Important Interventional Trials From CRT.20

Introduction

The 2020 Cardiovascular Research Technologies conference (CRT.20) provided an opportunity for interventional science early in the year and turned out to be the last in-person meeting before the COVID-19 pandemic took hold.

We have assembled commentary on five trials that provide insight into several ongoing clinical issues and controversies. Included are summaries of ultrathin, polymer-coated stents with encouraging results but still challenging the polymer biology versus the strut size for success. Also included are three valve trials covering anticoagulation versus antiplatelet therapy for patients undergoing transcatheter aortic valve replacement (TAVR), the outcomes for TAVR in low-risk patients, and an analysis of late outcomes for the Carillon (Cardiac Dimensions; Kirkland, WA) mitral repair device. Finally, we’ve included an analysis of the impact of antiplatelet discontinuation during non-cardiac surgical procedures.

An interesting and diverse set of topics summarized by an outstanding group of clinicians. Thanks to all the contributors for your expertise and skill. As always, any comments are appreciated.

Pattern of Antiplatelet Therapy During Non-Cardiac Surgery in Patients With Second-generation Drug-Eluting Stents
By George W. Vetrovec, MD, MACC
Editorial Team Lead, Invasive Cardiovascular Angiography & Interventions collection on ACC.org
Richmond, VA

Dr. Jung-Sun Kim and colleagues from the Severance Cardiovascular Hospital, Yonsei University in South Korea presented a provocative observational study at CRT.20 regarding perioperative management of antiplatelet therapy in patients post percutaneous coronary intervention with second-generation drug-eluting stents (DES) in patients undergoing non-cardiac surgery. The study addressed the dilemma of stopping or continuing antiplatelet therapy for non-cardiac surgery.

The authors collected retrospective data from 9 medical institutions that had performed 41,083 DES procedures over 10 years between 2008 and 2018. Of these, 3,791 had non-cardiac surgery operations, of which 3,582 were deemed eligible for inclusion (209 patients were excluded because of inadequate data, emergency surgery, and other miscellaneous high-risk issues). It's important to note that the decision to continue or discontinue antiplatelet therapy was at the discretion of the physicians, surgeons, or anesthesiologists. The patient populations were nearly evenly split between continuing (1,832) and discontinuing (1,750) antiplatelet therapy.

Antiplatelet therapy was sub-classified into three groups: Aspirin monotherapy, P2Y12 monotherapy, and dual antiplatelet therapy (DAPT). Discontinuation was defined as at least 1 day off antiplatelet treatment prior to surgery. Clinical outcomes were assessed at 30 days. Net adverse clinical events (NACE) comprised all-cause death, myocardial infarction (MI), stent thrombosis, or major bleeding; major adverse cardiac events (MACE) comprised cardiac death, MI, or stent thrombosis.

Baseline characteristics between groups identified relatively fewer men, less chronic renal disease, and less DAPT in the discontinuation group. Crude 30-day events were not different between groups, including death, bleeding, MI, and stent thrombosis. Overall, all-cause death and cardiac death were significantly less in the discontinuation group based on a greater incidence in the DAPT subgroup of the continuation group. In an adjusted NACE and bleeding risk, there was a trend to greater risk for antiplatelet therapy in the continuation group for intraabdominal surgery. Analysis of adjusted strategies for MACE revealed no specific factors comparing the groups.

An adjusted analysis for the impact of antiplatelet discontinuation showed a time relationship. There was no difference for discontinuation of antiplatelet treatment over <8 days; however, for the MACE risk group, there was a hazard in the adjusted analysis for effect of discontinuation of antiplatelet therapy for length >8 days.

Overall, discontinuation of antiplatelet therapy was common and seemed safe for 8 days or fewer. Although these data are interesting and potentially hypothesis-generating given the low thrombosis rate of current third-generation stents, there are limitations to applicability of the data. First, despite the adjusted covariate analysis, there is a possibility that confound bias was unrecognized in the decisions regarding continuing or discontinuing antiplatelet therapy. Given that drug levels of antiplatelet drugs decline over several days, one wonders if the difference in outcomes after 8 days represents a time frame in which patients have no residual platelet activity combined with patients likely with prolonged postoperative courses. In addition, MACE included only hard endpoints. Finally, there is the possibility that the Asian population may have different risk for bleeding that cannot be generalized to other populations.

