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Introduction

The 20th annual Cardiovascular Research Technologies (CRT) Conference took place in Washington, DC in February 2017. More than 2000 leading interventional and endovascular specialists attended the four-day international cardiology conference that features cutting-edge research in a unique boutique setting. Given its proximity to the Food and Drug Administration (FDA), a one-and-a-half day FDA Town Hall meeting was created to provide a rare forum for physicians, industry representatives, and governmental figures to discuss current and future technologies within cardiovascular medicine. The first session was dedicated to the field of structural cardiology and the second to current FDA regulatory processes and coronary and endovascular devices. The following is a summary of the current state of cardiovascular technology and the role of the FDA for future device trials.

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Patent foramen ovale closure: current state and future directions

The AMPLATZER patent foramen ovale (PFO) occluder was approved for commercial use by the FDA on October 28, 2016. The debate over the effectiveness of the device has been a long process, lasting more than 12 years . With an average patient follow-up of more than 5 years, the analysis demonstrated a 50% relative risk reduction in recurrent ischemic strokes in patients who were treated with an occluder device compared with standard medical management. When labeling new devices, FDA’s Andrew Farb, MD, pointed out that the FDA must consider indications for use, contraindications, warnings, precautions, adverse events, clinical studies, and directions for use. For the AMPLATZER PFO Occluder, Farb was clear that the Instructions for Use in this case directly reflect the RESPECT Trial investigational plan and outcomes, which was emphasized by the FDA representatives and physician specialists.

The AMPLATZER PFO Occluder is intended for percutaneous, transcatheter closure of a PFO to reduce the risk of recurrent ischemic stroke in patients who have had a cryptogenic stroke due to a presumed paradoxical embolism. Richard Benson, MD, a vascular neurologist in Washington, DC, emphasized the lack of support for PFO closure in the current ACC/AHA Guidelines, which categorizes a patient with cryptogenic ischemic stroke, known PFO and evidence of deep venous thrombosis (DVT) a Class IIb recommendation for percutaneous closure. He went on further to discuss the importance of a structured “Stroke Team” to fully evaluate each case on an individual basis in collaboration with a cardiologist, to honor the current guidelines while considering the newest evidence-based data that have emerged from the RESPECT Trial. Cardiologist Jon Resar, MD, with Johns Hopkins Hospital, agreed that patient selection is the key moving forward with this particular device. As the labeling specifies, the device should be limited to use in younger patients with PFO and truly cryptogenic non-lacunar ischemic strokes. The diagnosis of cryptogenic stroke is often challenging because it is a diagnosis of exclusion. All panelists emphasized that work-up must be diligent and comprehensive to rule out other potential causes such as atrial fibrillation, large vessel disease, or hypercoagulable disorders. In line with the vascular neurologist, Dr. Resar also encouraged the implementation of a “Brain/Stroke Team” to facilitate appropriate patient selection.

Finally, Dan Gutfinger, MD, PhD, a senior medical director with Abbott Vascular, emphasized the importance of a shared-decision making process that involves not only multiple physician specialists but also the patient, educating them on the evidence and reminding them that the AMPLATZER PFO Occluder does not protect against strokes unrelated to the device. From an industry standpoint, the appropriate rollout of the device will require appropriate patient selection and effective physician training and proctoring for implantation. Future research studies may refine patient selection by identifying septal features associated with higher stroke risk and validating clinical risk scoring systems.

2

Patent foramen ovale closure: current state and future directions

The AMPLATZER patent foramen ovale (PFO) occluder was approved for commercial use by the FDA on October 28, 2016. The debate over the effectiveness of the device has been a long process, lasting more than 12 years . With an average patient follow-up of more than 5 years, the analysis demonstrated a 50% relative risk reduction in recurrent ischemic strokes in patients who were treated with an occluder device compared with standard medical management. When labeling new devices, FDA’s Andrew Farb, MD, pointed out that the FDA must consider indications for use, contraindications, warnings, precautions, adverse events, clinical studies, and directions for use. For the AMPLATZER PFO Occluder, Farb was clear that the Instructions for Use in this case directly reflect the RESPECT Trial investigational plan and outcomes, which was emphasized by the FDA representatives and physician specialists.

