Treatment
Medical Management
Although the definitive therapy for AS is valve replacement, there are certain medications that may prove beneficial in both asymptomatic patients and in symptomatic patients who are not candidates for procedural intervention. Classically, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers were thought to be relatively contraindicated in AS, but retrospective analyses have suggested that the favorable effects of these medications on LV hypertrophy and LV remodeling may outweigh the risks, especially in patients with LV systolic dysfunction and AS. One study found a hazard ratio for all-cause mortality of 0.76 and a hazard ratio for cardiovascular events of 0.77 for AS patients treated with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers compared with untreated patients.
The judicious use of diuretics can aid in alleviating symptoms in patients with AS and volume overload, but care must be taken to avoid overdiuresis, as a substantial drop in preload can precipitate a fall in cardiac output with resultant hypotension. In addition, the use of β-adrenergic blocking medications in patients with severe AS is relatively contraindicated since the negative inotropic effect may lead to reduced contractile reserve and LV failure.
An emerging medication class for the treatment of AS is the PDE5 inhibitors, such as sildenafil and tadalafil. Early studies have shown beneficial effects on hemodynamic measurements after a single dose of a PDE5 inhibitor, including improvements in pulmonary and systemic vascular resistance, mean pulmonary arterial pressure, wedge pressure, stroke volume and systemic and pulmonary compliance. The ongoing ASPEN randomized trial is testing the hypothesis that longer-term treatment with tadalafil will have beneficial effects on LV structure and function as well as on pulmonary artery pressures in AS patients.
Surgical AVR
The definitive treatment of severe AS in the older population remains to be replacement of the AV. Surgical AVR is the primary modality for treating severely stenotic AVs. Improvements in surgical technique have led to improved outcomes in elderly patients undergoing AVR. A primary consideration in planning for AVR is the decision to implant a bioprosthetic or mechanical valve. Although mechanical valves are more durable, bioprosthetic valves are usually preferred in older patients as they do not require long-term systemic anticoagulation and older patients are less likely to require reintervention due to shorter life expectancy. With the emergence of TAVR, use of bioprosthetic valves may expand to include younger patients, with the expectation that valve-in-valve TAVR (i.e., transcatheter valve implantation at the site of a prior bioprosthetic valve) will be an option for patients who experience failure of the original bioprosthesis.
An important advance in the field of surgical AVR is the creation of new mechanical valves designed to decrease the risk of thrombus formation, thereby reducing the risk of valve thrombosis and stroke, and potentially reducing or eliminating the need for anticoagulation. Although this development is more likely to impact younger patients, it is possible that with reduced risk for bleeding and thromboembolic complications, these new mechanical valves may also be a viable alternative for older patients.
Another advancement in surgical AVR is the emergence of minimally invasive surgical techniques. New techniques for AVR using a right anterior thoracotomy or ministernotomy approach offer decreased recovery times and shorter hospital stays. In addition, new sutureless valves mounted on a self-expanding or balloon inflatable frame offer the advantages of easier deployment and the ability to remove debris from the AV annulus, which occasionally causes complications in TAVR. Potential contraindications to these less invasive approaches in older patients include porcelain aorta, any contraindication to cardiopulmonary bypass and severe aorto–iliac peripheral vascular disease.
Outcomes After Surgical AVR
As cardiac surgeons and anesthesiologists have gained experience with patients of advanced age, perioperative mortality rates following surgical AVR have declined. A recent systematic review and meta-analysis of outcomes in patients over the age of 80 years who underwent AVR found an overall early postoperative mortality of 6.7%; however, mortality was lower in series with a midpoint after 2000 compared with series with a midpoint before 2000 (5.8 vs 7.5%). In this analysis, pooled survival rates at 1, 3, 5 and 10 years after AVR were 87.6, 78.7, 65.4 and 29.7%, respectively.