Three-Year Outcomes From the Randomized BIOFLOW V Trial
By M. Chadi Alraies, MD, FACC
Detroit Medical Center Harper University Hospital
Detroit, MI

The BIOFLOW V (Safety and Effectiveness of the Orsiro Sirolimus Eluting Coronary Stent System in the Treatment of Subjects With up to Three de Novo or Restenotic Coronary Artery Lesions) trial randomized 1,334 patients 2:1 to the ultrathin-strut (60 mcm), bioresorbable-polymer Orsiro sirolimus-eluting stent (SES) (Biotronik; Bulach, Switzerland) or the thin-strut (81 mcm), durable-polymer Xience everolimus-eluting stent (EES) (Abbott Vascular; Santa Clara, CA). The 1-year and 2-year follow-up showed superior bioresorbable-polymer SES performance at 1 and 2 years with lower target lesion failure, target vessel MI, and target lesion revascularization (TLR) compared with durable-polymer EES. The bioresorbable-polymer SES received US Food and Drug Administration approval in February 2019 based on the 2-year results. The BIOFLOW V trial 3-year follow-up results were presented at CRT.20 and showed persistent divergence in the event rates regarding the absolute difference in target lesion failure. Indeed, patients who received bioresorbable-polymer SES had lower target lesion failure (8.6% vs. 14.4%; p = 0.003), lower target vessel MI (5.5% vs. 10.1%; p = 0.004), and lower ischemia-driven TLR (3.4% vs. 6.9%; p = 0.008). As noted by the investigator, the target vessel MI rates in the bioresorbable-polymer SES group were driven by fewer early periprocedural MI and fewer late spontaneous MI, and the clinically driven TLR advantage was driven by fewer late (>1 year) occurrences compared with durable-polymer EES. The landmark analysis between 30 days and 3 years showed divergence in the event rates of target vessel MI favoring bioresorbable-polymer SES stent (2.8% vs. 0.95%; p = 0.01). Similarly, the landmark analysis for ischemia-driven TLR between 30 days and 3 years favored bioresorbable-polymer SES at a rate of 1.5% compared with 4.7% in the durable-polymer EES group (p < 0.001). Furthermore, bioresorbable-polymer SES was associated with lower late/very definite/probable stent thrombosis compared with durable-polymer EES (0.1% vs. 1.2%; p = 0.018) despite similar DAPT adherence at 3 years in both groups: 35.5% (281/792) bioresorbable-polymer SES and 36.3% (145/400) durable-polymer EES (p = 0.53).

These findings were attributed to strut thickness or polymer composition or both. It is unclear if the thin strut or the bioresorbable polymer are driving lower MI and TLR. As explained by the investigators, the bioresorbable-polymer SES has a complex design, and it is hard to determine which component—the thinner struts or the bioresorbable polymer—is driving this outcome. I think both components have an influence. The bioresorbable-polymer SES was designed to not fully degrade until roughly 2 years. Nevertheless, at 1 year, the bioresorbable-polymer SES outcome was associated with significantly lower target vessel MI, which elude to the fact that thin struts might be the driving mechanism. Beyond 2 years, and once the absorption of the polymer is completed, the bioresorbable-polymer SES showed lower late TLR. The BIOFLOW V trials results demonstrated the true effect of strut thickness and polymer composition as key features for iterative DES development.

TAVR in Low-Risk Patients With Bicuspid Aortic Valve
By Zachary M. Gertz, MD, FACC
VCU Health Pauley Heart Center
Richmond, VA

The LRT (Low Risk TAVR) trial was designed to assess the feasibility of TAVR in patients with low surgical risk and included patients with bicuspid aortic valve stenosis. The study was single-arm and prospective with a primary endpoint of all-cause mortality at 30 days. A total of 61 patients with bicuspid aortic stenosis underwent a transfemoral TAVR procedure as part of the trial and were included in this analysis. There were no deaths or strokes at 30 days. Permanent pacemaker implantation was required in 13% of patients.

