Editor's Note: This Expert Analysis is part of a series presenting perspectives on major ACC.19 trials. Please follow this link for the companion articles.

Patients with bicuspid aortic valve (BAV) stenosis and the physicians caring for them face a pertinent question about the role of transcatheter aortic valve replacement (TAVR), especially in the wake of the recently reported results from two multicenter, randomized clinical trials in low-surgical risk patients.^1,2 Clinical trials comparing surgical aortic valve replacement (SAVR) to TAVR have systematically excluded aortic stenosis (AS) patients with BAV anatomy. Concern for poor clinical outcomes in this group of patients stem from anatomic concerns of a non-circular annulus leading to more perivalvular leaks and risk for rupture and sometimes very severe calcification that may contribute to peri-procedural strokes. Furthermore, most of these patients need an intervention at a young age, and up to half have an associated ascending aortic aneurysm.

Makkar and colleagues presented data from the Society of Thoracic (STS)/ American College of Cardiology (ACC) Transcatheter Valve Therapies (TVT) registry at ACC.19 analyzing the outcomes of 92,236 patients who underwent TAVR using a balloon-expandable valve (Edwards Sapien 3, Edwards Lifesciences, CA) from June 2015 to November 2018. Of these patients, 2,726 (3%) had a self-reported BAV and were compared to 79,096 patients with trileaflet valves (TAVs). It is important to note that this small percentage of BAVs implies many patients were excluded as a result of anatomic ineligibility. Also excluded were patients who underwent TAVR using the older generation, balloon-expandable valves and self-expanding valves. In a 1:1 propensity matched cohort (2,691 subjects in each group), the average age was 73 years and the STS predicted risk of operative mortality was 5.0%. Outcomes at 30 days showed no difference in survival (BAV: 2.6 vs. TAV: 2.5%, p = 0.82) but a higher rate of stroke (BAV: 2.4 vs TAV: 1.6%, p = 0.02) among bicuspid patients. With CMS-linkage, the combined endpoint of death and stroke were similar at 1-year (BAV: 12.9 vs. TAV: 14.1%, p = 0.75). Important secondary endpoints include a higher risk of annulus rupture (BAV: 0.3 vs. TAV: 0%, p = 0.02), conversion to open surgery (BAV: 0.9 vs. TAV: 0.4%, p = 0.03) and need for permanent pacemaker (BAV: 9.1 vs. TAV: 7.5%, p = 0.03). However, the rate of self-reported perivalvular leak (moderate or greater) at 30 days (BAV: 2.1 vs. TAV: 2.4%, p = 0.17) was similar between groups.

Procedural and 30-day outcomes have improved dramatically since early-generation TAVR valves have been used for BAV stenosis. While the risk of significant perivalvular regurgitation now appears similar between BAV and non-BAV patients, these data are self-reported and neither adjudicated nor assessed at a core lab. Annular rupture and need for permanent pacemaker are still a concern, but not to the degree as before.³ A novel finding in this study is the increased risk of peri-procedural stroke among BAV patients. The TVT registry does not allow for further details of stroke, but it is reasonable to assume an embolic etiology from the calcified valve itself. The implication is that cerebral embolic protection (already commercially approved) may have a salutary effect for TAVR for BAV. Whether a strategy of TAVR plus cerebral embolic protection is non-inferior to AVR remains to be studied.

Long-term outcomes beyond 1 year are largely unknown in BAV patients undergoing TAVR. Most relevant is the influence of TAVR on associated BAV aortopathy, particularly in younger patients (<60 years old). Leaving a potentially life-threatening aneurysm untreated is undesirable in most patients, but how big is too big? Guidelines recommend that aneurysms measuring 4.5 cm or larger be replaced at the same time as SAVR, and that replacement should be considered at 5.0 cm if the patient otherwise does not require SAVR.⁴ The low-risk TAVR trials took a more conservative approach and excluded patients with aneurysms greater than 4.0 cm.

On the other hand, the natural history of BAV aneurysm is more benign than previously thought and has led to a more conservative revision of guidelines. Moreover, our group has shown that the progression of BAV aortopathy may be partially mediated by mechanical wall shear stress, in particular when associated with concomitant valvulopathy such as aortic stenosis.⁵ Theoretically, abnormal wall shear stress from AS may be reduced after TAVR and decrease the future risk of aneurysm progression, but no data is available to support this hypothesis.

In conclusion, outcomes for TAVR in highly selected BAV patients with AS have improved significantly with newer generation balloon-expandable valves. TAVR is a reasonable option in patients with a high and intermediate surgical risk who have reasonable anatomy. However, the higher rate of stroke, annular rupture and need for permanent pacemakers should give us pause when considering this treatment option for typical, young BAV patients with low surgical risk. Further data are needed on the natural history of BAV aortopathy. Non-randomized registry data are forthcoming from both low-risk TAVR trials and may further elucidate the safety of TAVR in BAV patients. The time may come for a randomized clinical trial studying the appropriate treatment of AS in BAV patients—if the clinical equipoise exists. This would be the "lowest of the low-risk trials" and should include follow up of associated aortopathy. Until that time however, surgery should be considered the gold standard therapy for BAV patients.