Apart from mortality, common complications after AVR include respiratory failure, atrial fibrillation, myocardial infarction, stroke, acute renal failure, major bleeding and atrioventricular block requiring a pacemaker. Complication rates vary by study and patient characteristics, but tend to be higher in older patients. One study examining patients over the age of 80 years undergoing AVR reported complication rates of 2.4% for stroke, 5% for myocardial infarction, 23% for prolonged ventilation, 6% for pacemaker, 5% for dialysis, 26.5% for arrhythmia and 3.6% for re-exploration for bleeding. Similarly, analysis of high-risk patients randomized to AVR in the PARTNER study showed complication rates of 3.2% for stroke, 0.6% for myocardial infarction, 3.8% for major vascular disorders, 26.7% for major bleeding, 1% for endocarditis, 6.5% for renal failure and 5% for new pacemaker.
Intermediate and long-term outcomes following surgical AVR are excellent, with the majority of older patients, including octogenarians, reporting reduced symptoms and improved quality of life. Long-term survival following the procedure is comparable to the general population of similar age.
Balloon Aortic Valvuloplasty
Balloon aortic valvuloplasty (BAV) involves high-pressure balloon dilatation of the stenotic AV using catheters passed into the left ventricle via a retrograde transfemoral approach. BAV is not a primary treatment modality for severe AS since restenosis is common within 6–12 months and the risk of procedural complications, including stroke and worsening aortic regurgitation, is relatively high. BAV may be considered as a temporary measure to improve a patient's clinical condition so that he or she will be a more suitable candidate for subsequent AVR or TAVR. In older patients with severe AS in the context of major comorbidities, such as acute renal failure or pulmonary disease, BAV may be considered to determine whether relief of AS leads to overall clinical improvement, in which case AVR or TAVR may be appropriate. Several small studies have shown medium-term improvements in New York Heart Association functional classification, mean gradient and AV area in patients thought to be too sick for AVR or TAVR. Many of these patients were later able to undergo AVR or TAVR with outcomes that were similar to those who underwent AVR or TAVR without BAV. Thus, BAV may have an important role as a bridge to definitive therapy in select subpopulations of elderly patients with severe AS.
Transcatheter AVR
In a separate cohort of patients enrolled in the PARTNER trial, patients at high risk for surgery, but who were not deemed inoperable, were randomized to surgical AVR versus TAVR. Overall, 1-year survival was similar in the two groups and TAVR was noninferior to surgical AVR. With respect to periprocedural complications, vascular complications were more common in the TAVR group, whereas major bleeding and new-onset atrial fibrillation were more common in the surgical AVR group. There was also a nonsignificant trend towards more strokes in the TAVR group. At 2-years follow-up, mortality remained similar in patients randomized to TAVR or surgical AVR. The implications of this study are that TAVR can be considered in select patients who are deemed to have high surgical risk, thus expanding the patient population for which TAVR may be appropriate.
TAVR can be performed through one of several minimally invasive access routes, including transfemoral, transapical and transaortic approaches. The key determinants of which route is chosen are the size of the patient's common femoral and aorto–iliac vessels, the extent of peripheral vascular disease and the tortuosity of the large arteries. Current TAVR delivery systems require large arterial sheaths (18–24 Fr depending on size of the valve to be implanted); therefore, transfemoral access is only feasible if the minimum luminal diameter is 7 mm for the 23 mm, or 8 mm for the 26 mm Edwards SAPIEN® Transcatheter Heart Valve (Edwards Lifesciences LLC, CA, USA). The CoreValve® Transcatheter Aortic Valve (Medtronic Inc., MN, USA) has four available sizes, 23, 26, 29 and 31 mm, all of which use an 18-Fr delivery system requiring a minimum luminal diameter of 6 mm. An alternative for patients who are not candidates for the transfemoral route is the transapical approach, where a cardiac surgeon uses a left minithoracotomy to place a sheath through the apex of the heart, by which the valve delivery system is introduced. The transaortic approach involves a cardiac surgeon using a ministernotomy to expose the thoracic aorta, placing the sheath directly into the aorta, and then introducing the delivery system. Additional sites that are being explored include transcarotid and subclavian approaches, thus allowing greater flexibility in offering transcatheter valve replacement to patients with variations in vascular anatomy.
Most of the data supporting these alternate routes of vascular access involve case reports, case series or registry data, and there have been no randomized trials comparing access sites. Since more than 50% of patients in some centers do not qualify for transfemoral access, use of alternate sites has increased. A recent single-center comparison of outcomes after transaortic, transapical or transcarotid TAVR yielded outcomes that were similar to those for patients who underwent transfemoral TAVR. Furthermore, a recent systematic review established that outcomes after tranaxillary TAVR are similar to those after transfemoral TAVR.