Patients with bicuspid aortic valve stenosis have been excluded from randomized trials of TAVR because of technical concerns related to their different anatomy. Data from the BAVARD (Bicuspid Aortic Valve Anatomy and Relationship With Devices) registry showed that transcatheter valves are frequently under-expanded in bicuspid patients compared with patients with a tricuspid aortic valve. In tricuspid aortic stenosis, the annulus is the main point of constraint, but in bicuspid patients, the commissures and leaflets themselves may also limit the ability of the valve to fully deploy. Large registries have shown similar safety profiles in patients with bicuspid aortic stenosis at intermediate and higher risk who were treated with TAVR, compared with either tricuspid aortic stenosis patients treated with TAVR or bicuspid aortic stenosis patients treated with surgery, but data on low-surgical-risk patients with bicuspid aortic stenosis are lacking. In the LRT trial, a small cohort of low-risk patients with bicuspid aortic stenosis were followed for 30 days after TAVR, with excellent results with both balloon-expandable and self-expanding valves. These findings were reinforced by the recently presented Evolut Low Risk Bicuspid Study, which evaluated a self-expanding valve only. Whether patients with bicuspid aortic stenosis are better suited to one valve type or the other requires further investigation. Although both LRT and the Evolut Low Risk Bicuspid Study showed that TAVR can be safely performed in the bicuspid aortic valve stenosis population, longer-term follow-up is required before we accept TAVR as the preferred treatment for this group. Over time, under-expansion of the valve may result in more leaflet thrombus and faster valve degeneration, particularly in the younger populations included in these trials. More studies are required before we can definitively recommend TAVR as standard of care for low-risk patients with bicuspid aortic stenosis.

Pooled Analysis of Prospective Trials With the Carillon Device
By Scott Lim, MD
University of Virginia School of Medicine
Charlottesville, VA

Dr. Janusz Lipiecki and colleagues presented a pooled analysis of prospective trials with the Carillon mitral repair device for transcatheter repair of functional or secondary mitral regurgitation. The Carillon device was implanted in the coronary sinus in patients with 2-4+ echocardiography-adjudicated secondary mitral regurgitation depressed left ventricular ejection fraction in symptomatic subjects who were already on guideline-directed medical therapy. Their pooled study cohort came from the TITAN (Transcatheter Implantation of Carillon Mitral Annuloplasty Device) and TITAN II early feasibility studies and REDUCE FMR (A Sham-Controlled Randomized Trial of Transcatheter Indirect Mitral Annuloplasty in Heart Failure Patients With Functional Mitral Regurgitation), which was a randomized, blinded, sham-controlled trial (Figure 1). One of the key parts of this pooled analysis was that all studies were adjudicated by echocardiography, and the inclusion and exclusion criteria were consistent. They presented data on 74 subjects, age 67 +/-11 years, with a mean left ventricular ejection fraction of 31+/-8%, a left ventricular end-diastolic volume of 195+-58 mL, and an effective regurgitant orifice of 0.2 cm2. In the cohort, 41% were judged to have 2+ or less mitral regurgitation at baseline, and 59% had 3 or 4+. The analysis focused on survival of those implanted, with a survival of 73.1% at 2 years and 56.2% at 5 years. Primary determinants of 5-year survival were an improvement in symptoms and exercise performance and decrease in mitral regurgitation with intervention.

Lipiecki et al. note that one of the main limitations of their analysis was the lack of a significant control arm for comparison. In addition, the number of subjects enrolled was quite small overall. One of the appealing aspects of the Carillon device is that it is a relatively simple procedure to implant from a right internal jugular vein approach, which minimizes some of the operator-skill issues found in other transcatheter mitral repair devices. It also preserves options for future interventions on either the mitral valve or the coronary sinus, which is appealing. Unfortunately, the anatomy of the coronary sinus is such that not all screened subjects can ultimately be implanted with the device. During the question period on the panel, Lipiecki noted that approximately 15% of cases had to be aborted due to the coronary sinus anatomy. There are additional cases that screened out prior to the procedure due to risks to the circumflex artery, which can run under the coronary sinus.

Ultimately, the data presented by Lipiecki et al. is supportive for the recently started CARILLON Trial (Assessment of the Carillon® Mitral Contour System® in Treating Functional Mitral Regurgitation Associated With Heart Failure), which is intended to be a randomized, blinded, sham-controlled study of 352 subjects in the United States and Europe.

