Simvastatin And Ezetimibe In Aortic Stenosis Research Articles

Validation of the developed ASGARD risk score for safe monitoring of asymptomatic patients with non-severe aortic valve stenosis

Abstract Background The recommended standard monitoring of patients with non-severe aortic valve stenosis (AS) involves echocardiography surveillance at 1-2 year intervals. Since many of these costly routine echocardiograms yield no clinical consequences during a prolonged watchful waiting period, we propose to replace them with a risk stratification approach. Purpose The primary aim was to validate the ability of ASGARD risk score to a) identify low-risk AS patients who do not need new echocardiography for safe monitoring, and b) estimate optimal follow-up intervals. Methods We have developed the ASGARD risk score using data from 1196/1739 (69%) asymptomatic AS-patients with mild-to-moderate AS who were enrolled in the randomized, multicentre Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial. The primary outcome was a composite of AS-related outcomes, aortic valve replacement, or hospitalization with heart failure during a clinically relevant 2-year follow-up. From multivariable Cox proportional hazards regression analyses, we chose the best prognostic model with the lowest Akaike information criterion (AIC) values and p-values <0.05. The risk score included five predictors: age, sex, systolic blood pressure, N-terminal pro-brain natriuretic peptide (NT-proBNP), and last year's measurement of transaortic maximal velocity (Vmax). Kaplan-Meier plot visualized event rates stratified by quartiles of risk score. We validated the ASGARD risk score in an internal validation cohort of 543 patients (31% hold-out from SEAS-population) and an external validation cohort of 69 asymptomatic out-clinic patients with Vmax ≤4 m/s from six hospitals from capital city. Results Patients from the external validation cohort significantly differed from those in the development cohort in terms of higher age (mean [SD], 71.7 [8.5] vs. 67.4 [9.8] years, p<0.001), less prevalent left ventricular hypertrophy (13.0% vs. 37.5%, p<0.001), and higher event-rates (12.5 [95% CI, 7.6-20.8] vs. 4.5 [3.7-5.4] events per 100 patient-years of follow-up, p<0.001). The ASGARD risk score showed consistent predictive performance across the validation cohorts (external validation: area under the curve: 0.82 [95% CI, 0.73-0.91]; calibration-in-the-large, p=0.24; calibration slope, p=0.15; Brier score, 0.18). The score performed just as well or better than a new Vmax measurement (Figure 1A-1B). In the three upper ASGARD score quartiles, 95% of patients had less than 5% risk of AVR or heart failure until 7.5, 16.5, and 22.5 months, respectively (Figure 1C). Conclusion Without a new echocardiogram, the ASGARD risk score identifies patients at low risk for AS-related events among asymptomatic patients with non-severe AS. The ASGARD risk score also estimates the safe watchful-waiting period of 6, 15, 21, and 24 months for the four ASGARD risk score quartiles in decreasing order.Figure 1

ASGARD risk scores for long-term, individualized cardiovascular surveillance of low-risk patients with asymptomatic non-severe aortic valve stenosis: development and internal validation

Abstract Background Routine echocardiography of asymptomatic patients with non-severe aortic valve stenosis (AS) mainly focuses on the valve condition at 1-2 year intervals but has limited ability to predict the risk of other cardiovascular comorbidities. Thus, there is a compelling need to replace routine echocardiography for low-risk patients with more individualized cardiovascular surveillance for a safe period. Aim First, to develop and validate separate risk stratification models for AS-related events (AVE) and major cardiovascular events (MCE) to identify low-risk AS patients who can safely postpone routine echocardiography replaced by tailored risk stratification and adequate risk factor management. Second, to estimate optimal follow-up intervals according to risk stratification for each outcome. Methods We analyzed serial measurements from 69% of 1579 patients with mild-to-moderate AS who were asymptomatic and event-free one year after inclusion in the randomized, multicenter Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial. We developed two ASGARD risk scores using multivariable Cox proportional hazard regression analyses, designed as landmark analyses starting at year-1 and with a clinically relevant 2-year follow-up. The ASGARD scores estimated the risk of AVE (composite of aortic valve replacement or hospitalization with heart failure) and MCE (composite of myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft, stroke, and all-cause mortality). We estimated the prognostic models with backward elimination, selecting the lowest Akaike information criterion values and p<0.05. There were 7 predictors for AVE and 6 for MCE among current demographic, electrocardiograms, laboratory data, and echocardiographic measures one year earlier (baseline) (Figures 1A, 2A). We defined optimal follow-up for risk score quartiles at rates ≤5% visualized on Kaplan-Meier plots. We assessed model performance in 31% of patients held out for internal validation. Results ASGARD development models for both AVE and MCE risk demonstrated overall consistent predictive performance in the internal validation cohort, as evidenced by c-statistics, calibration-in-the-large, calibration slope, Brier score, and goodness-of-fit (all p>0.05) (Figure 1B-C, 2B-C). ASGARD predicted AVE risk similar to a new Vmax measurement (area under the curve [95% CI], 0.82 [0.78-0.87] vs. 0.85 [0.82-0.89) (Figure 1B), and MCE risk better than Framingham cardiovascular risk score (0.76 [0.70-0.82] vs. 0.68 [0.62-0.75]) (Figure 2B). The one-year event rates were ≤5% for the 2 lowest risk score quartiles (Figure 1D, 2D). Conclusion The ASGARD risk scores show promise for long-term, individualized cardiovascular surveillance of low-risk patients with non-severe AS without unnecessary echocardiography. Further studies are warranted for external model validation, continuous optimization, and exploring the potential for implementation in clinical practice.Figure 1Figure 2