References

1. Mack MJ, Leon MB, Thourani VH, et al. Transcatheter aortic-valve replacement with a balloon-expandable valve in low-risk Patients. N Engl J Med 2019. [Epub before print]
2. Popma JJ, Deeb GM, Yakubov SJ, et al. Transcatheter aortic-valve replacement with a self-expanding valve in low-risk patients. N Engl J Med 2019. [Epub before print]
3. Yoon SH, Bleiziffer S, De Backer O, et al. Outcomes in transcatheter aortic valve replacement for bicuspid versus tricuspid aortic valve stenosis. J Am Coll Cardiol 2017;69:2579-89.
4. Rinewalt D, McCarthy PM, Malaisrie SC, et al. Effect of aortic aneurysm replacement on outcomes after bicuspid aortic valve surgery: validation of contemporary guidelines. J Thorac Cardiovasc Surg 2014;148:2060-9.
5. Guzzardi DG, Barker AJ, van Ooij P, et al. Valve-related hemodynamics mediate human bicuspid aortopathy: insights from wall shear stress mapping. J Am Coll Cardiol 2015;66:892-900.

Clinical Topics: Acute Coronary Syndromes, Anticoagulation Management, Arrhythmias and Clinical EP, Cardiac Surgery, Congenital Heart Disease and Pediatric Cardiology, Diabetes and Cardiometabolic Disease, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Prevention, Pulmonary Hypertension and Venous Thromboembolism, Valvular Heart Disease, ACS and Cardiac Biomarkers, Anticoagulation Management and ACS, Anticoagulation Management and Atrial Fibrillation, Implantable Devices, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Aortic Surgery, Cardiac Surgery and Arrhythmias, Cardiac Surgery and CHD and Pediatrics, Cardiac Surgery and Heart Failure, Cardiac Surgery and VHD, Congenital Heart Disease, CHD and Pediatrics and Arrhythmias, CHD and Pediatrics and Imaging, CHD and Pediatrics and Interventions, CHD and Pediatrics and Prevention, CHD and Pediatrics and Quality Improvement, Acute Heart Failure, Heart Failure and Cardiac Biomarkers, Heart Transplant, Mechanical Circulatory Support, Pulmonary Hypertension, Interventions and ACS, Interventions and Imaging, Interventions and Structural Heart Disease, Interventions and Vascular Medicine, Computed Tomography, Echocardiography/Ultrasound, Nuclear Imaging, Hypertension, Smoking, Mitral Regurgitation

Keywords: Acute Coronary Syndrome, Acute Kidney Injury, Aneurysm, Dissecting, Aortic Aneurysm, Aorta, Aortic Valve Insufficiency, Aortic Valve, Aortic Valve Stenosis, Arrhythmias, Cardiac, Arterial Pressure, Atherosclerosis, Atrial Appendage, Atrial Fibrillation, Bicuspid, Biomarkers, Cardiac Surgical Procedures, Constriction, Pathologic, Constriction, Pathologic, Conversion to Open Surgery, Coronary Artery Bypass, Coronary Disease, Creatinine, Diagnosis, Differential, Disease-Free Survival, Dilatation, Echocardiography, Endovascular Procedures, Factor VII, Follow-Up Studies, Heart Defects, Congenital, Heart Transplantation, Heart Failure, Heart Valve Diseases, Heart Valve Prosthesis, Heart-Assist Devices, Hemodynamics, Hemorrhage, Hospital Mortality, Hospitalization, Hypertension, Hypertension, Pulmonary, Length of Stay, Liver Diseases, Mitral Valve, Mitral Valve Stenosis, Mitral Valve Insufficiency, Pacemaker, Artificial, Patient Selection, Percutaneous Coronary Intervention, Prospective Studies, Pulmonary Disease, Chronic Obstructive, Pulmonary Embolism, Pulmonary Veins, Pulsatile Flow, Quality Improvement, Quality of Life, Referral and Consultation, Registries, Reoperation, Renal Insufficiency, Research Personnel, Respiratory Insufficiency, Risk Factors, Smoking, Sodium, Spinal Cord Ischemia, Stroke, Stroke Volume, Surgeons, Surgical Instruments, Thrombosis, Tomography, X-Ray Computed, Transcatheter Aortic Valve Replacement, Treatment Outcome, Tricuspid Valve Insufficiency, Ventricular Dysfunction, Left, ACC Annual Scientific Session, ACC19

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