor for 3 months, while those with normal PR were continued on aspirin and clopidogrel and incorporated into a registry arm. PR was measured with the VerifyNow assay (Accriva Diagnostics) at 6 different time points after TAVI. HPR was defined as a P₂Y₁₂ reaction unit (PRU) value ≥208, as determined by international consensus recommendations.^22,23 The study protocol complied with the Helsinki Declaration and was approved by the centers’ research committees. Informed consent was obtained from each patient. 

Transcatheter valves were classified as balloon-expandable valve (BEV), self-expandable valve (SEV), or other valve types, comprising Lotus valves (Boston Scientific) and Direct Flow valves (Direct Flow Medical). A further analysis comparing valves with an annular vs a supra-annular design was performed. Transcatheter valve selection was made at the discretion of the implanting physician. Baseline PR measurement was conducted in all patients. A comparative analysis of PR following TAVI according to implanted bioprosthetic valve and antiplatelet treatment regimen was performed. 

Major adverse cardiovascular events (MACEs), a composite of death, stroke, and myocardial infarction, were recorded during 4-month follow-up after TAVI. An additional safety endpoint included hemorrhagic complications, as per Valve Academic Research Consortium (VARC)-2 criteria. Net adverse clinical events (NACEs) were defined as a combination of death, stroke, myocardial infarction and major bleeding.

Statistical analysis. Categorical variables are expressed as frequencies and percentages. For baseline characteristics, continuous variables are expressed as mean ± standard deviation; PRU as mean ± standard error. Chi-square tests or Fisher’s exact tests were used, where appropriate, to compare categorical variables between groups. ANOVA tests were used to evaluate the differences between the 3 different valve types in continuous variables.

Results

A total of 68 patients underwent TAVI implantation, including 32 BEVs (47.1%), 28 SEVs (41.2%), 6 Lotus valves (8.8%), and 2 Direct Flow Medical valves (2.9%). This corresponds to 28 Evolut-R valves (Medtronic), with a supra-annular design, that constitute the SEV group, and 40 valves with an annular disposition, including 32 Sapien 3 valves (Edwards Lifesciences), that constitute the BEV group.

One-half of the patients were male and mean age was 80.6 ± 7.1 years. The sample presented an intermediate surgical risk, with mean Society of Thoracic Surgeons (STS) score and EuroScore II of 5.8 ± 5.4% and 10.7 ± 7.8%, respectively. Mean left ventricular ejection fraction was significantly higher in the BEV group and NT-proBNP values were significantly greater in the SEV group, while previous transient ischemic attack, angina, and smoker status were more frequent in patients undergoing implantation with other valve types. No other significant differences in baseline characteristics across valve groups existed (Table 1). 

Mean baseline PRU was 132.8 ± 11.9 in the registry arm and 273.2 ± 9.2 in the randomized group, without differences according to allocated treatment group with either clopidogrel (269.4 ± 10.0) or ticagrelor (277.0 ± 8.5) (Figures 1A and 1B). Implanted valve types were evenly distributed across the registry and randomized groups (P>.05) (Table 1). 

Device sizes were bigger (96% >25 mm) and postdilation was more frequent (38.5%) in the SEV group, while surgical femoral closure was most frequent in patients undergoing BEV implantation (25.9%). TAVI procedures involving other valve types were more frequently performed under general anesthesia (75%), presented a higher incidence of intraprocedural valve recapture (37.5%), and entailed longer in-hospital stay (9.7 ± 2.1 days).

Baseline and follow-up PR values after TAVI according to implanted valve and allocated antiplatelet treatment are displayed in Figure 2. PR values within each antiplatelet regimen did not significantly differ according to bioprosthetic valve type, except for a tendency to greater PR in the other valve group compared with BEV and SEV, mainly at baseline, and at 6 hours and 24 hours post TAVI, without achieving statistical significance (P=.09, P=.05, and P=.07, respectively). This trend was maintained at follow-up in all clopidogrel-treated patients, but not in the ticagrelor group, which displayed a sustained reduction in PR after the first 24 hours. PR after TAVI was significantly lower in patients treated with ticagrelor at all time points and across all valve types (P<.01), both in the randomized group and when compared with registry patients (Supplemental Figure S1). 

Interestingly, about one-third of patients with normal baseline PR developed HPR to clopidogrel at 30 days post procedure (Figure 1B). These patients were evenly distributed across the different valve types and no significant differences in follow-up PR values of patients with and without baseline HPR existed. 

