Aortic stenosis is a valvular disease that progresses through various stages during a patient’s lifetime. As stenosis severity increases, the condition may reach a point of significant transvalvular gradient, progressing through a preclinical stage and subsequently a clinical stage characterized by the onset of symptoms. Once symptoms appear, the natural history of the disease is known to lead to a poor prognosis, making invasive treatment appropriate to correct the stenosis given the limited pharmacological options. However, it is this preclinical stage that is the focus of the current analysis, as some series have described sudden death episodes or hospital admissions due to heart failure decompensation, which could potentially be prevented by early intervention. 

That said, invasive management of an asymptomatic patient must always aim for a prognostic benefit, since, by definition, it cannot relieve any symptoms during this phase of disease progression. In other words, the patient “neither knows nor will ever know what to be grateful for from the procedure.” If complications occur, the benefit is counterbalanced, and potentially even a detriment is added, to a patient who, we must remember, was asymptomatic until that point. 

In the context of severe aortic stenosis, multiple parameters have been identified that may be associated with a poorer prognosis, thus tipping the balance towards intervention during the preclinical phase: 

Echocardiography 

• AVA <0.75 cm² or indexed <0.6 cm²/m² 

• Vmax 5 m/s 

• Severe LVH (asymmetrical septal or indexed LV mass) 

• Reduced left ventricular longitudinal strain (<12-16%) 

• Left atrial volume >12.2 cm²/m² (to prevent atrial fibrillation) 

• Indexed stroke volume <35 cc/m²  

Exercise Testing 

• Ischemic changes in ST segment during exercise 

• Ventricular arrhythmias during exercise 

• Reduction in left ventricular ejection fraction during or after exercise, compared to baseline 

• PSAP >60 mmHg during exercise 

• Increase in transvalvular gradient >18-20 mmHg during exercise 

• VO2 max <14 cc/Kg/min  

Computed Tomography 

• Aortic valve calcium density >300 AU/cm² in women and >500 AU/cm² in men 

• Calcium-score >1200 AU in women and 2000 AU in men 

Magnetic Resonance Imaging 

• Late gadolinium enhancement indicating myocardial fibrosis of unknown origin 

Biomarkers 

• Post-exercise NT-proBNP levels elevated compared to baseline 

The presence of multiple prognostic markers suggests that no single parameter is perfect, and that an integrated multimodal preoperative assessment, along with patient consensus, should guide the decision towards conservative or invasive management. 

 Clinical practice guidelines include several recommendations for the intervention of asymptomatic patients, all of them class IIa: presence of left ventricular dysfunction with ejection fraction <50%, objective symptom provocation during exercise testing, tripling of elevated biomarker levels, or presence of critical aortic stenosis with Vmax >5.5 m/s and/or AVA <0.6 cm². In previous editions of the guidelines, pulmonary hypertension during exercise testing was included as a criterion, but it is not present in current guidelines. It is possible that new evidence will shift the treatment paradigm, but so far, severe aortic stenosis in asymptomatic, operable patients has been a domain reserved for surgery, given that asymptomatic patients were not included in major clinical trials. 

Previous blog editions analyzed paper on asymptomatic patients with severe aortic stenosis. However, from the standpoint of randomized evidence, two clinical trials stand out: the AVATAR trial and the study by Kang et al., both comparing surgical aortic valve replacement to close surveillance, showing limited but significant superiority of the invasive option in terms of survival. 

 With the advent of TAVI and being thus far an uncharted area for clinical trials, there has been increasing interest in extending indications to this subgroup of patients, based on surgical experience. The first trial to undertake this analysis was the EVOLVED trial, with a superiority design, where 224 patients from 24 centers in the UK and Australia were randomized to invasive treatment versus close monitoring. It is noteworthy that a necessary sample size calculation of at least 356 patients was performed, hence the study presented limited statistical power. Patients corresponded to a low-surgical-risk population, with preserved ventricular function and low morbidity, with one-third of bicuspid aortic valves allowed in the cohort, three-quarters of which were surgically intervened, while the rest received TAVI. The primary outcome was a composite of all-cause mortality and unplanned hospitalization due to heart failure decompensation, which did not show significant differences between the two management strategies. All-cause mortality was equal in both groups, with a notable difference in unplanned admissions, higher in the monitoring group. In fact, after a median follow-up of 20 months, 77% had already been treated invasively, with almost a third being operated on within the first 12 months. The analysis did not break down results by invasive approach, whether surgery or TAVI, although, as mentioned, the proportion of patients was unequal. 

The EARLY-TAVR trial aimed to evaluate whether transcatheter aortic valve implantation (TAVI) could be beneficial as an early intervention in asymptomatic patients with severe aortic stenosis. Unlike the EVOLVED trial, EARLY-TAVR focused solely on TAVI using a transfemoral approach with Edwards Sapien 3® and 3 Ultra® systems. This trial included 901 patients, very close to the 900 initially proposed in the sample size calculation. A total of 75 centers across the United States and Canada participated, selecting patients with low surgical risk (average STS-PROM of 1.8%). 

