Lindman, Brian R.

BACKGROUND: The EARLY TAVR trial (Evaluation of TAVR Compared to Surveillance for Patients with Asymptomatic Severe Aortic Stenosis) demonstrated that early transcatheter aortic valve replacement (TAVR) was superior to clinical surveillance (CS) in asymptomatic severe aortic stenosis. The relative impact of early TAVR versus CS strategy by age is unknown. METHODS: The study population of the EARLY TAVR trial was stratified into 4 age groups: 65 to 69 years (n=141), 70 to 74 years (n=263), 75 to 79 years (n=250), and ≥80 years (n=247). Associations between age and the trial primary end point of death, stroke, or unplanned cardiovascular hospitalization; the composite end point of death, stroke, or heart failure hospitalization; and its individual components were examined. Interaction tests evaluated whether the treatment effect of early TAVR versus CS differed by age. RESULTS: No interaction was detected between age and the treatment effect of early TAVR versus CS for the composites or individual outcomes. We observed lower stroke rates with early TAVR compared with CS in the youngest (65–69 years, absolute risk reduction, 13%; P =0.008) and oldest (≥80 years; absolute risk reduction, 12.3%; P =0.029) age groups. The absolute difference in heart failure hospitalization rates between the early TAVR and CS arms at 2 years was greatest in the oldest patients (≥80 years, 9.1%; 75–79 years, 5.9%; 70–74 years, 5.1%; 65–69 years, 4.4%). In the CS group, time to conversion to AVR was similar across all age groups (median, 11 months; P =0.73). Approximately one-third of younger patients (65–69 years) in the CS arm presented with acute valve syndrome at the time of conversion, the frequency of which tended to increase with age ( P =0.06). CONCLUSIONS: In the EARLY TAVR trial, the relative benefit of early TAVR over CS was consistent among all age groups. The greatest absolute reduction in stroke rate with early TAVR compared with CS appeared in the youngest and oldest groups, whereas reduction in heart failure hospitalization was most pronounced in the oldest patients. These data suggest that early TAVR should be considered in all age groups above 65 years. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03042104.

Background: Calcific aortic valve stenosis (CAVS) is characterized by the progressive accrual of aortic valvular calcium (AVC), resulting in impaired valvular compliance and mechanics and impaired cardiac function leading to heart failure (HF). In a phase 2 trial of 23 patients with moderate CAVS, ataciguat (ATA), a soluble guanylate cyclase activator, relative to placebo slowed the deposition of AVC, decreases in aortic valve area (AVA; by continuity equation), and increases in diastolic dysfunction and left ventricular (LV) mass. ATA may have other favorable effects on ventricular, valvular, and/or vascular pathophysiology relevant to patients with CAVS. Hypothesis: We hypothesized that slowing the rate of AVC deposition is associated with improvements in valvular compliance and in measures of cardiac structure and function. Methods: A phase 2 study randomized patients with moderate CAVS 1:1 to receive ATA 200 mg/day or placebo for up to 12 months (NCT02481258). The primary endpoint was change in AVC assessed by cardiac CT, and measures of aortic valve function and cardiac structure and function were also assessed. AVA was calculated by the Modified Gorlin (Hakki) equation to additionally assess valvular compliance. Correlations between AVC, AVA, and other measures of cardiac structure and function were assessed by exploratory linear mixed models. Results: Changes in AVC from baseline were negatively correlated with changes in AVA (slope = −0.0002 [95% CI −0.0004, 0.0001]; Figure 1), such that patients with the least AVC deposition had minimal changes in AVA. Reciprocally, changes from baseline in AVA were positively correlated with changes in cardiac output (CO; slope = 0.16 [95% CI 0.13, 0.18]; Figure 2). Treatment with ATA, compared with placebo, was associated with improvements in systolic function. Changes in AVC deposition correlated with changes in CO (slope = −0.0007 [95% CI −0.0021, 0.0008]; Figure 3), and measured improvements in CO were generally more observed in patients with less of an increase in AVC, which were more frequently observed in those treated with ATA compared with placebo. Conclusions: These data suggest that slowing the rate of AVC deposition with ATA may result in improvements in CO through improved myocardial function and valvular compliance. Larger controlled trials are needed to assess such favorable myocardial/valvular effects that may help to preserve functional capacity and slow progression to HF.