Absolute change in PR after TAVI was comparable across all bioprosthesis and time intervals analyzed, with the exception of registry patients treated with other valve types, which presented a significantly greater percentage reduction in PR at 5 days (+22%, -2.4%, and -47% according to treatment group), probably in relation to slightly higher baseline PRU values (Figure 1B). Notwithstanding, no differences in PR values at 30 and 90 days in the 3 bioprosthesis groups were observed. 

A further analysis evaluated baseline and follow-up PR according to annular vs supra-annular valve design. No significant differences in PR within each treatment group were observed. Moreover, incidence of new-onset HPR after TAVI was comparable in annular vs supra-annular devices.

At 4-month follow-up, 8 patients (11.8%) met the definition of MACE, with 6 cardiovascular deaths (8.8%), 2 ischemic strokes (2.9%), and 1 spontaneous myocardial infarction (1.5%). Major bleedings occurred in 9 patients (13.2%), although there were no deaths related to hemorrhagic complications. All MACEs and bleeding events were comparable across the different bioprosthetic valves (Table 2), resulting in equivalent NACE rates. Vascular access-site complications and conduction disturbances developed in 2 patients (7.1%) and 16 patients (23.5%), respectively, without differences between valve types. No differences in clinical endpoints according to annular vs supra-annular valve design were observed.

Discussion

To the best of our knowledge, this is the first study to report PR values according to the type of transcatheter aortic valve implanted as well as antiplatelet regimen. The main findings can be summarized as follows: (1) PR after TAVI was not significantly affected by transcatheter valve type implanted. Furthermore, no significant differences in PR values according to supra-annular vs annular valve design existed. (2) Ticagrelor achieved a faster, more effective, and sustained reduction in PR after TAVI than clopidogrel, irrespective of valve type. Ticagrelor also attained a greater reduction in PR values than clopidogrel in patients with baseline HPR. (3) No differences in MACE rates or hemorrhagic complications according to treatment group or valve type were detected.

Optimal antithrombotic regimen after TAVI remains currently under debate. Despite lack of robust clinical evidence, most patients are managed with DAPT with aspirin and clopidogrel during the first months following TAVI. Increasing recognition of subclinical valve thrombosis with MSCT has raised concerns regarding DAPT with clopidogrel as the standard postprocedural therapy in TAVI.²⁴ Nevertheless, regular anticoagulation of these patients could lead to an increase in bleeding without clinical benefit. Indeed, single-antiplatelet therapy with low-dose aspirin may represent a reasonable treatment alternative in patients at high bleeding risk, but no definite data to establish firm recommendations exist to date.¹¹ Thus, strategies involving new-generation P₂Y₁₂ inhibitors, such as ticagrelor, represent an attractive alternative. 

Deficient response to clopidogrel has been previously reported in 20%-40% of patients with ischemic heart disease^15,16 and is related to worse outcomes.

Recently, the randomized REAC-TAVI trial²¹ identified baseline HPR to clopidogrel in over two-thirds of patients undergoing TAVI, in agreement with previous registries.^18-20 Importantly, about 30% of patients adequately responding to clopidogrel at baseline developed HPR at 30-day follow-up. 

In the current subanalysis of REAC-TAVI trial, we evaluated whether follow-up PR was influenced by transcatheter valve type implanted. Increased baseline PR in patients undergoing TAVI could act as a trigger for platelet deposition and thrombi formation on the surface of bioprosthetic leaflets, particularly during the first postprocedural months, before valve endothelialization. However, impact of PR values on subclinical valve thrombosis was not determined in the current study, as systematic evaluation with MSCT was not performed. Other mechanisms that could also promote valve thrombosis include traumatic injury during valve crimping, deployment, and postdilation, leading to microfissures in the bioprosthesis leaflets.^25,26 In addition, exposure of subendothelial tissue from degenerated native aortic valve leaflets in TAVI could constitute a further mechanism favoring thrombus formation in transcatheter valves as compared with surgical aortic valve replacement.^9,27 Finally, endothelial injury during the TAVI procedure, which implies use of stiff guidewires in the left ventricle and may disrupt calcifications at the annular and supra-annular level of the aorta, also enhances platelet adhesion and activation. 

In our sample, PR presented comparable baseline and follow-up values across the various valve types within each antiplatelet therapy group, ie, aspirin and clopidogrel vs aspirin and ticagrelor groups. Of note, the type of transcatheter valve implanted did not influence the incidence of new-onset HPR after TAVI. Similarly, annular vs supra-annular valve design exerted no significant influence in PR values on follow-up. 

