Calcific aortic stenosis (AS) in adults develops because of degenerative calcifications of the aortic cusps. This can occur in different settings such as a previous rheumatic inflammation, which leads to chronic destruction of the anatomically normal or at times a congenital abnormal valve (bicuspid aortic valve or the rarer unicuspid valve).1,2 A fusion of the commissures between the leaflets leaves a small central orifice for blood ejection.3 Calcific AS has now become the most common valvular disease in Western countries.4 It is a disease of the old and very old. Senile calcific AS affects 5% of the population 70 years or older in the United States.5 Calcification of the aortic valve is a disease that is progressive and shares many similarities with coronary artery disease. Endothelial dysfunction, inflammatory cell, cytokine activation, and low-density lipoprotein accumulation may eventually remodel cells in the aortic valve and promote the deposits of calcium hydroxyapatite crystals. These deposits stiffen and thicken the valve and prevent normal opening during systole. This creates an outflow obstruction for the left ventricle and, over time, results in concentric left ventricular hypertrophy and diastolic dysfunction.6–8 This process evolves over decades and symptoms frequently do not appear until the sixth, seventh, or eighth decade of life. The severity of AS is graded with Doppler echocardiography and is considered severe9 with a peak jet velocity of greater than 4 m/s, mean gradient 40 mm Hg or higher, and aortic valve area of less than 1 cm2.
Transcatheter aortic valve replacement (TAVR) is an evolving technology and medical procedure that has been developed with high-risk and inoperable patients in mind. The goal is to improve quality of life and put elderly patients back on the curve for natural life expectancy without AS. This new and exciting technology is the product of international collaboration and research over the past decade. In the United States, there are 2 transcatheter aortic valve systems available for use. The Edwards SAPIEN valve (Edwards Lifesciences Corp, Irvine, California) is commercially approved for extreme-risk or inoperable patients with severe senile calcific AS and is in clinical trials for high-risk populations. The Medtronic CoreValve (Medtronic, Inc, Minneapolis, Minnesota) is available within the US Pivotal trial for high- and extreme-risk patients. Traditionally, both valves are implanted via the retrograde approach, which is femoral artery access, and delivered via the aortic arch into the stenotic valve. The SAPIEN valve is also researched in the United States using an antegrade transapical approach.
Why Transcatheter Aortic Valve Replacement
Traditionally, the gold standard for treating AS is surgical aortic valve replacement (sAVR). Unfortunately, sAVR is, in many cases, not a viable option in the old and very old patient. Advanced age, heavy calcification, velocities greater than 4 m/s, and multiple comorbidities such as severe chronic obstructive pulmonary disease, end-stage renal disease, porcelain aorta, peripheral vascular disease, atrial fibrillation, and pulmonary hypertension are markers of poor outcomes.9 Often, patients are deemed unsuitable for sAVR because of high calculated surgical risk scores.10 This may often lead to a difficult decision-making process, and quite frequently, physicians do not offer patients surgery or patients themselves refuse surgery.11 The alternative treatment options are maximizing medical management such as reducing heart failure symptoms pharmacologically and/or balloon aortic valvuloplasty.12,13 Unfortunately, this is temporizing at best, carries procedural risks, and is not a long-term solution to this structural heart problem.14
History in the Making
The first percutaneous transcatheter implantation of an aortic valve prosthesis for calcific AS was described by Cribier et al15 in 2002. Nearly a decade later, Fairbairn et al14 conducted a study at the University of Leeds, United Kingdom. The goal of this study was to assess serial changes in patient health-related quality of life over time and identify predictors of patient benefit after they received TAVR. Although this study had limitations such as being a single-center study and limited sample size, it was a high-quality study and showed promising results. Figure 1 demonstrates changes in health component scores after TAVR. In summary, the greatest benefit was seen at 30 days of the Health Survey Scoring Demonstration (Short Form 12 question score) in pain, general health, physical role, and physical functioning, respectively. Scores in vitality, social functioning, and emotional and mental health also improved but were statistically not significant (Figure 1).14 In 2010, the French Ministry of Health supported the creation (funded by Edwards Lifesciences and Medtronic) of the largest TAVR registry in Europe at that time (FRANCE 2). A total of 3195 patients were enrolled between January 2010 and October 2011 and 34 centers in France were performing TAVR. The Edwards SAPIEN or Medtronic CoreValve systems were implanted via femoral (74%), subclavian (5.8%), or other (1.8%) approaches. The primary end point was death from any cause. Gilard et al16 reported the results of this prospective multicenter study. The 1-year survival rate of 76.0% in this registry resembled the rates in the SOURCE Registry, UK registries, and in cohort A of the Placement of AoRTic TraNscathetER Valve (PARTNER) trial. (The SOURCE Registry gathered data for 2 consecutive years at European centers after commercialization of the Edwards SAPIEN bioprosthesis, totaling 2339 patients).
