Need of Consideration

Statically speaking, bioprosthesis is not a valve of choice for young people regarding the physicians’ perspectives. Issacs et al.^[16] reported that, for patients aged 18 to 54, only 27% of the implants are bioprostheses and the remainder, mechanical. In contrast, as the bioprosthesis is in the development trend, there are increasing evidence suggesting a reduction in the age threshold for the use of a bioprosthetic valve, meaning that younger patients should be considered in the choice of type of prosthesis. This is corroborated by the long-term durability of bioprosthetic valves.

In the past, a major claimed disadvantage of the bioprosthetic valve was its lower durability, hence prone to valve deterioration or reoperation. However, the long-term follow-up of patients receiving bioprosthetic implants have revealed otherwise. Johnston et al.^[24] followed 12,569 patients who received the Carpentier-Edwards Perimount (CEP) aortic valves for 20 years. Results published in 2015 show that valve explant due to SVD is rare (15% overall). Valves have good durability also in younger patients, of whom 55% are spared from explants after 20 years. CEP valve durability in younger patients is also supported in a cohort study following patients under 60 years using CEP bioprosthesis for up to 20 years^[25]. It reported a low incidence of SVD, standing at only 37.2% ± 5.4% and with expected valve durability of 17.6 years.

Meanwhile, Edwards Prima Plus (EPP) Stentless Bioprosthesis also demonstrated good results, as suggested by Christ et al.^[26]. In their study, 120 patients with a median age of 53.1 received replacement with EPP valve and were followed for up to 14 years. Actuarial survival stands at 69.5% ± 5.5% at 10 years. Comparatively, the VA trial following patients of median age of 59 years receiving mechanical prosthesis only achieves survival rate of 47% in 10 years^[22]. Concerning effect of valve deterioration in EPP valve, freedom from reoperation reaches 85.6% ± 3.7% at 10 years^[26].

The Medtronic Mosaic^® porcine valve is another 3^rd generation bioprosthesis with long-term follow-up data available. Anselmi et al.^[27] conducted a retrospective cohort and analyzed the long-term durability of this valve for up to 15 years. Among the age group below 70 years old, the actuarial rate of freedom from SVD is 75.5% and the freedom of reoperation from SVD reaches 86.1%, at 15 years. It was also shown that the Mosaic prosthesis demonstrates a very low risk of endocarditis – the freedom from prosthesis endocarditis ranges from 97.6% to 98.9% among age groups and does not show statistical difference. No adverse prosthesis complications are age-dependent. That means younger patients implanted with the valve will not face higher risk of complications^[27].

Second-generation aortic valve prostheses have also demonstrated excellent durability. Yankah et al.^[28] evaluated the Mitroflow pericardial prosthesis by following up 1,513 patients over 21 years. Freedom from reoperation due to SVD was 88.6%. Anticoagulation could be withdrawn from 92% and antiplatelet agent from 90% of patients, after postoperative administration. Actuarial freedom from valve-related death was 83% at 20 years^[28].

Conclusions from various studies on CEP, EPP and Mitroflow valves appear congruent. Bioprosthetic valves used in SAVR have excellent durability. It gives rise to the question whether the age threshold of patients receiving bioprosthesis should be further reduced.

Present Evidence in Favour of Bioprosthesis in the Young

A meta-analysis by Lund and Martin published in 2006 compared the risk-adjusted mortality rate between bioprosthetic valve and mechanical valves in aortic valve replacement. This study included 32 articles (15 on mechanical valves and 23 on bioprosthetic valves), a total of 17,439 patients and 101,819 patient-years. Interestingly, the mean age of patients receiving mechanical implants is 58.0 while bioprosthesis is 68.8. It gives rise to doubt whether poorer outcomes in bioprosthesis recorded in some studies were contributed by the greater age and more comorbidities in recipients. After correction for age and significant risk factors, such as NYHA III and IV and CABG, no difference in mortality was found between the two types of valves, regardless of the patients’ age^[29]. Therefore, we can see that age should not be the only consideration in selecting the right type of valve for patients.

In another single-center study, patients (≤60), mean age 53.1, who underwent stentless aortic valve replacement between 1993 to 2001 were followed up for 17 years. Patients were divided into below and above the age of 50 years. Comparing the two groups, Christ et al. found that age was not a significant factor for survival and freedom from reoperation^[26]. The following items may provide some insight on how age and other factors affect the choice of prosthesis from different angles.

Long-Term Survival

One of the main focuses of the argument is the long-term survival of patients receiving the valve implants. In the Veterans Administration (VA) study, patients with mechanical valves had lower mortality rate (66%) compared to the bioprosthetic valve (79%) at 15 years^[22]. The Edinburgh heart valve study reported a survival advantage of mechanical valves over 12 years, but after 20 years there was no difference between the two valves^[30].

