Unmet Clinical Needs

The dilemma of managing elderly patients with severe aortic stenosis (AS) and complex comorbidities has tortured clinical cardiologists for the past several decades. Most patients 80 years and older with severe symptomatic aortic stenosis had not been receiving surgical valve replacement therapies. Studies have indicated that the main reasons for avoiding surgical therapy in such patients have been the perception of excessive surgical risk due to comorbidities and patient reluctance associated with prolonged recovery times. Clearly, the opportunity to consider a less invasive transcatheter treatment for AS had become a compelling clinical need. Early attempts with transcatheter balloon valvuloplasty in the 1980s and 1990s were frustrated by lack of adequate hemodynamic improvement, procedure-related complications, and prohibitive recurrence rates. Therefore, the concept of combining known balloon-expandable and self-expanding stent technology with known bioprosthetic valve technology that could be introduced via a catheter-based delivery system without open chest surgery for aortic valve replacement was immediately attractive to translational scientists.

The radical concept of transcatheter bioprosthetic valve replacement without surgery was heavily criticized by the overall cardiovascular community as being too dangerous, bordering on reckless, and highly unlikely to be an effective alternative to surgical procedures. Multiple obstacles needed to be overcome, including the development of innovative and low-profile delivery systems; confidence with predictable transcatheter valve securement in the aortic annulus; a means to account for the potential of embolic strokes; and mitigating against complications associated with contiguous anatomic structures that may result in conduction abnormalities, paravalvular regurgitation, aortic root or annulus rupture, and coronary artery obstruction. Nevertheless, thoughtful design iterations and deliberate procedural modifications have largely overcome these many concerns to provide a meaningful breakthrough therapy for patients with aortic valve disease.

Since the earliest cases of transcatheter aortic valve replacement (TAVR) in critically ill patients who were not surgical candidates, the technology and the procedure have incrementally evolved in parallel. Over the next decade, the anticipated growth of TAVR should reach close to 300,000 procedures worldwide, representing a four-fold increase. There are now more than 1,000 trained TAVR centers worldwide and the meticulous training programs have provided consistent “real-world” clinical outcomes, which are similar to the excellent results obtained in controlled clinical trials. In several countries, including Germany, Switzerland, and the United States, there are more TAVR than surgical aortic valve replacement cases. Unfortunately, despite the explosive growth of TAVR as an alternative to surgery, there are still many indicated patients who either have no access to TAVR or in whom disease severity awareness is lacking.

An important contribution to the acceptance of TAVR has been a rigorous clinical research pathway, especially in the United States. After developing new and appropriate clinical trial endpoint definitions, a series of clinical trials has reported in the medical literature over the past 10 years. The PARTNER (Placement of Aortic Transcatheter Valves) trials have enrolled more than 10,000 AS patients in a series of randomized clinical trials and observational registries. The first randomized PARTNER Trial demonstrated a 20% improvement in all-cause mortality through 5 years of follow-up compared with standard therapies in prohibitive risk patients who are not candidates for open surgery (1).

Once TAVR had become established as the treatment of choice in patients without surgical alternatives, another randomized trial was performed in high surgical risk patients compared with conventional surgery (2). TAVR was noninferior to surgery based on primary clinical endpoints, while providing secondary benefits such as reductions in acute kidney injury, bleeding complications, and new onset atrial fibrillation; the outcomes were equivalent at 5 years (3). More recently, more than 2,000 intermediate-risk patients were randomized in a trial comparing a next-generation TAVR system with open surgery (4). Again, TAVR was shown to be noninferior to surgery, while achieving statistical superiority in patients who were treated with transfemoral TAVR access. With mounting rigorous clinical trial data, society-based guidelines in both the United States (5) and Europe (6) have responded in recognizing TAVR as an appropriate less invasive alternative to standard SAVR in various indicated patient populations.

The relentless evolution of TAVR clinical growth has been driven by five factors: 1) the routine application of a multidisciplinary heart team process for patient evaluations and procedures; 2) the aforementioned commitment to evidence-based medicine; 3) rapid enhancement of the technology; 4) progressive simplification of the procedure; and 5) a striking reduction in procedure-related complications. The most recent version of the balloon-expandable Sapien transcatheter valve system in clinical trials has demonstrated striking reductions in 30-day all-cause mortality (1%), disabling strokes (1%), and para-valvular regurgitation (<3%) in a large cohort of intermediate-risk patients. Moreover, valve hemodynamics associated with TAVR have been equivalent or superior to surgically implanted valves, based upon meticulous echocardiographic assessments. TAVR in 2018 has become a routine procedure in an enlarging group of AS patients, in whom it can be performed without general anesthesia, with low risk for major complications, and with rapid ambulation followed by early discharge.

