Global Clinical Trial Experience of Bioprosthetic Leaflet Thickening/Thrombosis: Updates and Insights

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In this ACCEL interview, Vinod H. Thourani, MD, FACC, interviews Raj Makkar, MD, FACC, about the results of the PORTICO trial and discusses other insights regarding leaflet thickening and thrombosis.

Dr. Thourani: Tell us where this all started for you and how you brought this to the world.

Dr. Makkar: Almost two years ago, we suspended enrollment in the PORTICO IDE (investigational device exemption) trial, where we were randomizing patients to either transcatheter aortic valve replacement (TAVR) with the Portico valve or other commercially available valves. The computed tomography (CT) scans performed at 30 days revealed some things on the leaflets that concerned us.

Were these routine CTs?

The CTs were done basically to look at the frame. The CTs were done with contrast and in a couple of cases it was very clear there were hypo-attenuated lesions on the leaflets. On 4D reconstruction, clearly there was reduced leaflet motion. In fact, when we first looked at this, we were not even convinced this was a significant or positive finding, because these patients had normal gradients.

So, we have transthoracic echoes at 30 days that look good and the patient feels good. But the CT shows something.

Correct. We looked at this further and realized this was not an isolated finding. It was present in almost 15-20 percent of patients. This caused a bit of concern and alarm. We also found this was present in all the valves enrolled in the study - not just the Portico valve but also the SAPIEN valve and the CoreValve.

The Portico and the CoreValve are both self-expanding valves, and the SAPIEN valve is a balloon-expandable valve.

Correct. Based on these findings, we also started two registries – one at Cedars-Sinai and the other one in Denmark with Lars Søndergaard, MD. We pooled our experience and looked at different commercially available valves, including surgical valves. A major question was whether this was unique to TAVR devices or was present also on surgical valves. We observed that this was essentially a class effect – it was present in all tissue bioprosthetic valves.

For surgical valves, we commonly don’t do echoes or CTs at 30 days.

Yes, and in the TAVR world, we do echoes at 30 days, but the gradients in most of the patients were not elevated. I think it was a revelation that this finding of reduced leaflet motion was present in not an insignificant number of patients.

We were also surprised to find that even though one or two leaflets did not move, the gradients were not elevated in a lot of the patients. So, we tested this in a pulse-duplicator model, where blockers were placed on the leaflets and the gradients evaluated. Many times, we observed the exact same finding that the gradient was not elevated.

The gradients were okay, but there was one leaflet that was relatively immobile.

That is correct.

These data were published by you and your team in the New England Journal of Medicine. You’re the national principal investigator for the Portico trial, which is now enrolling again after having been halted while the issue of reduced leaflet motion was evaluated.

That is correct, because this was nothing unique to the Portico valve, but was present in all bioprosthetic valves. Through a series of steps, we came to a deduction that what we were observing on 4D CT angiograms was, in fact, related to thrombus. We didn’t understand this when we started the trial.

We observed that in the patients who are taking anticoagulants, the incidence of this finding was very, very low. In fact, not a single patient who was in therapeutic INR with warfarin had this finding.

Are you now changing the way you manage these patients with anticoagulation?

The short answer is no. In terms of routinely giving anticoagulation, we are not doing that yet, because we do not have a definitive connection between this imaging finding and clinical outcomes.

So you are not currently using aspirin and warfarin for every patient who has TAVR?

That is correct, but we are very vigilant in terms of screening patients with CT scans. If at follow-up they have any evidence of valve dysfunction, any evidence of clinical heart failure, thromboembolic events, or increase in gradient (from 8 to 16 or from 8 to 18), you’d normally overlook that. In that particular patient, we will do a CT scan to make sure that there is no thrombus in the leaflet.

Do you do a transesophageal echocardiogram (TEE) in these patients?

We feel that CT is the best way to image this. While you can see this finding on TEE, I think that often it was confirmatory rather than being the first imaging modality that points it out. While you can appreciate it, we believe that CT is the best method of assessing this.

Importantly, you’re saying that we must be vigilant about surveillance. Don’t do your TAVR and then leave the patients alone. Follow them at 30 days, which the TVT registry requires anyway, to get an echo to assess the gradient and if it’s abnormal get a CT scan. At Emory, we do a TEE for patients with a high creatinine level, because the CT scan is potentially harmful for their kidneys.

That is absolutely our practice as well, because I think you do not want to give more contrast to patients who have renal insufficiency.

Just to review, most of your patients will go home on aspirin and clopidogrel. Is that the pathway you have?

The current standard of care is dual antiplatelet therapy (DAPT). Interestingly, what we found in our analysis published in the New England Journal of Medicine was that DAPT was not protective in preventing this imaging finding. One could argue that, at least for this phenomenon of leaflet thickening, DAPT has no effect.

There are two studies evaluating this. The GALILEO study is randomizing patients post TAVR to the direct oral anticoagulant (DOAC) rivaroxaban or to DAPT. The ATLANTIS study will randomize patients to the DOAC apixaban or standard of care.

I think these imaging findings will help us. They’ve stimulated the field. They’ve forced us to look at these things more carefully and to start some of the randomized clinical trials. The U.S. Food and Drug Administration has mandated that we have imaging sub-studies in some of the lower-risk clinical trials that are ongoing right now. However, that research needs to be done, and we need to have some definitive conclusions before I would say that we should start treating patients with anticoagulants.

I think that’s very important, so hold your horses right now. I think it’s a great testament that the investigators of Portico have been able to at least tell us there’s something going on, not too concerned about it, but let’s really put some intense research into it.

This is the time that we should be doing multiple imaging registries and studies. For example, at Cedars, we now have almost 600 patients enrolled in the RESOLVE registry. We will be pooling our experience with the SAVORY registry, with our collaborators in Denmark. We hope to have about 1,000 patients with 4D CT angiograms. Hopefully that’ll give us an idea about whether this finding is more qualitatively and quantitatively different than in surgical aortic valves.

The surgical aortic valves need to be looked at too. As a surgeon, this woke me up as far as why haven’t I been checking these patients. We just assume the valves will last 10 to 15 years, which may not be the case. Maybe that’s why we have early structural valve deterioration on some surgical valves.

I think very good corroborative evidence for that is the Mayo Clinic study, where in the explanted bioprosthetic valves they found that thrombus was the basic pathology in almost 12 percent of cases. Here is a percentage of patients who have early failure, which is related to thrombus. So rather than indiscriminately doing CTs or indiscriminately giving anticoagulation, I think our study and some from other groups have shed light on this issue and forced us to be more vigilant. In select patients, when there is significant impairment of valve leaflets, I think it would be very reasonable to give anticoagulation.

I think this will become even more important as we go into lower-risk populations. Can you comment on the two low-risk trials and how to study this going forward in low-risk patients?

You’re right. I think the current population, the high-risk patients, may not be the best to understand the significance of this finding, because their comorbidities might drown any clinical impact this phenomenon might have. The low-risk patients, however, are ideal, because they’re going to live longer. I think we’re going to find out if this phenomenon has any impact on durability. Both of the low-risk randomized clinical trials have imaging sub-studies of almost 400 patients.

This interview has been edited for print from a transcript.

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