More effort was developed to compare the long-term outcome of two valves amidst continual development of bioprostheses that might deliver better results. A more recent randomised trial has been carried out by Stassano et al.^[31] to determine compare the long-term mortality of patients receiving biological and mechanical valve, especially within a younger population. A total of 310 patients aged 55 to 70 were included, and the St Jude Medical^® and CarboMedics^® mechanical valves were compared to the second generation Carpentier-Edwards valve. The study could not demonstrate a statistically significant difference in the 13-year survival rate between the two valves: the mortality in patients with bioprosthesis was 30.6% and in patients with mechanical prosthesis was 27.5%.

Difficulties were found in the evaluation of the long-term outcome of bioprosthesis in younger population. There are much fewer young patients requiring aortic valve implants compared to the older groups. They have a more diversified background and comorbidities.

Despite this, Ruel et al.^[32] attempted to analyse long-term outcomes of patients aged 18-50 who received aortic valve replacement. In their study, 309 patients received isolated aortic valve replacement and were followed up for 15 years^[32]. The survival rate between mechanical and biological valves shows no difference, regardless the reoperation rate or valve deformation. Survival rate of patients with mechanical prosthesis is 78.9% at 15 years, and with bioprosthesis is 79.2%. Meanwhile, Ruel suggested that bleeding events, both intracranial and extracranial, occur at a higher chance in patients with mechanical prosthesis, in conjunction with the finding that all bleeding events occur in patients using warfarin, except for two cases. Embolic stroke as a complication has no significant difference between the two prostheses.

Factors to Long-Term Survival after Valvular Implant

Various results seem to have demonstrated that long-term survival is not affected by the prosthesis type. In search of the other factors that contribute to the long-term mortality of patients receiving the operation, patient’s pre-morbidities and risk profiles are found to contribute much more^[33]. An example can be demonstrated by the cohort conducted by Brown et al.^[23]. Despite an advantage of mechanical over bioprosthetic valve is reported, the fact that clinicians preferentially offer bioprosthesis to patients with more pre-morbidities affects the patient outcome. Preoperatively, bioprosthetic valve patients had greater proportion of NYHA III or IV (72.7% vs. 62.9%) than mechanical valve patients. Rates of renal failure (5.5% vs. 4.6%) and diabetes (17.3% vs. 15.0%) are also higher in the bioprosthesis group^[23]. Whether it is the valve type affecting the patient outcome or the patient’s impression of pre-morbidities dictating the clinicians' choice remains a question.

Prosthesis Complications

In addition to the long-term mortality, late complications of the prosthesis should be compared. Mechanical prosthesis is more likely to cause complications that translate into profound morbidity. Stassano et al.^[31] reported odds of bleeding in mechanical prosthesis at 1.47% per patient-year, against 0.72% of bioprosthesis. Thromboembolism rate is 0.54% per patient-year for mechanical valve, 0.24% for bioprosthesis. Chikwe et al.^[33] reviewed various studies, finding that the annual rate of thromboembolism and bleeding is 3% and 2.8%, respectively, for the mechanical valve, higher than 2.5% and 1.5% for the bioprosthetic valve. These complications can be devastating and irreversible. They are also acute in onset and deprive the patients’ role in deciding a management direction. Whereas SVD, more likely a complication of bioprosthetic valve, is less acute in presentation, hemodynamics will not be a stake until late in course. Timely surveillance combined with intervention can reduce morbidity and mortality.

Structural Valve Deterioration

SVD is changed to the function of a bioprosthesis from a valve abnormality. In fact, SVD is limited to bioprosthesis and absent in mechanical valves^[31]. It consists of insufficient type or stenotic type, which is often characterised by calcification of the prosthesis. Valvular function deteriorates while heart function compensates. Prosthesis failure is the end result and requires reoperation. Thus, the incidence of SVD is constantly monitored in studies. This affects whether such prosthesis is suitable for young adults, who, due to longer life expectancy, will have higher lifetime chances of suffering from SVD.

Therefore, efforts should be devoted to reducing SVD. One question is whether different types of bioprosthesis affects the SVD rate. Mitroflow LXA valve has a SVD rate of 47% at 2 years and 82% at 3 years^[35]; and Hancock II has a freedom from SVD of 29.2% at 20 years^[36]. However, Mohammadi et al. studied 475 patients receiving Freestyle stentless bioprosthesis. The freedom rate from SVD reaches 95.8% at 10 years^[37]. Bourguignon et al. reports the SVD rate in CEP valves in patients younger than 60 years old as 84% at 10 years^[25].

