By the time this issue hits your desk it is anticipated that the first percutaneous aortic valve system will be approved for marketing in the USA. The approval of the Edwards SAPIEN transcatheter aortic valve is a landmark event in cardiology narrative and will surely enter the ‘Cardiology Hall of Fame’ as a device that changed the way we treat patients with aortic valve disease. Significant time has passed since the idea’s conception, prototype development by Percutaneous Valve Technologies, Inc., and the first valve implantation in Rouen, France, in 2002 by Dr. Alain Cribier. Prior to the implantation, this novel concept was considered unrealistic and unfeasible, and was heavily criticized by prominent physicians and leaders in the field. There were plenty of skeptics but plenty of believers too as a core of brave, enthusiastic investigators were willing to take the technology to the next step. It was, at first, difficult to miniaturize the technology and then deliver it to the aortic valve position; however, with conviction and persistence, investigators continued to iterate and improve the product to coincide with new delivery methods. These efforts led to the initiation of the pivotal clinical trial that granted device approval.

The development of transcatheter aortic valve replacement (TAVR) is a classic example of the myriad of ingredients that enable an innovation to be implemented in clinical practice. First, the unmet need; although aortic valve replacement surgery is the gold standard for the treatment of severe aortic stenosis, at least 30% of patients with severe aortic stenosis are reported to not undergo surgery for replacement of the aortic valve due to advanced age, left ventricular dysfunction, presence of prohibitive comorbidities, or death before the planned procedure. Furthermore, the calculated operative risk in these patients is extremely high and is felt to preclude surgery in about half of the symptomatic patients. In fact, survival analyses have demonstrated that the interval from the onset of symptoms to the time of death is approximately 2 years in patients with heart failure, 3 years in those with syncope, and 5 years in those with angina. More than 50% of deaths can be classified as sudden after a course of late heart failure and quality-of-life–limiting symptoms. Based on data from the 2009 Healthcare Utilization project, the estimated prevalence for severe aortic stenosis overall in the USA is approximately 360,000 cases, and by echo criteria 120,000 cases. Therefore, in terms of the unmet need, there is a large population with severe aortic stenosis without adequate treatment.

Second, a strategic partner; in order to move the innovation forward, inventors and start-ups must align with a strategic partner with the resources and the know-how to execute a great idea or a commercial device prototype to be tested safely in humans. In the case of transcatheter aortic valve implantation (TAVI), Edwards LifeSciences, LLC, partnered with inventors and Percutaneous Valve Technologies, Inc., to take on the role of strategic partner in order to modify the device and to support a robust clinical evaluation program, including but not limited to the support of a large randomized pivotal trial like PARTNER.

The third essential ingredient in the approval process is a robust randomized clinical trial to test the device against the standard of care and to demonstrate superiority or noninferiority to the gold standard technology. The PARTNER trial was unique and first of its kind in many aspects. It was a multidisciplinary team effort involving surgeons and interventional cardiologists. It was designed to be the first randomized clinical trial in two arms: one against medical therapy, including balloon angioplasty in inoperable patients ( n =358), and the other against surgical aortic valve replacement in 699 high-risk patients with aortic stenosis. The study’s primary end point was met in both arms; and based on those results, the FDA’s Circulatory System Devices Panel recommended approval of the Edwards SAPIEN valve for the inoperable arm in July 2011. By the time the device is approved for marketing, the PARTENR trial and its continuation arms will exceed enrollment of 3000 US subjects.

Like any new technology, TAVR is not exempt from complications. These include more vascular complications and higher rates of stroke and paravalvular leak when compared to the control group. The magnitude of these complications can be critical for approval and adoption of the technology when compared with the standard of care. While it is clear that these complications did not impede on the mortality benefit in the inoperable group, it is not clear how these complications will be judged against surgical aortic valve replacement.

Finally, it is important to note that the Edwards SAPIEN valve technology has been available for patients around the world for several years. CE Mark approval for European commercial sales of the Edwards SAPIEN transcatheter aortic heart valve technology with the RetroFlex transfemoral delivery system was granted in September 2007, almost 4½ years earlier than in the USA. The question of whether this gap can be closed without compromising patient safety is an interesting one. CE Mark approval can be granted without a randomized clinical trial, and one can argue that if a randomized clinical trial was not required in the USA we may have never seen an important randomized trial like PARTNER. On the other hand, efforts should be undertaken to reinvigorate the US regulatory process in order to shorten the regulatory gap for approval between Europe and the USA.

In closing, TAVI was changed to TAVR for reimbursement considerations, which are higher for valve replacement as compared to intervention . To me, changing from I to R reflects the transformation from I magination to R eality with the upcoming availability of the TAVR technology for clinical use in the USA. Although we welcome the approval with a great sense of responsibility and enthusiasm, the job is not over. Rigorous postmarketing plans are in place, and the adoption of the technology in clinical practice should be carefully monitored. Further iteration is needed to overcome the technology’s limitations so that TAVR produces a better reality than we could have ever imagined.