2024 Volume 31 Issue 10 Pages 1353-1364
Intervention for severe aortic stenosis (AS) has dramatically progressed since the introduction of transcatheter aortic valve replacement (TAVR). Decades ago, controversies existed regarding comparing clinical outcomes between TAVR and surgical aortic valve replacement (SAVR) in various risk profiles. Recently, we discussed the durability of transcatheter heart valves and their lifetime management after aortic valve replacement (AVR). Regarding the management of AS, we discuss the appropriate timing of intervention for severe aortic stenosis, especially in asymptomatic patients. In spite of dramatic progression of intervention for AS, there are no established medications available to prevent or slow the progression of AS at present. Basic research and genome studies have suggested several targets associated with the progression of aortic valve calcification. Randomized controlled trials evaluating the efficacy of medications to prevent AS progression are ongoing, which might lead to new strategies for AS management. In this review, we summarize the current management of AS and the drugs expected to prevent the progression of AS.
The incidence of aortic stenosis (AS) has been rapidly increasing with age in developed countries. Despite progress in medications for heart failure, the prognosis of patients with severe AS remains poor without intervention1).
In developed countries, aortic valve degeneration is the leading cause of AS, and its prevalence increases with age. Severe AS occurs in ＜1% of individuals ＜70 years old, but the incidence increases to about 7% among those ≥ 80 years old2-4). Currently, the modes of intervention that improves clinical outcomes are surgical aortic valve replacement (SAVR) and transcatheter aortic valve replacement (TAVR). Just after the introduction of TAVR, the indication for TAVR was limited to patients at high risk or deemed unable to undergo SAVR5, 6). However, since intermediate- and low-risk trials demonstrated comparable outcomes between TAVR and SAVR, the use of TAVR has rapidly expanded to patients across a broad spectrum of risk profiles7-13). Despite advancements in intervention therapy for AS, there is currently no medication to suppress its progression of AS.
We herein reviewed the current management and intervention of severe AS and perspectives on medications expected to prevent the progression of AS.
The leaflets of the aortic valve are structured into three distinct layers. The outermost layer adjacent to the aorta is composed of collagen fibers, whereas the opposite side outer layer adjacent to the left ventricle contains elastic fibers. These layers are lined with endothelial cells. The innermost layer is predominantly composed of valve interstitial cells (VICs)14).
The primary initiating factor in the development of aortic stenosis is endothelial damage or shear stress, which leads to the infiltration of low-density lipoprotein cholesterol (LDL-C) and lipoprotein(a) [Lp(a)]15-19).
Various bioactive lipid species are generated, attracting inflammatory mediators20). The stimulation of various signal transduction pathways induces a shift in VICs towards an osteogenic phenotype, which facilitates the fibrocalcific remodeling of aortic valve21, 22). Briefly, the calcification begins with an initial phase of lipid and inflammatory infiltration, followed by a phase of activation of factors which was associated with calcification20, 23).
Genome-wide association studies also have uncovered numerous genetic variants that are correlated with AS24, 25). These studies have shown that the incidence of AS is correlated with inflammation, calcification, and dyslipidemia, notably with elevated serum levels of Lp(a) and LDL-C.
The severity of AS was defined by referring to a peak transvalvular velocity, mean pressure gradient, and aortic valve area (and indexed aortic valve area) as measured by echocardiography. Severe AS can be divided into high-gradient (HG) AS with a peak transvalvular velocity ≥ 4.0 m/s or a mean pressure gradient ≥ 40 mmHg and low-gradient (LG) AS with a peak velocity ＜4.0 m/s and a mean pressure gradient ＜40 mmHg.
Currently, low-flow (indexed stroke volume ＜35 mL/m2) LG severe AS is further divided into low-flow LG (LFLG) AS with a reduced ejection fraction (EF) (classical LFLG severe AS), and LFLG AS with a preserved EF (paradoxical LFLG severe AS).