Background A classification system describing clinical presentation before aortic valve replacement (AVR) has recently been proposed (stable valve syndrome [SVS]), mildly symptomatic (progressive valve syndrome), or with acute and severe signs and symptoms (acute valve syndrome [AVS]). We aimed to evaluate the clinical impact, health care costs, and resource use associated with the mode of clinical presentation at the time of AVR among patients presenting with aortic stenosis. Methods Using the Market Clarity database (2017–2023), patients >18 years old with aortic stenosis and undergoing AVR (transcatheter or surgical) were included. Patients were categorized as SVS, progressive valve syndrome, or AVS based on their clinical presentation during the 1 year before AVR. All‐cause death, heart failure hospitalization, total health care costs (index hospitalization plus 1‐year follow‐up), and resource use were compared across clinical presentation groups using adjusted regression models. Results Of the 24 075 patients undergoing AVR for aortic stenosis, 270 (1.1%) had SVS, 10 195 (42.3%) progressive valve syndrome, and 13 610 (56.5%) AVS. Compared with SVS, AVS presentation was associated with increased risk of 1‐year death (adjusted hazard ratio [aHR], 2.93 [95% CI, 1.1–7.8]; P =0.03) and heart failure hospitalization (aHR, 4.15 [95% CI, 1.6–11.1]; P <0.01) after AVR. The total costs of AVR and 1‐year follow‐up were significantly higher in both the progressive valve syndrome (difference $27 410 [$13 507–$41 314]) and AVS groups (difference $36 267 [$22 302–$50 232]) compared with patients with SVS. Conclusions AVS was frequent among patients undergoing AVR and was associated with increase in death, heart failure hospitalization, health care costs, and resource use 1 year after AVR, and SVS presentation was associated with the best clinical and economic outcomes.

Abstract Background and Aims The TRISCEND II trial demonstrated superior clinical benefits for patients with ≥severe tricuspid regurgitation (TR) treated with the EVOQUE transcatheter tricuspid valve replacement (TTVR) system plus medical therapy vs medical therapy alone. This work reports 1-year and 18-month outcomes in patients stratified by baseline TR severity. Methods The multicentre, prospective TRISCEND II trial enrolled 400 patients with symptomatic, ≥severe TR, and randomized 2:1 to TTVR (n = 267) or control (n = 133). In a post hoc analysis, patients were stratified into severe TR (n = 172) and massive/torrential TR (n = 220) cohorts. Clinical and quality-of-life outcomes were reported at 1 year, with Kaplan–Meier estimates for all-cause mortality and heart failure (HF) hospitalization assessed at 18 months. Study oversight included an independent echocardiographic core laboratory, clinical events committee, and data safety monitoring board. Results One year after TTVR, TR was ≤mild in 95.2% of severe TR and 95.3% of massive/torrential TR patients. The primary safety and effectiveness endpoint (win ratio) favoured TTVR over control regardless of baseline TR severity: severe {1.64 [95% confidence interval (CI): 1.11, 2.43]} and massive/torrential [2.20 (1.55, 3.14)]. At 18 months, TTVR patients had similar mortality to controls [rate difference: severe 0.2% (−11.6, 11.9), massive/torrential −5.8% (−17.6, 6.0)], whereas HF hospitalization rates favoured TTVR in the massive/torrential cohort [vs control, severe 9.8% (−3.0, 22.7), massive/torrential -15.2% (−28.9, −1.5)]. Conclusions Patients with ≥severe TR benefit from TTVR, experiencing improvements in TR severity, functional capacity, and quality of life regardless of baseline TR severity, with a signal for greater benefit in patients with more advanced disease.

This Viewpoint advocates for prompt aortic valve replacement (rather than clinical surveillance) as the default strategy for patients with asymptomatic severe aortic stenosis.