With improving clinical results, TAVR is now being explored in a variety of important new clinical indications, including lower-risk patients and different anatomy challenges (e.g., bicuspid valves, originally a contraindication to TAVR). Also advancing the frontier: TAVR for severe aortic regurgitation (7), TAVR in asymptomatic severe AS; and TAVR in moderate AS and systolic heart failure. Similarly, the basic technology and accessory devices have evolved to ensure safe and predictable procedures under a variety of new conditions. An example of a new clinical indication for TAVR is the treatment of failed surgical bioprosthetic valves, which is a growing clinical dilemma and previously required repeat open surgery, often in high-risk elderly patients. The so-called valve-in-valve procedure (TAVR inside a failed surgical bioprosthesis) has now been studied in clinical trials (8) and approved by the U.S. Food and Drug Administration (FDA) as an important alternative to manage these difficult patients. (The FDA approved the Sapien 3 for valve-in-valve treatment for bioprosthetic aortic or mitral valve failure in patients who are at high or greater risk of complications from repeat surgery.)

TAVR is also being used in many patients with AS and other concomitant diseases such as coronary artery disease and mitral regurgitation. Large randomized trials in low-risk surgical patients are underway, which should complete the cycle in characterizing the utility of TAVR compared with surgery in even the most routine patients. To help manage the conundrum of calcific bicuspid aortic valve disease, enhanced devices are being developed, and new studies are being conducted in patients with severe “asymptomatic” AS and moderate AS with reduced left ventricular function and clinical heart failure. Without question, the almost universal availability of a less invasive transcatheter percutaneous femoral TAVR procedure has opened new clinical indications to manage different patient subsets with aortic valve disease.

To help manage many of these new clinical indications, a variety of accessory devices have been developed to further improve the procedure and reduce complications. Dedicated guidewires, expandable sheaths, new balloon valvuloplasty catheters, and cerebral protection devices to reduce strokes are all available in most parts of the world to enhance the TAVR experience. Adjunctive imaging techniques with three-dimensional echocardiography and computerized tomography have dramatically influenced the operator’s ability to properly screen patients, plan procedures, provide accurate intra-procedure device placement, perform post-procedure assessments to ensure optimal outcomes, and monitor valve long-term durability. The crucial use of standard and novel techniques to manage large-sized arterial access has also provided a major advantage to the “minimalist” rapid ambulation approach to TAVR, used by most centers in the world.

Although many of the fundamental concerns associated with TAVR more than a decade ago have been addressed and resolved, important issues remain that limit TAVR application in all patients and in all anatomic substrates. Recent observations have raised concerns that bioprosthetic valve leaflet thickening and thrombosis may be increased after TAVR. Changes in valve leaflet technology and/or the use of systemic anticoagulation therapies (often with novel new agents) may address this concern in the future. Ideally, the need for new pacemakers and the likelihood of strokes after TAVR should be reduced even further, especially in the lowest-risk patients. Further technological enhancements, including the use of cerebral embolic protection devices as well as futuristic image-based valve placement strategies, also may help to address these issues.

The last frontier for TAVR would appear to be the demonstration of bioprosthetic valve durability that is at least equivalent to surgical bioprostheses. Although mid-term analyses of 5-year valve durability based on serial echocardiograms have been encouraging, we need larger patient cohorts studied for more than 10 years to be convinced that the new generation of transcatheter bioprosthetic valves are sufficiently durable. Modifications in leaflet design, such as dry leaflet technology, and implant techniques may further contribute to improved durability. Moreover, given the availability of transcatheter valve-in-valve treatment for bioprosthetic valve failure, it may be acceptable to have valve durability that is slightly less than surgical valve counterparts supported by repeat TAVR procedures, much akin to the treatment of restenosis after angioplasty.

The breakthrough therapy of TAVR is a special example of successful translational medicine and has become a case study of collaborations among preclinical scientists, engineers, and clinical practitioners. Importantly, this multidisciplinary heart team should also include basic scientists, and other health care professionals who assist with patient screening and long-term patient management. The ultimate impact of TAVR has been to create a vital community of dedicated health care professionals who have synergized to create a new therapy for needy patients, which has served as the foundation for an entirely new subspecialty – structural heart disease.