Patients with LFLG AS with a reduced EF are recommended to undergo dobutamine stress echocardiography to distinguish between true severe AS and pseudo-severe AS. If patients have no flow reserve (ΔSV＜20%), the calcium score as determined by CT is recommended as a reference to distinguish whether severe AS is likely or not26, 27). It has been suggested that left ventricular (LV) systolic dysfunction in LG severe AS results from the delayed treatment of HG AS, leading to myocardial degeneration and fibrosis. Compared to HG AS, LFLG severe AS with a reduced EF is associated with poorer clinical outcomes, regardless of intervention28-33). In contrast, paradoxical LFLG AS has been considered to be causally linked to significant left ventricular hypertrophy, resulting in a reduced LV cavity34).
The outcomes for patients with paradoxical LFLG AS are subject to varying interpretations. Some studies have indicated high mortality rates in untreated patients with paradoxical LFLG AS35, 36) and suggest that AVR offers a survival benefit over conservative management37-39). Conversely, other studies suggest that the prognosis for patients with paradoxical LFLG AS under conservative management is similar to that of patients with moderate AS, showing no significant benefit from AVR40). Further studies specific to LG AS evaluating the clinical outcomes and the benefit of AVR over conservative therapy are warranted.
Because of the poor prognosis in patients with symptomatic severe AS, initial AVR strategy is recommended according to current guidelines27, 41). In contrast, the management of asymptomatic severe AS patients remains debated, including the benefit of early intervention. In the Japanese guidelines, the following situations in asymptomatic patients were recommended or considered reasonable to receive intervention: 1) patients with severe AS and reduced LVEF (LVEF ＜50%), 2) patients with concomitant SAVR procedure scheduled to undergo other cardiac surgery, 3) patients with severe AS and symptoms detected by exercise tests, 4) patients with severe AS and a decrease in blood pressure on exercise tests, 5) patients with very severe AS (Vmax ≥ 5 m/s, mPG ≥ 60 mmHg, or AVA ＜0.6 cm2), and 6) patients with severe AS and severe pulmonary hypertension (PASP at rest ≥ 60 mmHg) due to AS27). Watchful waiting is recommended for asymptomatic patients who do not meet the aforementioned criteria.
Regarding intervention for severe AS, only small observational studies have suggested the benefit of an early SAVR strategy compared to a conservative strategy in patients with asymptomatic severe AS. The CURRENT AS Registry (Contemporary Outcomes After Surgery and Medical Treatment in Patients With Severe Aortic Stenosis Registry), which was the largest retrospective study that enrolled consecutive patients with severe AS in Japan, suggested the benefit of the initial SAVR strategy compared to the conservative strategy in patients with asymptomatic severe AS42).
Recently, the RECOVERY trial (Early Surgery or Conservative Care for Asymptomatic Aortic Stenosis trial) which was a single-country, randomized controlled trial (RCT) supported initial SAVR strategy in asymptomatic patients with severe AS43). However, it is important to note that the RECOVERY trial only included patients with peak velocity ＞4.5 m/s and mainly bicuspid aortic valve, and no regular exercise testing was performed to confirm a “true asymptomatic” status.
To clarify these issues, the AVATAR trial (Aortic Valve Replacement Versus Conservative Treatment in Asymptomatic Severe Aortic Stenosis trial), a multinational RCT, was conducted and provided evidence concerning the benefit of the initial SAVR strategy in patients with severe AS, defined based on the common criteria (valve area ≤1 cm2 with aortic jet velocity ＞4 m/s or a mean transaortic gradient ≥ 40 mmHg) with asymptomatic AS confirmed by exercise testing44).
However, these studies only included patients who underwent SAVR for the AVR arm, which was quite different from current clinical practice. Therefore, RCTs comparing conservative management versus TAVR or conservative strategy versus initial intervention, including both SAVR and TAVR for asymptomatic severe AS, are warranted. The EARLY TAVR trial (Evaluation of TAVR Compared to Surveillance for Patients With Asymptomatic Severe Aortic Stenosis trial, NCT03042104), which compares TAVR with conservative management for asymptomatic severe AS patients with preserved ejection fraction (EF), is currently underway45).