However, PR values were numerically greater in patients in the other valve type group, compared with BEV and SEV, but this difference did not reach statistical significance, which was possibly related to the limited number of patients. Higher incidence of valve recapture in this group (implying increased procedural valve manipulation) is a plausible mechanism accountable for these findings. Furthermore, we must consider the differences in the design of the other valve types compared with the SEV and BEV types. Lotus has a denser stent frame composed of woven nitinol wires that provide significant radial force compared with the rest of transcatheter valves, and non-endothelialized metallic frames could promote thrombus formation.²⁸ In the case of the Direct Flow valve, the device (currently not commercially available) has bovine pericardial leaflets attached to a tubular, inflatable support structure that is covered with polyester fabric and a polymer exchange system. The impact of different transcatheter valve materials and designs on PR is still unknown. 

As reported by the REAC-TAVI trial,²¹ ticagrelor achieves a faster and more sustained reduction in PR than clopidogrel. In our sample, transcatheter valve type exerted no influence on the degree of PR inhibition with ticagrelor, which proved more effective than clopidogrel in all valve types and at all time points. Thus, until further evidence regarding antithrombotic management after TAVI emerges, DAPT with aspirin and ticagrelor might represent a reasonable alternative to aspirin and clopidogrel and merits further investigation, especially in non-responders to clopidogrel and patients at highest risk of thromboembolic complications. 

Study limitations. Our study has several limitations. First, the employed HPR cut-off value was derived from trials assessing thrombotic events in patients with coronary artery disease, as no data regarding the appropriate cut-off values following TAVI exist to date. Second, PR to aspirin was not measured. However, previous studies have reported low prevalence rates of high reactivity on treatment aspirin, which suggests a lower impact of this entity on subsequent ischemic events. Third, our study was designed to detect differences regarding the pharmacodynamics of different antiplatelet regimens and was thus underpowered for thrombotic and bleeding endpoints. Future trials specifically designed for this purpose will have to assess the impact of PR on outcomes after TAVI. Finally, we did not perform a systematic assessment with MSCT after TAVI in our study, so a possible relationship between PR after TAVI and subclinical leaflet thrombosis could not be analyzed. 

Conclusion

In our sample, PR after TAVI was not significantly affected by transcatheter valve type. Importantly, ticagrelor achieved a faster and more effective reduction in PR than clopidogrel, irrespective of valve type and baseline PR values. No significant differences in ischemic or hemorrhagic adverse events according to antiplatelet regimen or implanted valve type were observed. Further adequately sized studies assessing the role of ticagrelor in the postprocedural management of TAVI patients with power to detect differences in clinical events are warranted.

From the ¹Cardiology Department, Hospital Universitario de Salamanca, Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain; ²Centro de Investigación en Red de Enfermedades Cardiovasculares (Network Research Center for Cardiovascular Diseases), CIBER-CV, Madrid, Spain; ³Cardiology Department, Hospital Universitario Virgen de la Arrixaca, IMIB-Arrixaca, Murcia, Spain; ⁴Cardiology Department, Hospital Alvaro Cunqueiro, University Hospital of Vigo, Vigo, Spain; ⁵Cardiovascular Research Unit, Cardiology Department, Hospital Alvaro Cunqueiro, University Hospital of Vigo, Vigo, Spain; ⁶Cardiovascular Research Group, Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO, Vigo, Spain; ⁷Interventional Cardiology, University Hospital La Paz, Madrid, Spain, Instituto de Investigación del Hospital La Paz (IDIPAZ); ⁸Cardiology Department, Hospital Universitario de Bellvitge, Barcelona, Spain; and the ⁹Cardiology Department, Hospital Universitario Virgen de las Nieves, Granada, Spain.

Funding: This is an investigator-initiated trial, sponsored by the Spanish Society of Cardiology, and supported by AstraZeneca. Data monitoring, data entry, database maintenance, statistical analysis, and drafting and submission of the final manuscript was exclusively performed by the investigators. AstraZeneca played no role in the design of the study, data analysis, data interpretation, writing of the report, or in the decision to submit for publication. 

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Moreno reports personal fees (research, lectures, consulting, consulting, and/or proctoring) from Abbott Vascular, Biotronik, Boston Scientific, Edwards Lifesciences, Bayer, Ferrer, Braun, Palex Medical, Astra Zeneca, Daicchi-Sankyo, Medtronic, New Vascular Therapy, AMGEN, Iberhospitex, and Terumo. The remaining authors report no conflicts of interest regarding the content herein.

Manuscript accepted April 14, 2020.

Address for correspondence: Victor Alfonso Jimenez-Diaz, MD, MPH, Cardiovascular Research Unit & Cardiology Department, Hospital Álvaro Cunqueiro, University Hospital of Vigo, Estrada de Clara Campoamor, 341, 36312, Vigo, Spain.

Email: sooner_79@hotmail.com or victor.alfonso.jimenez.diaz@sergas.es 

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