Another question is if SVD is a modifiable factor. In fact, the incidence of early stenosis-type SVD is shown to be related to patient-prosthesis mismatch (PPM)^[38]. Interestingly, prosthesis size is to correlated to long-term survival and reoperation rate of SVD. Christ et al.^[26] claimed that, instead of age or prosthesis type, in patients with implant size ≤25 mm has a significant lower survival rate compared to patients with larger prostheses. As PPM can be a causative factor to stenosis-type SVD, the incidence of PPM can be minimised by increasing the aortic valve annulus during replacement surgery, through allowing the insertion of a larger size prosthesis. It seems worthwhile to explore whether surgical technique can reduce long-term reoperation from SVD by minimising PPM in young adults.

Anticoagulation

As discussed above, high bleeding rate in mechanical valves is attributed to the need for anticoagulation. However, warfarin administration affects patients in more ways. The protocol for anticoagulation in mechanical prosthesis is rigorous. Depending on the type of mechanical valve, the international normalized ratio (INR) target stands at 2.0-3.5 times of normal patients. The VA study examined high-level anticoagulation compared to low-level anticoagulation^[22]. High dose anticoagulation brings some benefits of antithrombosis but more risk of bleeding^[39]. Gastrointestinal bleeding can be a result.

Aside from risk of bleeding, anticoagulation also affects patients’ quality of life. Lifelong anticoagulation can cause inconvenience. Adherence can be an issue as younger adults tend to be less complacent with warfarin^[40]. hindering the entire management in patients receiving mechanical prosthesis. As for patients suffering from atrial fibrillation, INR target is further increased by 0.5 times the normal^[32]. Bioprosthetic valve patients with atrial fibrillation are also administered with anticoagulation with an INR targeting 2.0 to 2.5. It seems that in patients with atrial bioprosthetic valve with atrial fibrillation as a comorbidity, patients lose the advantage of bioprosthesis reducing bleeding incidences. However, atrial fibrillation is often age-related and young adults are less likely to suffer from it. They have a higher chance of enjoying freedom from anticoagulation compared to elderly patients. Therefore, bleeding events can be minimised.

Quality of Life

Ruel et al.^[32] also found that patients receiving bioprosthetic valves are more likely to enjoy a higher quality of life indicated by the higher score in the physical component of 12-Item Short-Form Health Survey (SF-12). Patients with bioprosthetic valves are more likely to be free from recurrent heart failure and disability, which have a significant influence on their quality of life. Added to all this, they have a better self-awareness – they are more satisfied with heart valve replacement and are less likely to perceive that heart valve replacement has impacted their daily lives.

Development in Bioprosthesis

With regard to developments in bioprosthesis for SAVR, there have been engagements in multiple fronts, including surgical approaches, incision method and valve design.

With the current bioprosthesis in use, surgical techniques are hoped to increase prosthesis longevity in young patients. According to Johnston et al.^[40], postoperative initial transvalvular gradient is related to prosthesis explantation for SVD and is more significant in young patients. It was also demonstrated that the small area of the valve orifice is related to a greater chance of stenosis-type SVD. Using selective root enlargement and choosing prostheses with larger orifice area carry the hopes of minimising SVD in the young with currently available prostheses. The sutureless valve is a new type of bioprosthesis. It is already mounted on the stent and requires minimal sutures during surgery, thus reducing bypass and cross-clamping times. High-risk patients susceptible to prolonged operation can benefit more from it^[15]. Rubino et al.^[41] studied the outcome of 314 patients receiving Sorin Perceval S bioprosthesis, of which 86.3% had ejection fraction >50% and mean age in 77.9 ± 5 years. In-hospital mortality of isolated valve replacement was only 1.4%. This lays the foundation of applying surgical valve replacement to high-risk patients previously considered unsuitable for extensive surgeries. Population of other risk profiles may also benefit from it in the future.

The Generation of Valvuloplasty

The gold standard of severe AS treatment has been the surgical aortic valve replacement (SAVR). Nevertheless, advanced age, left ventricular dysfunction and other comorbidities make SAVR infeasible in at least 30% of patients with severe AS^[42]. Prior to the prevalence of TAVR, patients with severe AS who are not surgical candidates would rely on medical treatment or balloon valvuloplasty. Median survival was only 2-3 years, on average, after symptoms appeared^[43,44].