Benefits of TAVR for patients with non-severe AS and reduced EF have also been reported. A propensity score-matched comparison of TAVR and conservative management for patients with moderate or pseudo-severe low-gradient AS suggested that TAVR had better outcomes than conservative management46). Currently, the TAVR UNLOAD trial (Transcatheter Aortic Valve Replacement in Patients With Reduced Ejection Fraction and Nonsevere Aortic Stenosis trial) (NCT02661451), an international, multicenter, randomized, open-label clinical trial comparing the efficacy and safety of TAVR vs. conventional therapy, is ongoing47).
Currently, SAVR and TAVR are the options for interventions that improve clinical outcomes. Just after the introduction of TAVR, indications for TAVR were patients who were at high risk or deemed inappropriate to receive SAVR. However, since the publication of intermediate- or low-risk trials that demonstrated comparable outcomes after TAVR and SAVR, TAVR has been spreading to patients with a wide range of risk profiles.
Regarding the selection of SAVR or TAVR, the 2021 European Society of Cardiology/European Association for Cardio-Thoracic Surgery (ESC/EACTS) guidelines recommend that the Heart Team decide the best intervention for each patient. This decision should consider the patient’s age, expected lifespan, comorbid conditions, anatomical and procedural specifics, relative risks of SAVR versus TAVR, long-term outcomes, prosthetic valve durability, and feasibility of the transfemoral TAVR approach. For patients ＜75 years old at low surgical risk, SAVR is preferred because of concerns about valve durability. For patients ≥ 75 years old or those at high surgical risk, TAVR, especially the transfemoral approach, is often the preferred option48).
In contrast, as a rough cutoff for age considering SAVR or TAVR, the 2020 American College of Cardiology/American Heart Association (ACC/AHA) guidelines recommend SAVR for patients with severe AS who are ＜65 years old or have a life expectancy ＞20 years and require AVR. However, for symptomatic patients with severe AS who are 65–80 years old and have no anatomical contraindications to transfemoral TAVR, either SAVR or transfemoral TAVR is recommended49).
The Japanese guidelines also emphasize that the final decision should be made after a discussion by the valvular disease team, considering various factors. A clear age criterion for TAVR or SAVR has not yet been established in these guidelines, but they suggest that TAVR is better for patients ＞80 years old, while SAVR is better for those ＜75 years old27).
When considering the mode of intervention, long-term durability data of transcatheter heart valves (THVs) after TAVR are also crucial. The long-term durability of THVs is not well evaluated, primarily because these devices were initially used in older, high-risk patients who often did not live long term50).
Following the establishment of the standardized criteria of structural valve deterioration (SVD), several studies reported outcomes regarding durability of THVs after TAVR for up to 10 years (Table 1)51-58). However, few studies have compared TAVR and SAVR regarding valve durability. The latest results of the NOTION trial demonstrated that the 10-year incidence of severe SVD was significantly lower in TAVR than in SAVR59).