High-sensitive Troponin T is not associated with the progression of asymptomatic mild to moderate aortic stenosis: a post hoc substudy of the SEAS trial

Abstract Background Aortic stenosis (AS) and coronary artery disease (CAD) share pathophysiological pathways, as reflected by frequent concomitant revascularization in patients undergoing aortic valve replacement (AVR). High-sensitive Troponin T (hsTnT) is a proven biomarker of cardiomyocyte overload and injury, and predicts postoperative mortality after AVR. However, it is unknown if hsTnT can predict AVR, mortality or ischemic coronary events (ICE) in asymptomatic AS patients. Purpose To investigate the hypothesis that increased hsTnT is associated with more severe AS and a higher risk of adverse outcomes in asymptomatic AS patients without overt CAD. Methods hsTnT concentrations were examined at baseline and after 1-year follow-up in 1739 asymptomatic AS patients enrolled in the randomized, double-blind Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study. The main inclusion criteria were: left ventricular (LV) ejection fraction >55%, transaortic maximal velocity between 2.5–4.0 m/s, and no history of CAD. The primary exposure variable was increased hsTnT (>14 pg/mL according to the assay manufacturer, Roche). This study's primary endpoint was a composite of competing risk outcomes: all-cause mortality as the first event, AVR without revascularization, and ICE (defined as myocardial infarction before AVR, PCI before or combined with AVR, or any CABG). Multivariable regression examined associations between hsTnT and clinical variables. Cox proportional hazards regression models were adjusted for age, sex, creatinine, LV mass index, mean aortic pressure gradient (Pmean) and stratified by center and lipid-lowering treatment. We analyzed outcomes during 5-year follow-up from baseline. Results At baseline, 453 (26.0%) patients had increased hsTnT and 302 (17.4%) had moderate-severe AS with a mean (SD) aortic valve area of 0.8 (0.2) cm2 and Pmean of 33.2 (8.8) mmHg. The median annual hsTnT change from baseline to year 1 was 0.8 pg/mL (IQR, −0.4 to 2.3), regardless of AS severity (P=0.08). In adjusted models, log(hsTnT at baseline) was associated with age, sex, creatinine, and LV mass index (all P<0.05), but not with AS severity (P=0.36). The incidence rate ratio for ICE (Figure 1) in patients with increased vs normal baseline hsTnT concentrations was 2.32 (95% CI, 1.72–3.11, P<0.001). In adjusted Cox regression, increased hsTnT was associated with an increased 5-year ICE risk (HR 1.64; 95% CI, 1.18–2.29, P=0.003), but neither with AVR without revascularization nor death (Figure 1). Conclusion In these asymptomatic AS patients without overt CAD, hsTnT is often normal and remains stable during 1 year of follow-up regardless of AS severity. Increased hsTnT is associated with CAD-related events, but neither to AS severity nor AVR without concomitant revascularization. This analysis does not support routine hsTnT measurement in asymptomatic AS to predict AVR related to AS progression, although hsTnT could improve the risk assessment for ICE. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Main sponsor (SEAS): Merck & Co Inc, Whitehouse Station, New JerseyBlood analysis sponsor: Roche Diagnostics International Ltd, Switzerland

Association of Annual N-Terminal Pro-Brain Natriuretic Peptide Measurements With Clinical Events in Patients With Asymptomatic Nonsevere Aortic Stenosis

