By Jeffrey Zimmet, MD, PhD

Associate Professor of Medicine, University of California, San Francisco; Director, Cardiac Catheterization Laboratory, San Francisco VA Medical Center

Dr. Zimmet reports no financial relationships relevant to this field of study.

SYNOPSIS: In this large contemporary, prospective transcatheter aortic valve replacement registry, oral anticoagulation appears to be protective against valve degeneration but is associated with increased mortality. The strongest predictors of mortality at three years were male gender, renal failure, and atrial fibrillation.

SOURCE: Overtchouk P, Guedeney P, Rouanet S, et al. Long-term mortality and early valve dysfunction according to anticoagulation use: The FRANCE-TAVI registry. J Am Coll Cardiol 2018; Aug 22. pii: S0735-1097(18)36960-2. doi: 10.1016/j.jacc.2018.08.1045. [Epub ahead of print].

The story of anticoagulation after transcatheter aortic valve replacement (TAVR) starts with the design of the pivotal trials, which prescribed dual antiplatelet therapy (DAPT) for a period of three to six months after deployment. That decision resulted from expert cardiologist opinion at the time (the TAVR valve looks like a giant stent, after all) rather than from patient-level data. Although DAPT remains the standard recommendation for these devices, many patients are treated with single antiplatelet therapy or oral anticoagulation, depending on the characteristics of the patient and the experience of the treatment center.

Although valve thrombosis causing hemodynamically significant early valve failure is rare, several studies in recent years have demonstrated that a significant percentage (as high as 20% in some series) of TAVR valves develop imaging findings of organized thrombus that are seen on 4D-CT or on transesophageal echocardiography (TEE). These are too subtle to be seen on the transthoracic echocardiograms (TTE) that are performed more typically as follow-up in TAVR patients. There is increasing recognition that relatively modest increases in transvalvular gradients seen by standard echo may represent early valve thrombosis. Importantly, treatment of such patients with warfarin typically results in resolution of the thrombosis. In addition, patients post-TAVR who are maintained on oral anticoagulants demonstrate a very low rate of these thrombotic imaging findings.

FRANCE-TAVI is a large prospective, nationwide registry that contains data on TAVR patients from 48 centers in France that were collected between 2013 and 2015. Overtchouk et al sought to determine whether the type of antithrombotic therapy used post-TAVR affects long-term mortality. Further, they looked for increases in transaortic gradient by TTE as a marker of bioprosthetic valve dysfunction (BVD), defined as an increase in prosthetic gradient of at least 10 mmHg between baseline and follow-up, or a new prosthetic gradient ≥ 20 mmHg on follow-up.

Of the nearly 13,000 patients included in the registry, 11,469 survived to discharge with known antithrombotic treatment and were analyzed for mortality. A total of 2,555 patients had the necessary data from at least two echocardiographic evaluations, and the authors assessed this group for BVD.

In a multivariable regression analysis, chronic renal failure, male gender, and history of atrial fibrillation were the weightiest independent mortality correlates. Anticoagulation exposure at discharge was one of several additional independent correlates of mortality, which also included such factors as nonfemoral access, moderate-to-severe prosthetic regurgitation, and small valve size. In the analysis of valve deterioration, nonfemoral TAVR access and anticoagulation at discharge were found to be protective, while high body mass index, prior TAVR, and chronic renal failure were predictive of BVD. Neither aspirin nor clopidogrel were independently associated with either mortality or BVD.

The authors concluded that male gender, renal failure, and atrial fibrillation affected mortality in the post-TAVR population the most. Anticoagulation decreased the risk of valve dysfunction; nonetheless, it remained independently predictive of mortality.

COMMENTARY

Although DAPT remains the standard recommendation, studies to date have not shown any advantage to DAPT vs. single antiplatelet therapy, usually with aspirin alone, while the rate of bleeding episodes increases. In keeping with this, the results of the Overtchouk et al study suggest no mortality advantage to either aspirin or clopidogrel and no protective effect of these medications regarding BVD. The most recent American Heart Association/American College of Cardiology guidelines (2017) assign a IIb indication to prescribing up to six months of clopidogrel in addition to aspirin after TAVR.

Oral anticoagulation has been protective against subclinical valve thrombosis in prior small trials using advanced imaging (4D-CT and TEE) post-TAVR. As expected, FRANCE-TAVI confirms a reduction in BVD with anticoagulation at discharge. Interestingly, the results also suggest that anticoagulation increases mortality independently of atrial fibrillation. Here, the most recent guideline update has gotten ahead of the data, suggesting that it is reasonable to prescribe a vitamin K antagonist for at least three months after TAVR in patients at low bleeding risk. There are a lack of data on the direct oral anticoagulants (DOACs) in this field, with several ongoing trials investigating these agents in post-TAVR patients. One of these trials, GALILEO, ended prematurely in October when investigators found that low-dose rivaroxaban plus aspirin was associated with increased rates of death or a first thromboembolic event (11.4% vs. 8.8%), all-cause mortality (6.8% vs. 3.3%), and bleeding (4.2% vs. 2.4%) compared with DAPT. Full results of that study remain unpublished.

Despite its status as standard therapy, DAPT appears to offer few concrete benefits post-TAVR while conferring higher bleeding risks. We should maintain a low threshold for paring this down to single antiplatelet therapy in patients with significant bleeding risks. Oral anticoagulation, including vitamin K antagonists and DOACs, reduces the risk of subclinical valve thrombosis. However, data available to date suggest this does not improve outcomes. The Overtchouk et al study suggests an association with increased mortality. Until more data are available, oral anticoagulants should be limited to patients with a concrete indication such as atrial fibrillation.