Concomitant CABG and AVR

Concomitant CABG performed with SAVR has been an independent risk factor for postoperative survival. Indication for this procedure includes: 1) patients with symptomatic aortic valve pathology with coronary heart disease discovered during preoperative angiogram; 2) patients requiring CABG with their underlying aortic valve pathology revealed in preoperative investigation; and 3) patients with concurrent aortic valve and coronary artery diseases. It is mostly agreed that CABG should be provided during SAVR in patients expected to have acceptable long-term survival rate. Multiple studies have reported a decrease in survival for combined surgery, compared to isolated SAVR. Alsoufi et al.^[56] have reported 249 patients undergoing concomitant CABG with SAVR, observing that long-term survival is compromised compared to isolated SAVR, or isolated CABG. The same conclusion is drawn by Ruel et al.^[32]. This could be a result of the longer surgery time for a complex procedure, or the higher likelihood of patients with concurrent diseases carrying comorbidities.

However, the choice of prosthesis is still debated. Akins et al.^[57] performed a retrospective cohort on 750 patients who received combined SAVR and CABG procedures. They claimed that patients who receive bioprostheses had a better outcome, fewer related complications like myocardial infarction and the need of reintervention and lower cardiac mortality^[57]. It can be attributed to mechanical valves a greater cardiac compromise or, conversely, the group of patients receiving bioprostheses are older than the mechanical group and are more likely to develop other life-threatening diseases. Contrarily, Alsoufi et al.^[56] reported that bioprosthetic valve patients receiving combined procedure are associated with greater early morbidity, compared to f mechanical prosthesis recipients. This difference may again be contributed by older age, poorer NYHA function, and other characteristics in patients that physicians tend to offer bioprostheses^[56].

The study remains inconclusive in terms of guiding choice of valve in concomitant AVR and CABG. When the age threshold of bioprosthesis implantation is also concerned in the context of combined procedures, further studies should be carried out to determine whether it will benefit younger patients with better baseline comorbidities. It can only be concluded that there is a wide variety of patients warranting the combined CABG and SAVR procedure. Efforts should be devoted to identifying the extent of coronary artery disease and aortic valve disease, comorbidities and other factors in order to provide a tailor-made treatment in the best interest of patients.

Coronary Artery Disease and TAVR

From 40 to 75% of patients undergoing TAVR have significant coronary artery disease (CAD), which can be managed by percutaneous coronary intervention (PCI)^[58]. There has been debate on whether PCI should be done before, combined or after TAVR. Holistic evidence on the long-term outcomes of various approaches is still lacking.

Compared with the combined procedure, PCI prior to TAVR allows the patient to undergo a lower accumulated contrast dose. A study has shown that the contrast dose received by patients with PCI before TAVR was lower than that received by those receiving concomitant PCI and TAVR (292.3 ± 117.5 vs. 171.9 ± 68.4 ml)^[59]. This is of particular importance because renal impairment is prevalent in patients receiving TAVR. Added to that, conducting PCI before TAVR may reduce the chance of hemodynamic instability in the TAVR procedure^[60]. However, this result has not been reproduced by other studies.

For concomitant PCI and TAVR procedure, there are advantages and disadvantages shown in different studies. Penkalla et al. reported comparable survival in up to 3 years in CAD patients having TAVR and PCI and patients without CAD having TAVR alone^[61]. However, Singh et al. showed that patients receiving concomitant PCI and TAVR have significantly higher mortality when compared with patients receiving TAVR alone (10.7% vs. 4.6%)^[62]. More studies are needed to comprehend the long-term outcomes of concomitant PCI and TAVR on patients.

Concerning PCI after TAVR, there are only a few reports reporting its outcome, probably as a result of a major technical problem – cardiologists may experience difficulty accessing the coronary ostia for PCI after TAVR^[60]. Its long-term effect still needs to be confirmed.

Minimally Invasive SAVR

In the recent decade, the minimally invasive approach to aortic valve replacement has become increasingly popular. By definition, it aims to achieve access to the aortic valve without full sternotomy. It can be classified into intercostal access and limited sternotomy^[63]. It aims to cause less pain to patients, achieving faster recovery, shorter hospitalisation, less blood loss and less trauma. Recently, Nguyuen et al^[64]. have published a multi-institutional retrospective review of 1,503 patients receiving minimally invasive SAVR. Among patients with ejection fraction >40%, it was found that they have better short-term outcome – including less bleeding, shorter ICU stay and hospitalisation and new-onset atrial fibrillation than AVR patients with full sternotomy, while in patients with EF <40% the difference is not significant. However, it was found that the minimally invasive approach would need a longer CPB and cross-clamping time^[65]. The procedure becomes more challenging and would be a risk factor for high-risk patients. In younger patients, however, it might be a considerable alternative, as they are more likely to be able to endure a longer procedure^[66]. Combined with the sutureless prosthesis, faster implantation can translate into reduced operative time in the minimally invasive approach^[67,70]. It does not only apply to younger but higher risk population, especially the population group indicated with TAVR.