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Subclinical leaflet thrombosis more common with TAVR vs. surgical AVR
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WASHINGTON — Subclinical leaflet thrombosis occurred at a rate of about 12% in patients who received bioprosthetic valves and was significantly more common among patients who underwent transcatheter, as compared with surgical, aortic valve replacement, Raj R. Makkar, MD, reported at the American College of Cardiology Scientific Sessions.
In an analysis of data from the RESOLVE and SAVORY registries, Makkar, associate director of Cedars-Sinai Heart Institute, and colleagues sought to learn more about the prevalence of subclinical leaflet thrombosis and its effects on patients undergoing TAVR or surgical AVR.
Of 931 patients who underwent CT, 890 had interpretable CT — 626 from RESOLVE and 264 from SAVORY — and were included in the analysis. Median time from aortic valve replacement to CT was 83 days for the entire cohort. However, median time differed significantly between patients who underwent TAVR vs. those who underwent surgical AVR (58 vs. 162 days).
Subclinical leaflet thrombosis, defined as reduced leaflet motion on CT, was noted in 11.9% of all patients included in the analysis. Baseline characteristics were mostly similar for patients with and without reduced leaflet motion, but patients with reduced leaflet motion were older (82 vs. 79 years; P = .0009) and had less atrial fibrillation than those with normal leaflet motion (16% vs. 29.9%; P = .003).
Prevalence was considerably higher among the 752 patients who underwent TAVR compared with the 138 who underwent surgical aortic valve replacement (13.4% vs. 3.6%; P = .001), according to the data. The researchers also found that leaflet thickness (5.01 mm vs. 1.85 mm; P = .0004) and the percentage of leaflet motion restriction were greater in the TAVR group vs. the surgery group (71% vs. 56.9%; P = .0004).
It is important to note, however, that patients in the two groups differed, Makkar said. At baseline, patients who underwent surgical AVR were younger (72 vs. 81 years; P < .0001) and had fewer comorbidities.
Anticoagulation vs. antiplatelet therapy
Results showed that subclinical leaflet thrombosis was less common among patients receiving anticoagulants compared with no anticoagulation (3.6% vs. 14.7%; P < .0001), and novel oral anticoagulants were as effective as warfarin (2.8% vs. 4.3%; P = .72). Subclinical leaflet thrombosis also occurred less frequently among patients receiving anticoagulants than among those receiving antiplatelet monotherapy (3.6% vs. 15.6%; P < .0001) or dual antiplatelet therapy (3.6% vs. 14.9%; P <.0001).
In a multivariate analysis, independent predictors of reduced leaflet motion were age (OR = 1.04; 95% CI, 1.01-1.07), left ventricular ejection fraction (OR = 0.98; 95% CI, 0.97-1), valve type (OR = 0.33; 95% CI, 0.11-0.96) and anticoagulation (OR = 0.24; 95% CI, 0.1-0.58), Makkar said.
Further, in an analysis of a subgroup of 58 patients who underwent a second CT scan, subclinical leaflet thrombosis resolved in all 36 patients who received anticoagulants but persisted in 20 of 22 patients not receiving anticoagulants (P < .0001).
However, discontinuation of anticoagulation after resolution of subclinical leaflet thrombosis may also have had an effect. Four of eight patients in whom anticoagulation was discontinued experienced recurrence, whereas all 15 patients who received continued anticoagulation did not (P = .008).
More patients with subclinical leaflet thrombosis had aortic valve gradients greater than 20 mm Hg and increases of at least 10 mm Hg compared with those with normal leaflet motion (14% vs. 1%; P < .0001), according to the data.
Clinical events
Makkar said that stroke rates after AVR were not significantly different between patients with and those without reduced leaflet motion. However, subclinical leaflet thrombosis was linked to higher rates of transient ischemic attack (5.7% vs. 0.9% HR = 7.02; 95% CI, 2.35-20.9) and all strokes or TIAs (10.4% vs. 3.4%; HR = 3.27; 95% CI, 1.62-6.59).
“The imaging findings in our analysis question the current standard of care of DAPT after TAVR; thus, DAPT can be considered dispensable in the appropriate clinical setting. Our
findings raise the issue if anticoagulation is more appropriate in certain patients,” Makkar said.
“Our data also call for clinical trials of routine CT imaging and anticoagulation as TAVR moves into lower-risk patients and for the first time provide evidence on the efficacy of novel oral anticoagulants on bioprosthetic valve thrombosis.”