Recent studies have questioned the presumed low-risk status of patients with asymptomatic nonsevere aortic stenosis (AS). Whether annual N-terminal pro-brain natriuretic peptide (NT-proBNP) measurements are useful for risk assessment is unknown. To assess the association of annual NT-proBNP measurements with clinical outcomes in patients with nonsevere AS. Analysis of annual NT-proBNP concentrations in the multicenter, double-blind Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) randomized clinical trial was performed. SEAS was conducted from January 6, 2003, to April 1, 2008. Blood samples were analyzed in 2016, and data analysis was performed from February 10 to October 10, 2021. SEAS included 1873 patients with asymptomatic AS not requiring statin therapy with transaortic maximal flow velocity from 2.5 to 4.0 m/s and preserved ejection fraction. This substudy included 1644 patients (87.8%) with available blood samples at baseline and year 1. Increased age- and sex-adjusted NT-proBNP concentrations at year 1 and a 1.5-fold or greater relative NT-proBNP concentration change from baseline to year 1. Moderate AS was defined as baseline maximal flow velocity greater than or equal to 3.0 m/s. Aortic valve events (AVEs), which are a composite of aortic valve replacement, cardiovascular death, or incident heart failure due to AS progression, were noted. Landmark analyses from year 1 examined the association of NT-proBNP concentrations with outcomes. Among 1644 patients, 996 were men (60.6%); mean (SD) age was 67.5 (9.7) years. Adjusted NT-proBNP concentrations were within the reference range (normal) in 1228 of 1594 patients (77.0%) with NT-proBNP values available at baseline and in 1164 of 1644 patients (70.8%) at year 1. During the next 2 years of follow-up, the AVE rates per 100 patient-years for normal vs increased adjusted NT-proBNP levels at year 1 were 1.39 (95% CI, 0.86-2.23) vs 7.05 (95% CI, 4.60-10.81) for patients with mild AS (P < .01), and 10.38 (95% CI, 8.56-12.59) vs 26.20 (95% CI, 22.03-31.15) for those with moderate AS (P < .01). Corresponding all-cause mortality rates were 1.05 (95% CI, 0.61-1.81) vs 4.17 (95% CI, 2.42-7.19) for patients with mild AS (P < .01), and 1.60 (95% CI, 0.99-2.57) vs 4.78 (95% CI, 3.32-6.87) for those with moderate AS (P < .01). In multivariable Cox proportional hazards regression models, the combination of a 1-year increased adjusted NT-proBNP level and 1.5-fold or greater NT-proBNP level change from baseline was associated with the highest AVE rates in both patients with mild AS (hazard ratio, 8.12; 95% CI, 3.53-18.66; P < .001) and those with moderate AS (hazard ratio, 4.05; 95% CI, 2.84-5.77; P < .001). The findings of this study suggest that normal NT-proBNP concentrations at 1-year follow-up are associated with low AVE and all-cause mortality rates in patients with asymptomatic nonsevere AS. Conversely, an increased 1-year NT-proBNP level combined with a 50% or greater increase from baseline may be associated with high AVE rates. ClinicalTrials.gov Identifier: NCT00092677.

Transcatheter Aortic Valve Implantation During the COVID-19 Pandemic

Transcatheter aortic valve implantation (TAVI) outcomes during the coronavirus disease 2019 (COVID-19) pandemic have not been fully evaluated and some structural programs in the world have been suspended during this period. We sought to evaluate and compare clinical outcomes in patients undergoing TAVI in pandemic versus nonpandemic era. In a single center, we compared 198 TAVI patients performed during 2019 to 59 patients performed during the COVID-19 pandemic period (March 1st to June 30th, 2020). Primary outcome was procedural success according to VARC criteria and 30-day mortality rates. VARC-defined procedural success was high in both groups (93.3% vs 96.6%; p = 0.53). There were no differences in any vascular complications (26% vs 19%; p = 0.3), permanent pacemaker implantation (11.8% vs 15.3%; p = 0.63), and length of hospital stay (5.2 vs 4.2 days; p = 0.29). Thirty-day mortality was similar (3% vs 3.4%; p = 1.0). We had no documented COVID-19 disease in our patients during follow up. In conclusion, TAVI procedures can be performed effectively and safely during the COVID-9 pandemic, using a minimalist approach, early discharge, and by maintaining proper use of personal protective equipment.