A common complication was the need for a permanent pacemaker (15.6%). The authors concluded the TAVR procedure to be a reasonable option for this subset of patients.16
National Developments and Ongoing Research
The Edwards SAPIEN valve is made of bovine pericardial tissue leaflets with a Carpentier-Edwards thermafix process balloon-expandable stainless steel frame polyethylene terephthalate skirt. It is available in 2 sizes, 23 and 26 mm, and it fits patients with annuli of 18 to 25 mm. It is has a RetroFlex 3 Delivery System balloon-expandable valve technology (Edwards Lifesciences, 2012). The PARTNER trial (sponsor: Edwards Lifesciences) was 1 of the most complex studies in cardiology and cardiothoracic surgery. The purpose was to determine the safety and effectiveness of the device and delivery systems (transfemoral and transapical). This trial had 2 arms: the high-risk operable patient (cohort A) and the extreme-risk or inoperable patient (cohort B). The high-risk patients were randomized 1:1 to either TAVR or sAVR. In the TAVR arm, some patients had iliofemoral approach, and if the vessels were not good enough, a transapical approach was used. The inoperable, or cohort B, patients were randomized 1:1 to TAVR or medial management, which might include balloon aortic valvuloplasty (ClinicalTrials.gov).
The Medtronic CoreValve is an 18F delivery system and it treats annuli from 18 to 29 mm. It is a self-expanding nitinol frame with porcine pericardial leaflets (Medtronic, 2012). This valve can also be implanted via the trans-subclavian approach or direct aortic approach via ministernotomy in patients with difficult iliofemoral anatomy or severe peripheral vascular disease. The Medtronic CoreValve US Pivotal study (sponsor: Medtronic Inc) is ongoing and being conducted across 45 sites within the United States. It looks at the safety and efficacy of the Medtronic CoreValve System as an alternative in high-risk and extreme-risk patients. Enrollment is completed for the extreme-risk cohort and data are now being evaluated. CoreValves continue to be implanted with Food and Drug Administration approval in extreme-risk patients under the Continued Access Study. Primary outcome measures are all-cause death and major stroke at 1 year and secondary outcome measures are all-cause death, myocardial infarction and major stroke, and reintervention (surgery or additional PCI for repair or redo valve). No results have been made public thus far. Start date of the study was November 2010, estimated study completion date will be November 2017, and final data collection date for primary outcome measure will be May 2013 (ClinicalTrials.gov).
Patient Selection Criteria for Transcatheter Aortic Valve Replacement
Patients receiving either valve have certain characteristics.17 The average age is 83.1 ± 8.6 years, and diagnosis of senile degenerative aortic valve stenosis is established by echocardiographically derived criteria (mean gradient >40 mm Hg or jet velocity >4.0 m/s and an initial aortic valve area of ≤0.8 cm2 or indexed effective orfice area <0.5 cm2/m2). Patients are rejected for the procedure if they show evidence of an acute myocardial infarction and if they underwent any peripheral interventional coronary procedure within the last 30 days. Other exclusion criteria are leukopenia (white blood cell count <1000 mm3), thrombocytopenia (platelet count <50 000 cells/mm3), history of bleeding diathesis, or hypercoagulable states. Further exclusion criteria are untreated clinically significant coronary artery disease requiring revascularization, cardiogenic shock manifested by low cardiac output, vasopressor dependence, or mechanical hemodynamic support and the need for emergency surgery for any reason. Figure 2 outlines the PARTNER study design, which divides the subjects into the high-risk group and the inoperable group (Figure 3), with primary endpoint being all-cause mortality (Figure 4).