Although numerous transcatheter valve prostheses are being developed and tested worldwide, the majority of the experience to date is with the SAPIEN valve and the CoreValve, which are depicted in Figure 1. The balloon-expandable SAPIEN valve is approved for commercial use in the USA and Europe, and the next-generation SAPIEN XT valve is being investigated in the ongoing PARTNER II study. The self-expanding CoreValve is commercially available in Europe and is currently being investigated in the USA to determine its safety and efficacy in high-risk and very high-risk patients. To date, no studies have compared outcomes of TAVR using the SAPIEN valve with the CoreValve in a prospective manner, but a retrospective analysis of pooled data showed no significant differences in major outcomes between the two systems, except that pacemaker placement was required more frequently with the CoreValve. The Direct Flow Medical® Transcatheter Aortic Valve System (Direct Flow Medical Inc., CA, USA), the Sadra Lotus™ Valve (Boston Scientific, MA, USA) and the Portico™ Transcatheter Aortic Valve Implantation System (St Jude Medical Inc., MN, USA) have completed clinical trials in Europe, and US trials are expected to be initiated within the next year.
(Enlarge Image)
Figure 1.
Two widely used transcatheter aortic value prostheses. (A & B) Edwards SAPIEN® Transcatheter Aortic Valve System (Edwards Lifesciences LLC, CA, USA) and (C) CoreValve® Transcatheter Aortic Valve (Medtronic Inc., MN, USA).
(A & B) Reproduced with permission from Edwards Lifesciences LLC; (C) reproduced with permission from Medtronic Inc.
Despite the several different approaches for TAVR, the same basic steps are employed. A hybrid operating room is utilized and, in most cases, the patient is placed under general anesthesia. Once appropriate monitoring and arterial and venous access have been obtained, a wire is introduced retrograde into the left ventricle from the aorta, over which a valvuloplasty balloon can be placed. With overdrive pacing of the right ventricle simulating ventricular tachycardia and decreasing the cardiac output temporarily, BAV is carried out. Once this has been accomplished, the appropriately sized valve is introduced and placed into position. TEE and fluoroscopic guidance are utilized to ensure appropriate valve positioning prior to deployment. When using a SAPIEN valve, the valve is placed into the correct position and overdrive pacing is restarted. The valve is then deployed by inflating the balloon upon which the valve had been crimped. For the CoreValve, overdrive pacing is not required and the self-expanding valve is unsheathed, which causes it to be deployed while allowing some adjustment of its position. The function of the new prosthesis, including the presence and severity of perivalvular aortic regurgitation, is assessed by TEE. The access sheaths are then removed and hemostasis is achieved with surgical closure, a percutaneous closure device or manual pressure. The patient is extubated and monitored, usually in an intensive care unit. The duration of the procedure is usually less than 3 h.
Cost–effectiveness
Several cost–effectiveness analyses have examined the economic impact of TAVR versus AVR or standard therapy. Using data from the PARTNER randomized trial in high-risk patients, Reynolds et al. explored the costs of TAVR versus AVR and found similar overall costs and quality-adjusted life years (QALYs) for the two procedures. However, when the data were stratified by TAVR access site (transfemoral vs transapical), transfemoral TAVR was economically dominant to AVR with a cost saving of approximately US$1250 per patient and a gain in QALYs. Conversely, transapical TAVR was economically dominated by AVR with additional costs of almost US$10,000 per patient and lower QALYs. Reynolds et al. also performed a cost–effectiveness analysis of the inoperable cohort of the PARTNER trial and found that TAVR increases life expectancy at an incremental cost per QALY of US$61,889, which is within an acceptable range relative to other procedures. Thus, these analyses suggest that TAVR is an economically reasonable procedure in both inoperable and high surgical risk patients, and that transfemoral TAVR is cost saving relative to AVR in patients at high surgical risk.
Multiple studies have examined quality-of-life outcomes in elderly patients undergoing TAVR. Using the Short Form 36 Health Survey before and after TAVR, significant improvements in physical health scores were documented at 3 months after the procedure, with no change in mental health scores. Furthermore, significant improvement in both physical and mental health scores have been demonstrated 1 year after TAVR compared with the pre-TAVR baseline using both the Short Form 36 and Short Form 12 version 2 Health Surveys. Similar improvements in physical and mental health quality-of-life outcomes were found at 6-months follow-up after TAVR in patients greater than 80 years of age.