The AMPLATZER PFO Occluder is intended for percutaneous, transcatheter closure of a PFO to reduce the risk of recurrent ischemic stroke in patients who have had a cryptogenic stroke due to a presumed paradoxical embolism. Richard Benson, MD, a vascular neurologist in Washington, DC, emphasized the lack of support for PFO closure in the current ACC/AHA Guidelines, which categorizes a patient with cryptogenic ischemic stroke, known PFO and evidence of deep venous thrombosis (DVT) a Class IIb recommendation for percutaneous closure. He went on further to discuss the importance of a structured “Stroke Team” to fully evaluate each case on an individual basis in collaboration with a cardiologist, to honor the current guidelines while considering the newest evidence-based data that have emerged from the RESPECT Trial. Cardiologist Jon Resar, MD, with Johns Hopkins Hospital, agreed that patient selection is the key moving forward with this particular device. As the labeling specifies, the device should be limited to use in younger patients with PFO and truly cryptogenic non-lacunar ischemic strokes. The diagnosis of cryptogenic stroke is often challenging because it is a diagnosis of exclusion. All panelists emphasized that work-up must be diligent and comprehensive to rule out other potential causes such as atrial fibrillation, large vessel disease, or hypercoagulable disorders. In line with the vascular neurologist, Dr. Resar also encouraged the implementation of a “Brain/Stroke Team” to facilitate appropriate patient selection.

Finally, Dan Gutfinger, MD, PhD, a senior medical director with Abbott Vascular, emphasized the importance of a shared-decision making process that involves not only multiple physician specialists but also the patient, educating them on the evidence and reminding them that the AMPLATZER PFO Occluder does not protect against strokes unrelated to the device. From an industry standpoint, the appropriate rollout of the device will require appropriate patient selection and effective physician training and proctoring for implantation. Future research studies may refine patient selection by identifying septal features associated with higher stroke risk and validating clinical risk scoring systems.

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Left atrial appendage closure: a second look on future studies

Following FDA approval of the WATCHMAN device in March 2015, the Center for Medicare and Medicaid Services (CMS) issued a national coverage determination (NCD) that required the establishment of a prospective national registry. Prior to the national registry, Reddy et al. analyzed procedural safety data in the initial post-approval launch by collecting data reported to the manufacturer. The analysis, published in January 2017, included 3822 consecutive patients who underwent left atrial appendage closure with WATCHMAN by 382 physicians at 169 U.S. centers. Half of the procedures were performed by newly trained operators. The main findings were that the acute procedural success rate was 95.6% and the rate of serious adverse events, such as cardiac tamponade, was 1.02% . Despite the large number of inexperienced operators, the procedural success and device safety were in line with those seen in clinical trials.

The prospective national registry began enrollment in December 2015. Kenneth Stein, MD, from Boston Scientific, described a post-approval analysis of 2000 consecutively enrolled WATCHMAN patients in the registry. The first data analysis from acute procedural results is expected at the end of first quarter in 2017. In addition, the commercial rollout of the occluder device has revealed a knowledge gap in optimal medical management in patients at high risk for bleeding in the immediate post-device implantation period. To address the safety and effectiveness of the WATCHMAN device in patients who are contraindicated for anticoagulation, Boston Scientific is sponsoring the ASAP-TOO Study ( NCT02928497 ), which will compare LAA occlusion to single antiplatelet therapy or no therapy. To encourage enrollment of women in clinical trials, Boston Scientific has also established the WIN-Her Initiative (Women Opt In for Heart Research) to identify barriers for women to join research studies, develop strategies to address the barriers, and pilot the strategies in such trials as ASAP-TOO. Finally, future studies are looking into feasibility and safety of combining percutaneous interventions into one procedure, such as transcatheter aortic valve replacement (TAVR) and left atrial appendage closure. However, the logistics of such development remain difficult due to the reimbursement structure in the U.S.