Figure 1

Figure 1
Reprinted with permission from Witte KK et al.1

Anticoagulation vs. Antiplatelet Therapy After TAVR in Low-Risk Patients
By Adam Z. Banks, MD
Center for Structural Heart Disease, Duke University Medical Center
Durham, NC

J. Kevin Harrison, MD
Center for Structural Heart Disease, Duke University Medical Center
Durham, NC

The LRT 2.0 trial, presented by Dr. Toby Rogers at CRT.20, reported the TAVR leaflet image findings at 30 days following TAVR. Their group studied the TAVR leaflet morphology and leaflet motion in 94 patients employing four-dimensional computed tomography (CT) angiography or transesophageal echocardiography at 30 days post-TAVR. These patients, who had been clinically assessed to be standard risk for open surgical valve replacement, had been randomly assigned after TAVR treatment to receive either aspirin 81 mg/d plus warfarin or aspirin 81 mg/d alone. This study found a trend to more hypoattenuated leaflet thickening in the group treated with aspirin monotherapy (8/49) compared with the aspirin plus warfarin group (2/43). No difference in valve function by echocardiographic Doppler gradient or valve regurgitation was seen. There were no differences in clinical complications or bleeding at 30 days between the 2 groups of patients.

We congratulate the authors for their detailed study of these 94 patients and support their goal to define optimal antithrombotic medical therapy for patients after TAVR. The LRT 2.0 trial calls into question our current strategy for antiplatelet therapy following TAVR. Certainly, the current guidelines recommending the use of DAPT with aspirin plus clopidogrel were defined empirically during a decade that included rapid advances in devices and delivery system. The current study utilized aspirin alone in the antiplatelet therapy arm. Importantly, the clinical importance of these leaflets findings remains incompletely defined. The initial LRT trial showed that hypoattenuated leaflet thickening was not associated with a difference in valve hemodynamics at 1 year. It remains unclear whether hypoattenuated leaflet thickening is associated with an increased incidence of stroke or reduced valve durability. Furthermore, the CT registries in the PARTNER 3 (Placement of Aortic Transcatheter Valves 3) trial demonstrated that hypoattenuated leaflet thickening resolved in over half of patients at 1 year without anticoagulation and that 21% of patients without hypoattenuated leaflet thickening at 30 days developed hypoattenuated leaflet thickening at 1 year. We are hopeful that the long-term follow-up of the patients in the PARTNER 3 CT registries and the Evolut Low Risk (Evolut Surgical Replacement and Transcatheter Aortic Valve Implantation in Low Risk Patients) trial will provide information on the long-term implications of hypoattenuated leaflet thickening after TAVR.

We look forward to the formal publication of this work presented at CRT.20. Although the data from this modest cohort of patients do not provide compelling information to change current antithrombotic practice after TAVR, it serves to provide very detailed anatomic valve leaflet data at 30 days after TAVR and is hypothesis-generating, supporting the need for larger randomized trials to define optimal antithrombotic treatment of patients following TAVR.

References

  1. Witte KK, Lipiecki J, Siminiak T, et al. The REDUCE FMR Trial: A Randomized Sham-Controlled Study of Percutaneous Mitral Annuloplasty in Functional Mitral Regurgitation. JACC Heart Fail 2019;7:945-55.

Keywords: Angina, Unstable, Acute Coronary Syndrome, Coronary Artery Disease, Drug-Eluting Stents, Myocardial Infarction, Myocardial Ischemia, Myocardial Revascularization, Polymers, Secondary Prevention, Sirolimus, Stents, Thrombosis, Cardiac Surgical Procedures, Cardiomyopathies, Coronary Sinus, Heart Failure, Heart Valve Diseases, Myocardial Infarction, Mitral Valve Annuloplasty, Mitral Valve Insufficiency, Percutaneous Coronary Intervention, Stents, Stroke Volume, Aortic Valve Insufficiency, Aortic Valve Stenosis, Aspirin, Atrial Fibrillation, Cardiac Surgical Procedures, Geriatrics, Heart Failure, Heart Valve Diseases, Heart Valve Prosthesis, Pacemaker, Artificial, Stroke, Transcatheter Aortic Valve Replacement, Vascular Diseases, Tomography, Transcatheter Cardiovascular Therapeutics, Acute Kidney Injury, Aortic Valve Stenosis, Atrial Fibrillation, Cardiac Surgical Procedures, Geriatrics, Heart Failure, Heart Valve Diseases, Heart Valve Prosthesis, Pacemaker, Artificial, Stroke, Transcatheter Aortic Valve Replacement, Vascular Diseases


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