| Paper | Design | Published year | Valve type | N of patients | F/u period | Incidence of BVF/SVD |
|---|---|---|---|---|---|---|
| Deutsch et al | Prospective single-center registry | 2018 | CoreValve or SAPIEN | 300 | 7 year |
Cumulative incidence function: SVD: 14.9% (CoreValve 11.8% vs. SAPIEN 22.6%) |
| Barbanti et al | Prospective single-center registry | 2018 | CoreValve or SAPIEN XT | 288 | 8 year |
Cumulative incidence function: BVF: 4.51% Moderate SVD: 2.39% Severe SVD: 5.87% Kaplan–Meier method Survival free from severe SVD: 97.5% Survival free from BVF: 95.4% |
| Eltchaninoff et al | Prospective single-center registry | 2018 | balloon-expandable valve | 378 | 8 year |
Death-competing risk analysis: SVD: 3.2% BVF: 0.58% Kaplan–Meier method: Freedom from SVD: 87.2% Freedom from BVF: 96.6% |
| Holy et al. | Prospective single-center registry | 2018 | CoreValve | 152 | 8 year |
Cumulative incidence function: BVF: 4.5% Kaplan–Meier method: BVF: 7.9% |
| Testa et al. | Prospective multi-center registry | 2020 | CoreValve | 990 | 8 year |
Cumulative incidence function (death- competing risk analysis) BVF: 2.5% Moderate SVD: 3.0% Severe SVD: 1.6% |
| Sathananthan et al. | Single-centre registry | 2021 | Cribier, SAPIEN or CoreValve | 235 | 10 year |
Cumulative incidence: SVD or BVF: 6.5% |
| Elbasha et al. | Prospective single-center registry | 2024 | CoreValve | 302 | 10 year |
Cumulative incidence function : freedom from SVD: 97.9% freedom from BVF 96.1% Kaplan–Meier method : freedom from SVD: 80.9% freedom from BVF 78.8% |
| NOTION trial | Randomized, multicenter trial | 2024 | CoreValve | 280 | 10 year |
Cumulative incidence function (death- competing risk analysis) severe SVD: TAVI 1.5%, SAVR 10.0% BVF: TAVI 9.7%, SAVR 13.8% |
SVD, structural valve deterioration; BVF= Bioprosthetic Valve Failure; TAVI=Transcatheter Aortic Valve Implantation; SAVR, surgical valve replacement
In summary, the durability of THVs could be considered favorable at this time. Further long-term data are required.
According to American guidelines, statin therapy is recommended for patients with calcific AS. However, it is not recommended for preventing AS progression, as it has shown no benefit in this regard because prior RCTs did not demonstrate the effect of statins in suppressing the progression of AS60-62). Therefore, statin recommendations are made for the prevention of associated atherosclerotic events rather than preventing the progression of AS itself.
Currently, no medications have been definitively proven to prevent AS progression. However, several potential drugs are being investigated for their effects on AS prevention. Langsted et al. indicates that patients with proprotein convertase subtilisin/kexin type 9 (PCSK9) loss-of-function mutations, who have decreased levels of LDL and Lp(a), exhibit a reduced risk of aortic valve calcification63). A recent genome study also found that individuals with the PCSK9 R46L loss-of-function variant had a reduced risk of aortic valve calcification compared to controls, indicating a connection between PCSK9 and valve calcification in AS64). PCSK9 is an enzyme synthesized by the liver that binds to LDL receptors, directing them towards lysosomal degradation65). Genome studies have identified that particular variations in the PCSK9 gene are associated with low LDL-C and cardiovascular events66, 67). Therefore, several studies demonstrated PCSK9 inhibitors reduce LDL-C and decrease cardiovascular events68, 69).
An exploratory analysis of the FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) trial has shown that PCSK-9 inhibitor are correlated with reduction in AS related events70). Notably, a recent study have demonstrated elevated PCSK9 expression in stenotic aortic valves, and reduction of calcium levels in vitro after administration of anti-PCSK9 antibody71).
In addition, a genetic study on PCSK9 found that a weighted genetic risk score calculated from 10 independent SNPs at the PCSK9 locus was associated with LDL-C levels, but not Lp(a) levels, which was suggested to be associated with calcified AS. This suggests that the potential preventive effect of PCSK9 variants on aortic valve calcification might be partly due to LDL-C reduction and may not be related to changes in Lp(a).
Therefore, the effect of the PCSK9 inhibitor on the progression of AS might not only be attributed to LDL-C and Lp(a) reduction. For instance, the aforementioned randomized controlled trial showed that LDL-C-lowering therapy with statins demonstrated no preventive effect on valve calcification progression60-62). PCSK9 might influence aortic valve calcification through multiple mechanisms, including local inflammation at the valve site.
