Reduced leaflet motion after transcatheter aortic-valve replacement
Selected in The New England Journal of Medicine by D. Giacoppo , A.H. Frangieh
The GALILEO-4D was a dedicated substudy that sought to evaluate the effect of oral anticoagulation with rivaroxaban on bioprosthetic aortic valve leaflet thickening and motion impairment.
References
Authors
De Backer O, Dangas GD, Jilaihawi H, Leipsic JA, Terkelsen CJ, Makkar R, Kini AS, Veien KT, Abdel-Wahab M, Kim WK, Balan P, Van Mieghem N, Mathiassen ON, Jeger RV, Arnold M, Mehran R, Guimarães AHC, Nørgaard BL, Kofoed KF, Blanke P, Windecker S, Søndergaard L; GALILEO-4D Investigators
Reference
N Engl J Med. 2019 Nov 16 [Epub ahead of print]
Published
November 2019
Link
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Our Comment
This joint review is part of the PCRonline GLOBAL Journal Club Initiative by selected members of the EAPCI/PCR Journal Club and EAPCI young ambassadors, and is based on the underlying idea of “Bringing peers together, exchanging ideas, towards a common standard of care”.
Why this study – the rationale/objective?
Transcatheter aortic valve implantation (TAVI) has become the standard of care for an increasing number of patients with aortic stenosis. However, the broadening of indications and the implementation of advanced diagnostic tools during follow-up have enabled new clinical issues that have not yet adequately addressed.
Hypoattenuated leaflet thickening - characterized by a thin layer of thrombus covering the aortic side - and reduced leaflet motion, as detected by four-dimensional volume-rendered computed tomography (4D-CT), have been reported in aortic bioprosthetic valves implanted both by transcatheter or surgical approaches. Some observational studies have raised concerns about a possible causal association between subclinical leaflet thrombosis and ischemic cerebrovascular events, systemic embolism, and accelerated bioprosthesis degeneration.
Antiplatelet therapy after TAVI is mostly empirical and wide variations across centres and regions exist. New-generation oral anticoagulants have shown in other settings some advantages compared with warfarin and in some reports, oral anticoagulation after TAVI seemed to be associated with decreased bioprosthetic valve dysfunction. However, whether systematic use of a new-generation oral anticoagulants after TAVI can reduce the occurrence of subclinical leaflet thrombosis and decrease the incidence of thromboembolic events over follow-up is unknown.
How was it executed – the methodology?
The Global Study Comparing a Rivaroxaban-Based Antithrombotic Strategy to an Antiplatelet-Based Strategy after Transcatheter Aortic Valve Replacement to Optimize Clinical Outcomes (GALILEO) trial was designed to investigate whether rivaroxaban at a dose of 10 mg daily can reduce the risk of thromboembolic events after successful TAVI in patients without an established indication for oral anticoagulation.
The GALILEO-4D was a dedicated substudy that sought to evaluate the effect of oral anticoagulation with rivaroxaban on bioprosthetic aortic valve leaflet thickening and motion impairment. Briefly, patients included in the GALILEO trial after successful TAVI for aortic stenosis were enrolled at 12 sites in the GALILEO-4D substudy. Patients were randomly assigned to rivaroxaban at a dose of 10 mg once daily plus aspirin at a dose of 75-100 mg once daily for 3 months, followed by rivaroxaban monotherapy, or to clopidogrel at a dose of 75 mg once daily plus aspirin at a dose of 75-100 mg once daily for 3 months, followed by aspirin monotherapy.
The endpoints of the GALILEO-4D substudy were assessed at 90 ± 15 days by 4D-CT scan and transthoracic echocardiography. The primary endpoint was the percentage of patients with at least one valve leaflet with reduced motion of grade 3 or higher (i.e., involving >50% of the leaflet). Secondary endpoints were the percentage of valve leaflets with reduced motion of grade 3 or higher, the percentage of patients with at least one thickened leaflet, the percentage of valve leaflets with thickening, and echocardiography measures, including transprosthetic mean gradient and aortic valve area. Major clinical safety and efficacy endpoints included all-cause death, disabling and non-disabling stroke, thromboembolic events and major or life-threatening bleeding.
What is the main result?