The session concluded with a presentation on shared decision-making. Megan Coylewright, MD, MPH, from Dartmouth-Hitchcock Medical Center, highlighted the importance of shared decision making for appropriate patient selection within a broad spectrum of patients who may meet criteria for WATCHMAN device. Shared decision-making represents good clinical practice, is included in the FDA approved labeling, and is required by CMS for coverage. Eliciting the patient’s values and preferences is often the hardest but most important step for clinical decision-making and is most relevant for situations in which: (1) more than one reasonable option exists, (2) there is uncertainty in the evidence, or (3) patient preferences are distinct from healthcare professionals. Research within the academic community and interactions with the FDA are ongoing in this area to help determine how patients measure success and how to best implement this in future studies.

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Transcatheter mitral therapy: emerging therapies for functional mitral regurgitation

Functional or secondary mitral regurgitation is often described as a disease of the left ventricle. A rather simple problem but a complex disease process, functional mitral regurgitation is typically characterized by normal mitral valve leaflets but a dilated left ventricle resulting in displacement of the papillary muscles leading to restricted leaflet motion and a dilated mitral annulus. The pathophysiology has subsequently led to a variety of treatment strategies but no gold standard. In addition, the argument remains whether progressive left ventricular dysfunction is the cause of mitral regurgitation or an effect. The complex nature of the disease has led to vague recommendations by professional societies concerning surgical treatment, which subsequently have made indications for transcatheter strategies even more uncertain. Agencies such as the FDA must consider all the unknowns when going forward with emerging therapies.

Currently, the 2014 AHA/ACC Valve Guidelines recommend optimizing medical therapy and pursuing cardiac resynchronization therapy for patients with functional mitral regurgitation . However, surgery for stand-alone symptomatic severe secondary mitral regurgitation is a IIB recommendation. Vinayak Bapat, MBBS, from Guy’s and St Thomas’ Hospital, London, UK, highlighted that more research is needed in this area but also argued that there are inherent problems with evaluating surgical outcomes as all results are dependent on volume of the participating institution; there are a variety of techniques and often variability in expertise vital to management, such as echocardiography. Ultimately, he feels that all patients should receive optimal medical management prior to surgical consideration, the question of surgical repair versus replacement must be answered, a comprehensive “Heart Team” must take part in the decision process, and modern, less invasive surgical techniques will likely achieve better outcomes.

Emerging percutaneous technologies hold promise for the treatment of functional mitral regurgitation. Percutaneous options under study include devices for leaflet apposition (MitraClip), and devices mimicking surgical annuloplasty (e.g., Cardioband, Carillion). Ori Ben-Yehuda, MD, of Columbia University, states that future clinical trials must be efficient, focus on appropriate patient selection, and aim for achievable but clinically relevant endpoints such as heart failure hospitalizations, exercise capacity, and quality of life. The COAPT Trial ( NCT01626079 ) is ongoing with hopes to provide some answers to the questions above.

JoAnn Lindenfeld, MD, a heart failure specialist at Vanderbilt Heart and Vascular Institute, argues that the data may currently support a combination of percutaneous valve repair along with optimal medical therapy. Specifically, improvement in mitral regurgitation parallels the changes seen in left ventricular remodeling in patients treated with beta-blockers or with cardiac resynchronization therapy. In addition, median blood pressure increase seen in patients treated with cardiac resynchronization therapy in the COMPANION and CARE-HF trials allows for potentially significant up-titration of the medical therapy . More research is needed and with the development of new devices, the FDA stressed the importance identifying a comparator, involving a Heart Failure team to assure appropriate patient selection and uniform medical therapy, and incorporating patient-centered outcomes when considering effectiveness.