Heartbeat: time to treat the whole patient, not just the valve, when calcific aortic stenosis is present

A key consideration in timing of aortic valve replacement (AVR) for patients with aortic stenosis (AS) is whether there is an increased risk of sudden cardiac death (SCD) that might...

Prospective Evaluation of Malignancy in 17,708 Patients Randomized to Ezetimibe Versus Placebo: Analysis From IMPROVE-IT

BackgroundAn increased risk of malignancy was reported with simvastatin/ezetimibe in 1,873 patients in the SEAS (Simvastatin and Ezetimibe in Aortic Stenosis) trial. ObjectivesThe purpose of this study was to clarify this unexpected finding in a larger sample size of patients stabilized after acute coronary syndrome, we conducted a prospective systematic analysis of malignancy events in IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial). MethodsWithin IMPROVE-IT, 17,708 patients post–acute coronary syndrome were randomized to either ezetimibe 10 mg or matching placebo on a background of simvastatin 40 mg who took ≥1 dose of the study drug. Suspected tumors (benign and malignant) reported by investigators or identified from a review of adverse events were adjudicated by oncologists without knowledge of drug assignment. The primary malignancy endpoint included new, relapsing, or progressive malignancies (excluding nonmelanotic skin malignancies). The secondary endpoint was death due to malignancy. ResultsIn this trial, 1,470 patients developed the primary malignancy endpoint during a median 6 years of follow-up. The most common malignancy locations were prostate (18.9%), lung (16.8%), and bladder (8.8%) with no differences by treatment group (p > 0.05 for each location). Kaplan-Meier 7-year rates of malignancies were similar with ezetimibe and placebo (10.2% vs. 10.3%; hazard ratio: 1.03; 95% confidence interval: 0.93 to 1.14; p = 0.56), as were the rates for malignancy death (3.8% vs. 3.6%; hazard ratio: 1.04; 95% confidence interval: 0.88 to 1.23; p = 0.68). ConclusionsAmong 17,708 patients receiving simvastatin 40 mg daily, those randomized to ezetimibe 10 mg daily had a similar incidence of malignancy and deaths due to malignancy compared with those receiving placebo during a median follow-up of 6 years (96,377 patient-years). (IMPROVE-IT: Examining Outcomes in Subjects With Acute Coronary Syndrome: Vytorin [Ezetimibe/Simvastatin] vs Simvastatin [P04103]; NCT00202878)

Sudden cardiac death in asymptomatic patients with aortic stenosis

ObjectiveWe retrospectively analysed outcome data from the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study to assess the incidence and potential risk factors of sudden cardiac death (SCD) in this...

Relation of Lipid-Lowering Therapy to Need for Aortic Valve Replacement in Patients With Asymptomatic Mild to Moderate Aortic Stenosis

In this study, we aimed to determine if pretreatment low-density lipoprotein (LDL) levels and aortic stenosis (AS) severity alter the efficacy of lipid-lowering therapy on reducing aortic valve replacement (AVR). We used 1,687 patients with asymptomatic mild-to-moderate AS, who were randomly assigned (1:1) to 40/10 mg simvastatin/ezetimibe combination versus. placebo in the simvastatin and ezetimibe in aortic stenosis (SEAS) trial. Pretreatment LDL levels (>4 mmol/L) and peak aortic jet velocity (3 m/s) were used to partition study participants into 4 groups, which were followed for a primary endpoint of AVR. Cox regression with tests for interaction was used to study the effect of randomized treatment in each subgroup. During a median follow-up of 4.3 years (IQR 4.2 to 4.7 years; total 7,396 patient-years of follow-up), 478 (28%) patients underwent AVR and 146 (9%) died. A significant risk dependency was detected between simvastatin/ezetimibe combination, LDL levels and mild versus moderate AS on rates of AVR (p = 0.01 for interaction). In stratified analyses, randomized treatment, therefore, reduced the rate of AVR in patients with LDL levels >4 mmol and mild AS at baseline (HR 0.4; 95% CI: 0.2 to 0.9). There was no detectable effect of randomized treatment on the need for AVR in the 3 other participants subgroups. We conclude, that in a secondary analysis from a prospective randomized clinical trial, treatment with simvastatin/ezetimibe combination reduced the need for AVR in a subset of patients with mild AS and high pretreatment LDL levels (Unique identifier on clinicaltrials.gov: NCT00092677).