Among the 231 patients enrolled in the GALILEO-4D substudy, 115 were assigned to rivaroxaban plus aspirin and 116 to clopidogrel plus aspirin. In the intention-to-treat analysis, patients assigned to rivaroxaban plus aspirin had a lower proportion of at least one valve leaflet with reduced motion of grade ≥3 compared with those assigned to clopidogrel plus aspirin (2.1% vs. 10.9%, percentage difference -8.8, 95% confidence interval -16.5 to -1.9).
In the per-protocol analysis, results were consistent (0% vs. 9.6%, percentage difference -9.6, 95% confidence interval -17.2 to -3.4). Hypoattenuated thickening of at least one leaflet was found in a lower proportion of patients assigned to rivaroxaban plus aspirin compared with those assigned to clopidogrel plus aspirin (12.4% vs. 32.4%, percentage difference -20.0, 95% confidence interval -30.9 to -8.5).
However, there was no significant difference between anticoagulation therapy- and antiplatelet therapy-based strategies with respect to the echocardiography measures of interest, including mean aortic valve gradient (10 ± 5 mmHg vs. 10 ± 5 mmHg) and aortic valve area (1.8 ± 0.5 vs. 1.8 ± 0.4 cm2), central aortic valve regurgitation, and paravalvular leak. Overall, moderate hemodynamic structural valve deterioration was reported in 4 of 207 patients (1.9%).
No significant difference between groups across major clinical endpoints was observed. A total of 4 (3.5%) thromboembolic events occurred in the anticoagulation therapy-based strategy group, while 2 (1.7%) events occurred in the antiplatelet therapy-based strategy group.
Critical reading and the relevance for clinical practice
The GALILEO-4D substudy showed that in patients without an established indication for long-term anticoagulation who underwent successful TAVI for aortic stenosis, a preventive treatment based on oral anticoagulation with rivaroxaban at a dose of 10 mg once daily reduced the incidence of significant leaflet thickening and motion impairment at 3-month follow-up.
Although the GALILEO-4D substudy confirmed findings emerged from previous observational studies, the results should be viewed in light of some considerations. First, patients enrolled in the substudy are not necessarily representative of the common TAVI population that includes substantial proportions of patients with atrial fibrillation or an indication for oral anticoagulation.
Second, the GALILEO-4D substudy showed also that, on the one hand, echocardiography was not useful in identifying patients with leaflet thrombosis, on the other hand, reduced leaflet motion and increased leaflet thickening did not produce any significant difference in common echocardiography functional parameters.
Indeed, mean aortic valve gradient and aortic valve area were quite comparable between groups as well as both central aortic valve regurgitation and paravalvular leak, that were almost only of mild degree. However, these results were observed at 3-months follow-up and it might be reasonable to expect at long-term follow-up detrimental effects of early subclinical leaflet thrombosis on bioprosthesis function.
Third, although the small sample size of the GALILEO-4D substudy does not allow to draw conclusions in terms of clinical endpoints, given the application of the same eligibility criteria, it might be reasonable to consider the results of the GALILEO trial as applicable also to the GALILEO-4D substudy. In the GALILEO trial, the advantage in terms of leaflet thrombosis of a rivaroxaban-based strategy collides with the significant risk increase in major bleeding (hazard ratio 2.02, 95% confidence interval 1.09 to 3.76) and the higher mortality (hazard ratio 1.69, 95% confidence interval 1.13 to 2.53) as compared with an antiplatelet therapy-based strategy.
Finally, regardless of the presence of early subclinical leaflet thrombosis, in the GALILEO trial clinical efficacy outcomes were not improved at long-term follow-up in patients assigned to a rivaroxaban-based strategy compared with an antiplatelet therapy-based strategy. Indeed, in the GALILEO trial the incidences of stroke and systemic embolism did not differ between groups.
In absence of setting-specific validated tools permitting the stratification of patients according to the individual propensity of bioprosthesis degeneration against the individual risk of major bleeding, current evidence does not support the use of oral anticoagulation after TAVI outside the established indications.
However, patients with subclinical leaflet thrombosis at 4D-CT and low empirical risk of bleeding might theoretically take advantage of oral anticoagulation. The exploration of long-term effects of oral anticoagulation in patients with early 4D-CT signs of subclinical leaflet thrombosis and acceptable risk of bleeding is mandatory to define whether this treatment can still have a role.
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