Clinical trials are warranted to evaluate the efficacy of PCSK9 inhibitors in suppressing aortic valve calcification progression. The impact of PCSK9 inhibitors on aortic valve calcification is currently being investigated (Table 2)72).
| Drugs | Trial Name | Design | Treatment | Population | Primary outcome | N of patients | F/u period | Results (vs. placebo) |
|---|---|---|---|---|---|---|---|---|
| Statin | SALTIRE | Randomized, double-blind trial | Atorvastatin 80mg daily vs. placebo | Patients with calcific AS (Avmax ≥ 2.5m/s and aortic-valve calcification on echocardiography) | Change in AVmax and aortic-valve calcium score | 155 | 25 months |
AVmax: adjusted mean difference (95%CI): 0.002 (-0.066 to 0.070) m/s per year Ratio of AV calcium score (95%CI): 0.998 (0.947 to 1.050) |
| SEAS | Randomized, double-blind trial | Simvastatin 40mg plus ezetimibe 10mg vs. placebo | Asymptomatic patients with mild to moderate AS | Composite of major CV events | 1873 | 52.2 months |
Primary outcome: HR (95%CI): 0.96 (0.83-1.12) AVR: HR (95%CI): 1.00 (0.84-1.18) |
|
| ASTRONOMER | Randomized, double-blind trial | Rosuvastatin 40 mg daily vs. placebo | Asymptomatic patients with mild to moderate AS | Peak AS gradient by echocardiography | 269 | 3.5 years |
Annualized increase in the peak AV gradient: 6.3mmHg in the rosuvastatin group and 6.1mmHg in the placebo group (P=0.83). |
|
| PCSK9 inhibitor | FOURIER (exploratory analysis) | Randomized, double-blind trial | Evolocumab(140 mg every 2 weeks or 420 mg monthly) vs. placebo | Patients with stable ASCVD and statin therapy | AS events (new or worsening AS or AVR) | 27564 | 2.2 years | AS events: HR (95%CI): 0.66 (95% CI, 0.40-1.09) |
| NCT03051360 | Randomized, double-blind trial (Phase2) | PCSK9 inhibitor vs. placebo | Patients with mild to moderate AS | Progression of the Calcium score measured by cardiac CT (Agatston score) and by NaF PET | 140 (estimated) | 2 years | Status unknown | |
| NCT04968509 | Randomized, single-blind trial (Phase3) | PCSK9 inhibitors and statins vs. Statins | Patients with mild or moderate CAS or asymptomatic severe AS | Average annual change in peak aortic jet velocity | 160 (estimated) | 24 months | Recruiting | |
| Apolipoprotein(a) Inhibitor | NCT05646381 | Randomized, double-blind trial (Phase2) | Pelacarsen 80mg vs. placebo | Patients with mild to moderate AS and Lp(a) ≥ 175 nmol/ L | Change in AVmax and aortic valve calcium score |
502 (estimated) |
36 months | Recruiting |
AS, aortic stenosis; AVmax, maximum aortic valve velocity; HR, hazard ratio; CI, confidence interval; CV, cardiovascular; AVR, aortic valve replacement; ASCVD=Atherosclerotic Cardiovascular Disease; PCSK9=Proprotein convertase subtilisin kexin 9.
NaF PET=sodium fluoride positron emission tomography
Lp(a) has also been investigated as a potential therapeutic target in AS. Lp(a) is a lipoprotein particle that includes the central core of triglycerides and cholesterol esters. This core is encased by a monolayer of phospholipids, along with an apolipoprotein-B100 molecule, to which apolipoprotein(a) (apo[a]) is attached73). The concentration of Lp(a) in plasma is predominantly determined by genetic factors, specifically the LPA gene, which encodes apo(a). This gene includes multiple kringle domains, with a kringle IV type 2 (KIV-2) domain featuring a variable number of repeats. The variation in these repeats affects the size of apolipoprotein(a), resulting in significant size diversity74).