Background: Left ventricular (LV) mass regression after aortic valve replacement (AVR) for aortic stenosis (AS) is a favorable effect of LV unloading, but its relationship to improved clinical outcomes is unclear. We examined the effect on clinical outcomes after transcatheter AVR (TAVR) of: 1) amount of LV mass index (LVMi) regression; and 2) persistent severe LV hypertrophy (LVH). Methods: Of 2115 patients with symptomatic AS at high surgical risk receiving TAVR in the PARTNER randomized trial or continued access registry, 462 (55% women) who had severe LVH (LVMi ≥149 g/m 2 men, ≥122 g/m 2 women, by ASE criteria) at baseline (BL) and LVMi measured 6 mo post-TAVR were included in our analysis. The effect of LVMi regression was evaluated by comparing outcomes in patients with greater vs. lesser decrease (dichotomized by median % change) in LVMi between BL and 6 mo, and in those without vs. with persistent severe LVH 6 mo post-TAVR. Cox PH models evaluated rates of all-cause mortality (6-12 mo), rehospitalizations (through 1 yr), and the composite of these two outcomes. Results: LVMi decreased from 173±32 (BL) to 121±25 g/m 2 (6 mo) (p<0.001) in those with greater LVMi regression, and from 164±30 (BL) to 158±34 g/m 2 (6 mo) (p<0.001) in those with lesser LVMi regression. Patients with greater vs. lesser LVMi regression had similar baseline clinical characteristics, a lower rate of rehospitalization (10.5% vs. 19.9%, p=0.006) and lower rate of the composite endpoint of death or rehospitalization (13.2% vs. 21.4%, p=0.02), but a similar rate of death (4.9% vs. 4.8%, p=0.86). Persistent severe LVH at 6 mo post-TAVR was present in 54% (58% of whom were women). Patients without vs. with persistent severe LVH had similar baseline clinical characteristics, a lower rate of rehospitalization (11.9% vs. 18.1%, p=0.053) and lower rate of the composite endpoint of death or rehospitalization (13.3% vs. 20.7%, p=0.03), but a similar rate of death (3.9% vs. 5.7%, p=0.42). Similar results were obtained when including patients with moderate or severe LVH. Conclusions: In high-risk patients with severe AS and severe LVH undergoing TAVR, greater LV mass regression and resolution of initially severe LVH at 6 months are associated with a lower rate of death or repeat hospitalization.

Abstract Objective Our objective was to evaluate the impact of various blood pressures (BPs) on coronary perfusion and valvular hemodynamics following aortic valve replacement (AVR). Background Lower systolic and diastolic (SBP/DBP) pressures from the recommended optimal target range of SBP < 120–130 mmHg and DBP < 80 mmHg after AVR have been independently associated with increased cardiovascular and all‐cause mortality. Methods The hemodynamic assessment of a 26 mm SAPIEN 3 transcatheter aortic valve (TAV), 29 mm Evolut R TAV, and 25 mm Magna Ease surgical aortic valve (SAV) was performed in a pulsed left heart simulator with varying SBP, DBP, and heart rate (HR) conditions (60 and 120 bpm) at 5 L/min cardiac output (CO). Average coronary flow (CF), effective orifice areas (EOAs), and valvulo‐arterial impedance (Zva) were calculated. Results At HR of 60 bpm, at SBP < 120 mmHg and DBP < 60 mmHg, CF decreased below the physiological lower limit with several different valves. Zva and EOA were found to increase and decrease respectively with increasing SBP and DBP. The same results were found with an HR of 120 bpm. The trends of CF variation with BP were similar in all valves however the drop below the lower physiological CF limit was valve dependent. Conclusion In a controlled in vitro system, with different aortic valve prostheses in place, CF decreased below the physiologic minimum when SBP and DBP were in the range targeted by blood pressure guidelines. Combined with recent observations from patients treated with AVR, these findings underscore the need for additional studies to identify the optimal BP in patients treated with AVR for AS.

Introduction: Pulmonary hypertension (PH) is associated with increased mortality after surgical or transcatheter aortic valve replacement (TAVR) for aortic stenosis (AS). Hypothesis: We hypothesized that clinical or hemodynamic factors might influence the relationship between significant PH and increased mortality. Methods: Among patients with symptomatic AS at high or prohibitive surgical risk receiving TAVR in the PARTNER I randomized trial or registry, 2180 patients with an invasive measurement of mean pulmonary artery pressure (mPAP) recorded were included. PH was defined as: none (mPAP<25 mmHg), mild (25 to <35), and mod/sev (≥35). Results: One year all-cause mortality was worse with increasing severity of PH: none (n=785, 18.6%), mild (n=838, 22.7%), and mod/sev (n=557, 25.0%) (p=0.01). The association between mod/sev PH (vs. no PH) and 1y mortality varied by sex and renal function (interaction p=0.03 and p=0.06, respectively). In females, mod/sev PH was associated with increased mortality (24.6% vs. 14.1%, HR 1.89, 95% CI 1.32-2.73); in males it was not (24.9% vs. 22.2%, HR 1.12, 95% CI 0.82-1.52). Additionally, mod/sev PH was associated with mortality in those with glomerular filtration rate (GFR) <40 (HR 1.76, 95% CI 1.28-2.42), but not in those with GFR ≥40. In a multivariable Cox PH model of patients with mod/sev PH, oxygen dependent lung disease, cerebrovascular disease, lower GFR, and lower baseline transvalvular mean gradient were each independently associated with increased 1y mortality (p<0.05 for all), whereas pulmonary artery compliance was the only hemodynamic variable associated with mortality (p=0.043) (Table). Conclusions: The relationship between mod/sev PH and increased mortality after TAVR is altered by sex and renal function. While lower pulmonary artery compliance is associated with increased mortality in patients with significant PH, clinical factors appear to be more influential in stratifying risk than hemodynamic indices.