Lingering questions
In an accompanying editorial published in The Lancet, Jeroen J. Bax, MD, PhD, of Leiden University Medical Center, and Gregg W. Stone, MD, of Columbia Medical Center and the Cardiovascular Research Foundation, noted that many questions remain, including whether all patients should be offered chronic anticoagulation despite the risks, whether patient selection should be guided by imaging, optimal duration of treatment and more.
They also put the clinical findings into context.
“Registries are able to show associations, but are unable to establish causality. As findings from this study were unable to show any permanent meaningful clinical sequelae to subclinical leaflet thrombosis, only randomized trials can address these questions,” they wrote.
“Thus, in our estimation, changes in the guidelines of the type and timing of imaging surveillance and therapy after [surgical AVR] and TAVR are premature on the basis of current knowledge. Nonetheless, this study has provided important new information to guide future investigation.” – by Melissa Foster
Reference:
Makkar RR, et al. Joint American College of Cardiology/New England Journal of Medicine Late-Breaking Clinical Trials. Presented at: American College of Cardiology Scientific Session; March 17-19, 2017; Washington, D.C.
Bax JJ, Stone GW. Lancet. 2017;doi: /10.1016/S0140-6736(17)30764-X.
Chakravarty T, et al. Lancet. 2017;doi:10.1016/S0140-6736(17)30757-2.
Disclosure: Bax reports that his institution has received unrestricted research grants from Biotronik, Boston Scientific, Edwards Lifesciences and Medtronic. Makkar reports receiving consultant fees and research grants from Edwards LifeSciences, Medtronic and St. Jude Medical. Stone reports that his employer receives royalties from Abbott Vascular for the sale of MitraClip and that he has other financial ties that are not relevant to the present study.
Perspective
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Chandan Devireddy, MD, FACC, FSCAI
The combined imaging and outcomes data of the RESOLVE and SAVORY registries provide further weight to the concern that TAVR may pose a risk of subclinical leaflet thrombosis in certain patients. Is it, however, time to sound the sirens of alarm? It is difficult to claim the sky is falling on TAVR from this study alone. Without prospective consecutively collected data, there is a great risk of bias in comparing TAVR vs. surgical AVR in this manner. Marked differences are noted in the time from valve implantation to CT imaging between TAVR and surgical AVR which may reflect some inherent confounding in the types of patients enrolled in the registry.
Independent of whether TAVR patients experience more leaflet thrombosis than surgical AVR patients, the RESOLVE and SAVORY investigators have provided firm proof that subclinical leaflet thrombosis is a real complication and that 4-D volume rendered imaging with CT is a valuable tool in diagnosing it. Based on these registries, it would seem wise to have a low threshold to acquire 4-D imaging to assess leaflet thickness and mobility in any TAVR patient with an unexplained sudden rise in gradient.
In order to learn if TAVR patients (or potentially all AVR patients) would benefit from more aggressive anticoagulation, we can only hope that the currently enrolling ATLANTIS and GALILEO studies will shed further light. If benefit is found with anticoagulation, difficult decisions remain. Which patients stand to benefit the most? Is one transcatheter valve platform more likely to clot than another? Can anticoagulation ever be discontinued in those who need it? TAVR has revolutionized our ability to treat valvular heart disease. Hopefully, such studies will help us optimize the longevity and performance of this technology which has already improved so many lives.
Perspective
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Howard C. Herrmann, MD, FACC, MSCAI
This is essentially the largest study to date of CT scans in people after TAVR and surgical valve replacement. However, although it’s the largest, it is not a perfect study. There are two caveats: These were not consecutive patients and not all CT scans were done at exactly the same time point. With those caveats, it’s hard to be sure of what confidence intervals to put around those incidences of leaflet thrombosis and leaflet thickening.
That said, there are a couple of takeaway points. First, it appears that the incidence of subclinical leaflet thrombosis was higher with TAVR than surgery. Second, treatment with anticoagulants is good and warfarin seemed to be equivalent to novel oral anticoagulants. Third, most of the events were asymptomatic and did not translate into clinical events. That suggests that some of these subclinical leaflet thromboses may resolve without therapy since we are not seeing problems of this magnitude years out in the follow-up studies.
So, the point is that it may still be too early to treat all patients with warfarin or novel oral anticoagulants because the event rate was somewhere between 4% and 13%, of which only a minority of patients have clinical events. That would mean we would be treating more than 90% of patients with a blood thinner that they do not need or from which they would not benefit. The goal is therefore finding out where the risk-benefit is, how long to treat patients and which patients should be treated, which is the aim of trials like GALILEO and ATLANTIS.
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