Increased Lp(a) as well as LDL carry a risk of inducing atherosclerotic cardiovascular disease (ASCVD), similar to LDL75). Lp(a) is also suggested to be associated with aortic valve stenosis19, 70, 75-78). Moreover, genome-wide association studies have demonstrated a link between calcific AS and Lp(a), particularly genetic variations in the LPA locus which is a key determinant of Lp(a) levels17). Lp(a) is thought to significantly contribute to AS development through its role as a carrier of oxidized phospholipids which leads to inflammation and cailcification, potentially initiating the osteogenic differentiation of VICs79, 80).
In contrast, Kaiser et al. suggested that Lp(a) is associated with the onset of calcification of the aortic valve but not the progression of aortic valve calcification81). Large studies evaluating the association between Lp(a) and progression of AS and AS-related events are warranted.
Recently, several drugs that significantly reduce Lp(a) levels by inhibiting apo(a) synthesis have been developed, and clinical studies evaluating the efficacy of ASCVD and AS are ongoing. Antisense oligonucleotides have shown reductions in Lp(a) levels in RCTs (NCT05581303, NCT04023552)82). Pelacarsen, a N-acetylgalactosamine (GalNac)-added antisense oligonucleotide, allows for targeting specific to hepatocytes, and a phase 3 Lp(a) HORIZON trial evaluating the efficacy of pelacarsen to reduce cardiovascular outcomes in patients with LDL-C-lowering therapy and Lp(a) ＞70 mg/dL is ongoing (NCT 04023552). In addition, a phase 2 trial evaluating the impact of pelacarsen on the progression of calcified AS is ongoing as well (NCT 05646381)
Olpasiran is a GalNac-conjugated small interfering ribonucleic acid (siRNA) that degrades apo(a) mRNA and prevents protein translation. The phase 3 OCEAN(a) Outcomes trial (Olpasiran Trials of Cardiovascular Events and Lipoprotein[a] Reduction trial) evaluating the effect of olpasiran treatment in patients with ASCVD and elevated Lp(a) levels is currently ongoing (NCT 05581303). In addition, a phase 2 trial evaluating the efficacy of other siRNAs is ongoing as well (NCT 05537571, NCT 05565742).
Muvalaplin is an oral drug that interferes with the noncovalent binding between apo(a) and apoB100, thereby inhibiting the formation of disulfide bonds and ultimately preventing the creation of Lp(a)83).
Further studies are warranted to evaluate the effectiveness of Lp(a) inhibitors in preventing the progression of calcific AS.
2) Anti-Hypertensive Therapy and Renin–Angiotensin–Aldosterone System (RAAS) BlockadeFor patients with Stage A asymptomatic AS, standard antihypertensive therapy is recommended to manage hypertension and mitigate left ventricular overload. While the association between hypertension and aortic valve calcification is debated84), the SEAS trial (The Simvastatin and Ezetimibe in Aortic Stenosis trial) highlighted the fact that hypertension in asymptomatic AS patients increases the risk of ischemic heart disease and mortality. However, this study did not suggest that controlling hypertension prevents AS progression. Consequently, current guidelines emphasize managing hypertension to prevent atherosclerotic complications rather than halting the progression of AS.
Several RCTs have evaluated the efficacy of RAAS blockade for AS. RIAS trial (A prospective, double-blind, randomized controlled trial of the angiotensin-converting enzyme inhibitor Ramipril In Aortic Stenosis trial) suggested ramipril have regressed LV hypertrophy in moderate-to-severe calcified AS85). In contrast, the ROCK-AS trial (The Potential of Candesartan to Retard the Progression of Aortic Stenosis trial) suggested that candesartan was not shown to improve the LV function or symptoms in patients with severe symptomatic calcified AS86). Currently, several ongoing RCTs are assessing the utility of RAAS blockade to prevent the progression of AS or LV remodeling and dysfunction (NCT03666351, NCT 04913870). In brief, although there is limited evidence of RAAS blockade to slow the progression of AS, ACE inhibitors (ACEI) or angiotensin receptor blockers (ARB) are recommended for patients with AS and hypertension87, 88).