The EARLY-TAVR population presented higher morbidity rates compared to those in the EVOLVED trial, particularly with a higher prevalence of diabetes mellitus and coronary artery disease, affecting over a quarter of patients in both groups, which contrasted with 3-6% prevalence in the EVOLVED cohort. Approximately 8% of patients had a bicuspid aortic valve, and left ventricular function was preserved across the study population. Unlike the EVOLVED trial, EARLY-TAVR did not use predictors of poor prognosis for patient selection. In the EVOLVED trial, inclusion was based on criteria such as left ventricular hypertrophy and/or myocardial fibrosis detected on MRI, which resulted in a high exclusion rate of patients who did not present these prognostic markers. 

The primary outcome of the EARLY-TAVR trial was a composite of mortality, stroke, and unplanned hospitalization, and significant differences were observed in favor of the TAVI group, despite the study originally being designed as a non-inferiority trial. Mortality rates were similar between groups, as were stroke rates, while unplanned hospitalizations primarily drove the composite outcome in favor of the TAVI group. During the first six months of the study, one in four patients in the conservative management group underwent TAVI due to symptom onset, and by the end of two years, more than 70% of the conservatively managed patients had received valve intervention. There were no significant differences in procedural or post-procedural outcomes between patients who underwent early TAVI and those who eventually received TAVI after adopting a conservative management approach. 

COMMENTARY: 

Commentaries on the interpretation of these studies, particularly EARLY-TAVR, have been varied. Some emphasize its somewhat positive outcome, suggesting a potential expansion of treatment scope into previously untouched pathology segments. At last year’s TCT congress in Washington, the primary author of the trial, Philippe Généreux, stated, “It seems that there is no advantage in waiting.” This was supported by a cautious statement from Gilbert Tang, who said, “Changes in clinical guidelines or consensus documents are needed to emphasize that patients with asymptomatic severe aortic stenosis require closer follow-up.” However, given the action-reaction dynamics between new evidence and clinical guidelines, it would be no surprise if upcoming changes are directed towards bolstering therapeutic measures rather than conservative management. 

Critically, John Mandrola argued that the study “experimented on patients, with much time and money invested, yet yielded little learning.” By including patients prematurely without establishing a reason (as the EVOLVED study did) to treat asymptomatic patients, the study fails to answer the questions that Heart Teams must consider: when, and most importantly, to whom? 

This critique is compounded by aspects of the study design, as noted by Josep Rodés-Cabau and John Mandrola, focusing on the rapid symptomatic conversion within the control group. Essentially, the intervention group exhibited a kind of “curative faith” unproven thus far, while the control group experienced an “anxiety-driven rush” to seek treatment as soon as possible. The psychological burden of being assigned to a watch-and-wait approach likely intensified the perception of symptoms, prompting patients to seek hospitalization at the earliest opportunity. 

This phenomenon has been documented in similar trials involving potentially malignant diseases, creating a state of “cancerophobia” in patients. Additionally, given that all patients were purportedly asymptomatic—where ergometry results were inconsistent, and sometimes solely based on patient history—there should have been an equivalent number of admissions in the TAVI group while they awaited their procedures. However, those in the TAVI group who began to develop mild symptoms would likely have refrained from hospital admission (especially in systems where healthcare costs are high and public coverage is limited) since they were already scheduled for imminent treatment. This specific bias is precisely what seems to render the outcomes of the study “positive.” 

In essence, we are again confronted with a study that appears to have a “goal-oriented” design, masking a false impartiality to achieve a predetermined outcome. As it stands, “the purpose of medical science should not be to design studies with positive results, but rather to address clinically relevant questions.” Unfortunately, it seems likely that future clinical practice guidelines will extend the indications for TAVI without a firm scientific foundation. To draw from a familiar saying, “greed breaks the sack”—as long as there is money to cover these expenses. If studies like this one influence consensus documents, then good medical practice and ethical research may ultimately be the ones to lose. 

REFERENCES:

Kang DH, Jang JY, Park SJ, Kim DH, Yun SC, Song JM, Park SW, Chung CH, Song JK, Lee JW. Watchful observation versus early aortic valve replacement for symptomatic patients with normal flow, low-gradient severe aortic stenosis. Heart. 2015 Sep;101(17):1375-81. doi: 10.1136/heartjnl-2015-307528.

Banovic M, Putnik S, Penicka M, Doros G, Deja MA, Kockova R, et al.; AVATAR Trial Investigators. Aortic Valve Replacement Versus Conservative Treatment in Asymptomatic Severe Aortic Stenosis: The AVATAR Trial. Circulation. 2022 Mar;145(9):648-658. doi: 10.1161/CIRCULATIONAHA.121.057639. Epub 2021 Nov 13. Erratum in: Circulation. 2022 Mar;145(9):e761. doi: 10.1161/CIR.0000000000001057.

Loganath K, Craig NJ, Everett RJ, Bing R, Tsampasian V, Molek P, et al.; EVOLVED investigators. Early Intervention in Patients With Asymptomatic Severe Aortic Stenosis and Myocardial Fibrosis: The EVOLVED Randomized Clinical Trial. JAMA. 2024 Oct 28:e2422730. doi: 10.1001/jama.2024.22730.

Généreux P, Schwartz A, Oldemeyer B, Cohen DJ, Redfors B, Prince H, Zhao Y, Lindman BR, Pibarot P, Leon MB. Design and rationale of the evaluation of transcatheter aortic valve replacement compared to surveillance for patients with asymptomatic severe aortic stenosis: The EARLY TAVR trial. Am Heart J. 2024 Feb;268:94-103. doi: 10.1016/j.ahj.2023.11.019.