Patient Selection
With advances in surgical AVR and the evolution of TAVR, an increasing number of octogenarians and nonagenarians are being considered for these procedures. However, determining which procedure is most appropriate for a given patient may be challenging. To facilitate the decision-making process, new models of risk stratification that incorporate gerocentric concepts are being developed.
Standard surgical risk modeling tools, such as the European System for Cardiac Operative Risk Evaluation (EuroSCORE) and Society of Thoracic Surgeons score, estimate a patient's cardiac surgical risk based on selected clinical parameters. Although these widely used scores provide insight into the risk for adverse outcomes associated with surgical AVR or TAVR, they are based on a limited number of clinical variables and may not accurately reflect risk in older patients with multiple comorbidities. Specifically, the models fail to adequately adjust for very old age (≥85 years), advanced heart failure (New York Heart Association class III or IV), chronic liver disease, or acute or chronic kidney disease. Moreover, as interventional cardiologists and cardiac surgeons gain more experience working with elderly patients, there has been increasing recognition of the impact of functional impairments and frailty on procedural risk and clinical outcomes. For example, a single-center study by Green et al. showed that frailty was independently associated with increased 1-year risk of mortality following TAVR with a hazard ratio of 3.5, despite the fact that there was no association between frailty and early procedural outcomes. Thus, new models are needed that more accurately assess risk in multimorbid older patients.
Box 2 provides a list of commonly used metrics for evaluating frailty. Determining a patient's ability to perform activities of daily living (ADLs) and instrumental ADLs provides a useful starting point for assessing functional capacity. Gait speed and hand grip strength can be easily and quickly measured in the clinical setting, and correlate well with more comprehensive frailty assessments. In one study, functional performance status, measured by the Karnofsky index, was a significant predictor of TAVR procedural success, and patients with good functional status tended to derive more benefit from the procedure. Another study evaluating the Six-Minute Walk Test before and after TAVR showed that, while baseline values were not predictive of procedural outcomes, they did predict long-term mortality.
The Multidimensional Geriatric Assessment has also been evaluated as a predictor of mortality and major adverse cardiovascular and cerebral events after TAVR. Components of the Multidimensional Geriatric Assessment included the Mini-Mental Status Examination for cognition, the Mini-Nutritional Assessment, Timed Get Up and Go test for mobility, ADLs, instrumental ADLs, preclinical mobility disability and the Fried frailty score. In models adjusting for the Society of Thoracic Surgeons score or logistic EuroSCORE, the Mini-Mental Status Examination, Mini Nutritional Assessment, Timed Get Up and Go test, ADLs, preclinical mobility disability and Fried frailty scores were significantly associated with all-cause mortality and major adverse cardiovascular and cerebral events at 30 days and 1 year after TAVR. These frailty indices have also been shown to predict functional decline after TAVR, whereas the Society of Thoracic Surgeons score and EuroSCORE do not.
Based on these findings, routine assessment of frailty should be an integral part of the screening process prior to proceeding with AVR or TAVR. In addition, a global assessment of other comorbidities is important, as patients with disabling arthritis or severe neurological disorders may derive little or no benefit from AVR or TAVR, even if the procedures are technically feasible.
Owing to the complexity of the decision-making process involving multiple patient-centered and procedural factors, the pre-AVR/TAVR evaluation should be performed by a multidisciplinary team comprising experienced cardiovascular surgeons and anesthesiologists, interventional cardiologists, geriatricians, heart failure specialists, imaging specialists, nurses and social workers. This team-based approach allows care to be optimally tailored to each patient's circumstances, while providing realistic expectations to the patient and family regarding likely outcomes during and after the procedure. Accurate identification of patients whose symptoms and limitations are primarily due to AS – rather than competing comorbidities – is of fundamental importance in the preprocedural clinical evaluation prior to TAVR or surgical AVR. Ultimately, the treatment team should strive to provide appropriate patient-centered care, taking into consideration the patient's preferences regarding invasive treatment versus more palliative goals of care.