3) Anti-Inflammation TherapyInflammation is a key contributor to valvular fibrosis and calcification and plays critical roles in macrophages, monocytes, mast cells, and T cells in leaflet remodeling. Macrophages secrete vascular endothelial growth factor (VEGF), matrix metalloproteinases (MMPs), tumor necrosis factor-α (TNFα), and interleukin-1 (IL1), with elevated MMPs and reduced tissue inhibitors of metalloproteinases (TIMPs), causing collagen accumulation by VICs and the formation of fibrous tissue. TNFα and IL1β activate nuclear factor-kappa B (NfκB) pathways, increasing interleukin-6 (IL6) levels, while cytokines and oxidized lipids drive mineralization and osteogenesis through osteogenic pathways22). Targeting MMPs to slow valve calcification and CAS progression remains a novel therapeutic area for exploration.
4) Anti-Calcification TherapyAccording to a meta-analysis, the use of bisphosphonates is linked to a reduction in valve calcification89). Bisphosphonates are suggested to reduce circulating levels of pro-calcifying substances such as calcium and phosphate, thereby exerting an anti-calcifying effect on aortic tissue. At the valve level, this is associated with reductions in proinflammatory cytokines, such as IL1, IL6, and TNFα, inhibition of metalloproteases, and differentiation changes in VICs. However, the efficacy of bisphosphonates for valve calcification is still inconclusive, and a clinical RCT will be required to clarify the findings90-92).
Denosumab, a receptor activator of nuclear factor-κB ligand (RANKL) inhibitor, was suggested to inhibit calcification of VICs in preclinical studies93). However, SALTIRE2 (the Study Investigating the Effect of Drugs Used to Treat Osteoporosis on the Progression of Calcific Aortic Stenosis) trial suggested RANKL inhibitors were not effective in progression of AS94). Chronic kidney disease (CKD) was associated with aortic valve calcification95, 96). Guerraty et al. demonstrated a dose-dependent association between CKD and aortic valve calcification95). The COFRASA study found that CAS progression in elderly CKD patients is related to secondary hyperparathyroidism and low vitamin D levels97). The ADVANCE study suggested that cinacalcet, a calcium receptor agonist, combined with low-dose vitamin D could slow the progression of vascular and valvular calcification in dialysis patients98). However, its effectiveness in preventing valvular calcification in non-dialysis CKD patients remains unknown.
Interventions for severe AS have dramatically progressed since the introduction of TAVR. Recently, data evaluating the long-term durability of THVs for up to 10 years were reported, and lifetime management for young patients with severe AS after AVR, including re-AVR, are warranted. Regarding the management of AS, recent RCTs demonstrated that the clinical outcomes of patients with severe AS who received early SAVR were superior to those of patients treated with a conservative strategy. Currently, RCTs comparing TAVR with conservative management for asymptomatic patients with severe AS with a preserved EF are ongoing. Furthermore, RCT comparing TAVR and conventional therapy for patients with symptomatic moderate AS and reduced EF are ongoing.
Despite the dramatic progression of interventions for AS, there are currently no definitive medications to prevent or inhibit the progression of aortic valve stenosis. As the mechanisms underlying the pathogenesis of AS become clearer, the efficacy of drugs targeting factors associated with AS progression is being actively investigated. In particular, RCTs are currently underway for PCSK9 inhibitors and Lp(a)-lowering agents. Further elucidation of the mechanisms underlying the development and progression of AS and specific preventive therapies is warranted.
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