Objective Pulmonary hypertension (PH) is associated with increased mortality after surgical or transcatheter aortic valve replacement (TAVR) for aortic stenosis (AS), and when the pulmonary artery pressure is particularly elevated, there may be questions about the clinical benefit of TAVR. We aimed to identify clinical and haemodynamic factors associated with increased mortality after TAVR among those with moderate/severe PH. Methods Among patients with symptomatic AS at high or prohibitive surgical risk receiving TAVR in the Placement of Aortic Transcatheter Valves (PARTNER) I randomised trial or registry, 2180 patients with an invasive measurement of mean pulmonary artery pressure (mPAP) recorded were included, and moderate/severe PH was defined as an mPAP ≥35 mm Hg. Results Increasing severity of PH was associated with progressively worse 1-year all-cause mortality: none (n=785, 18.6%), mild (n=838, 22.7%) and moderate/severe (n=557, 25.0%) (p=0.01). The increased hazard of mortality associated with moderate/severe PH was observed in females, but not males (interaction p=0.03). In adjusted analyses, females with moderate/severe PH had an increased hazard of death at 1 year compared with females without PH (adjusted HR 2.14, 95% CI 1.44 to 3.18), whereas those with mild PH did not. Among males, there was no increased hazard of death associated with any severity of PH. In a multivariable Cox model of patients with moderate/severe PH, oxygen-dependent lung disease, inability to perform a 6 min walk, impaired renal function and lower aortic valve mean gradient were independently associated with increased 1-year mortality (p<0.05 for all), whereas several haemodynamic indices were not. A risk score, including these factors, was able to identify patients with a 15% vs 59% 1-year mortality. Conclusions The relationship between moderate/severe PH and increased mortality after TAVR is altered by sex, and clinical factors appear to be more influential in stratifying risk than haemodynamic indices. These findings may have implications for the evaluation of and treatment decisions for patients referred for TAVR with significant PH. Trial registration NCT00530894.

Background— Tricuspid regurgitation (TR) and right ventricular (RV) dysfunction adversely affect outcomes in patients with heart failure or mitral valve disease, but their impact on outcomes in patients with aortic stenosis treated with transcatheter aortic valve replacement has not been well characterized. Methods and Results— Among 542 patients with symptomatic aortic stenosis treated in the Placement of Aortic Transcatheter Valves (PARTNER) II trial (inoperable cohort) with a Sapien or Sapien XT valve via a transfemoral approach, baseline TR severity, right atrial and RV size and RV function were evaluated by echocardiography according to established guidelines. One-year mortality was 16.9%, 17.2%, 32.6%, and 61.1% for patients with no/trace (n=167), mild (n=205), moderate (n=117), and severe (n=18) TR, respectively ( P <0.001). Increasing severity of RV dysfunction as well as right atrial and RV enlargement were also associated with increased mortality ( P <0.001). After multivariable adjustment, severe TR (hazard ratio, 3.20; 95% confidence interval, 1.50–6.82; P =0.003) and moderate TR (hazard ratio, 1.60; 95% confidence interval, 1.02–2.52; P =0.042) remained associated with increased mortality as did right atrial and RV enlargement, but not RV dysfunction. There was an interaction between TR and mitral regurgitation severity ( P =0.04); the increased hazard of death associated with moderate/severe TR only occurred in those with no/trace/mild mitral regurgitation. Conclusions— In inoperable patients treated with transcatheter aortic valve replacement, moderate or severe TR and right heart enlargement are independently associated with increased 1-year mortality; however, the association between moderate or severe TR and an increased hazard of death was only found in those with minimal mitral regurgitation at baseline. These findings may improve our assessment of anticipated benefit from transcatheter aortic valve replacement and support the need for future studies on TR and the right heart, including whether concomitant treatment of TR in operable but high-risk patients with aortic stenosis is warranted. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01314313.