Outcomes to Date
Smith et al18 continue to strengthen the hypothesis from the original PARTNER trial, that the TAVR is noninferior to the gold standard surgical approach in the high-risk patient. Primary outcome measures are mortality in 1 year for the duration of the study (September 2014). Secondary outcome measures (functional improvement, evidence of prosthetic valve dysfunction, length of hospital stay, improved quality of life) were tested at 30 days, 6 months, and 1 year. Limited data are currently published, and at this point, we know that death rates from any cause were reduced in the transcatheter group at 30 days (3.4% TAVR, 6.5% sAVR; P = .07) and 1 year (24.2% TAVR, 26.8% sAVR; P = .44) compared with the surgical group. Rates of major strokes were increased in the transcatheter group at 30 days (3.8% TAVR, 2.1% sAVR; P = .2) and at 1 year (5.1% TAVR, 2.4% sAVR; P = .07). Improved symptoms (eg, shortness of breath and generalized fatigue) at 30 days were greater in the transcatheter group, but at 1 year, no difference was observed. Major vascular complications were more frequent with the transcatheter group at both times (30 days: 11% TAVR, 3.2% sAVR, P ≤ .001; 1 year: 11.3% TAVR, 3.5% sAVR, P ≤ .001; however, major bleeding (30 days: 9.3% TAVR, 19.5% sAVR, P ≤ .001; 1 year: 14.7% TAVR, 25.7% sAVR, P < .001) and new-onset atrial fibrillation (30 days: 8.6% TAVR, 16% sAVR, P = .006; 1 year: 12.1% TAVR, 17.1% sAVR, P = .07) were increased in the surgical group at both times.18 Reiss et al19 confirmed results from the PARTNER cohort B study as TAVR being superior compared with standard medical treatment in relation to overall survival and cardiac functional status. The Food and Drug Administration approved coverage for the Edwards SAPIEN valve in inoperable patients (Medicare coverage with certain and specific guidelines). Expanding this technology to a broader group of patients will take more research and the continued development of this technology. The durability of the valves will ultimately determine expanded use to other populations such as the congenital bicuspid AS patients or a younger population. Even though preliminary data show no improvement in outcomes over 1 year and increased risk in stroke, health-related quality of life significantly improved immediately after the procedure and was maintained at 1 year.14 Figure 1 illustrates the greatest benefit at 30 days of the Health Survey Scoring Demonstration (SF-12 score) in pain, general health, physical role, and physical functioning, respectively.
These complex patients require a team approach such as the interventional cardiologist, primary cardiologist, cardiac surgeons, and highly trained nursing staff. The TAVR nurse coordinator is a core member of the team, and the contributions of that individual are vital to program success. She/He must perform a careful and thorough assessment of these elderly patients with multiple comorbidities. Once the procedure is performed, femoral access sheaths are removed in the operating room before the patient is transported to the intensive care unit. The patients usually spend a short time in the intensive care unit and are predisposed to common concerns such as delirium and infection. Strokes and Transient Ischemic Attacks however, are a major source of morbidity in patients after TAVR20 and are greatest in the first 24 hours after the procedure.21 Vascular complications such as retroperitoneal hemorrhage, femoral or iliac artery dissection, and development of a femoral pseudoaneurysm and new-onset atrial fibrillation are also very specific to this patient population and require careful monitoring by skilled nursing staff.1 Furthermore, the high acuity of patients undergoing TAVR and the need for intra-arterial contrast medium could compromise renal function. A careful selection process of appropriate patients and prompt recognition and treatment of possible postprocedural events by carefully trained nurses are of highest importance. This will ensure that TAVR continues to evolve as a viable option to treat severe AS in the old and very old patient population.
- The Edwards SAPIEN valve (PARTNER trial) and the Medtronic CoreValve (The Medtronic CoreValve US Pivotal study) are currently available in the United States.
- Death rates from any cause are reduced in the transcatheter group at 30 days and 1 year.
- Rates of major strokes are increased in the transcatheter group at 30 days and at 1 year.
- Degree of symptom improvement at 30 days was greater in the transcatheter group, but at 1 year, no difference was observed.
- These complex patients need a team approach between the interventional cardiologist, primary cardiologist, cardiac surgeon, and highly trained nurses, such as a TAVR nurse coordinator.
- Durability of the valves will ultimately determine expanded use to other populations.
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