Effect of simvastatin and ezetimibe on suPAR levels and outcomes

Background and aimsSoluble urokinase plasminogen activator receptor (suPAR) is an inflammatory marker associated with cardiovascular disease. Statins lower both low-density lipoprotein (LDL)-cholesterol and C-reactive protein (CRP), resulting in improved outcomes. However, whether lipid-lowering therapy also lowers suPAR levels is unknown. MethodsWe investigated whether treatment with Simvastatin 40 mg and Ezetimibe 10 mg lowered plasma suPAR levels in 1838 patients with mild-moderate, asymptomatic aortic stenosis, included in the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study, using a pattern mixture model. A 1-year Cox analysis, adjusted for established cardiovascular risk factors, allocation to study treatment, peak aortic valve velocity and baseline suPAR, was performed to evaluate relationships between change in suPAR with all-cause mortality and the composite endpoint of major cardiovascular events (MCE) composed of ischemic cardiovascular events (ICE) and aortic valve related events (AVE). ResultsAfter 4.3 years of follow-up, suPAR levels had increased by 9.2% (95% confidence interval [CI]: 7.0%–11.5%) in the placebo group, but only by 4.1% (1.9%–6.2%) in the group with lipid-lowering treatment (p<0.001). In a multivariate 1-year analysis, 1-year suPAR was strongly associated with all-cause mortality, hazard ratio (HR) = 2.05 (1.17–3.61); MCE 1.40 (1.01–1.92); and AVE 1.42 (1.02–1.99) (all p<0.042) for each doubling of suPAR; but was not associated with ICE. ConclusionsSimvastatin and Ezetimibe treatment impeded the progression of the time-related increase in plasma suPAR levels. Year-1 suPAR was associated with all-cause mortality, MCE, and AVE irrespective of baseline levels (SEAS study: NCT00092677).

Effect Modifications of Lipid-Lowering Therapy on Progression of Aortic Stenosis (from the Simvastatin and Ezetimibe in Aortic Stenosis [SEAS] Study)

Observational studies indicate that low-density lipoprotein (LDL) cholesterol acts as a primary contributor to an active process leading to aortic stenosis (AS) development. However, randomized clinical trials have failed to demonstrate an effect of lipid lowering on impeding AS progression. This study explored if pretreatment LDL levels and AS severity altered the efficacy of lipid-lowering therapy. The study goal was evaluated in the analysis of surviving patients with baseline data in the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial of 1,873 asymptomatic patients with mild-to-moderate AS. Serially measured peak aortic jet velocity was the primary effect estimate. Linear mixed model analysis adjusted by baseline peak jet velocity and pretreatment LDL levels was used to assess effect modifications of treatment. Data were available in 1,579 (84%) patients. In adjusted analyses, lower baseline peak aortic jet velocity and higher pretreatment LDL levels increased the effect of randomized treatment (p = 0.04 for interaction). As such, treatment impeded progression of AS in the highest quartile of LDL among patients with mild AS at baseline (0.06 m/s per year slower progression vs placebo in peak aortic jet velocity, 95% confidence interval 0.01 to 0.11, p = 0.03), but not in the 3 other quartiles of LDL. Conversely, among patients with moderate AS, there was no detectable effect of treatment in any of the pretreatment LDL quartiles (all p ≥0.14). In conclusion, in a non-prespecified post hoc analysis, the efficacy of lipid-lowering therapy on impeding AS progression increased with higher pretreatment LDL and lower peak aortic jet velocity (SEAS study: NCT00092677).

Antihypertensive Treatment With β-Blockade in Patients With Asymptomatic Aortic Stenosis and Association With Cardiovascular Events.

BackgroundPatients with aortic stenosis (AS) often have concomitant hypertension. Antihypertensive treatment with a β‐blocker (Bbl) is frequently avoided because of fear of depression of left ventricular function. However, it remains unclear whether antihypertensive treatment with a Bbl is associated with increased risk of cardiovascular events in patients with asymptomatic mild to moderate AS.Methods and ResultsWe did a post hoc analysis of 1873 asymptomatic patients with mild to moderate AS and preserved left ventricular ejection fraction in the SEAS (Simvastatin and Ezetimibe in Aortic Stenosis) study. Propensity‐matched Cox regression and competing risk analyses were used to assess risk ratios for all‐cause mortality, sudden cardiac death, and cardiovascular death. A total of 932 (50%) patients received Bbl at baseline. During a median follow‐up of 4.3±0.9 years, 545 underwent aortic valve replacement, and 205 died; of those, 101 were cardiovascular deaths, including 40 sudden cardiovascular deaths. In adjusted analyses, Bbl use was associated with lower risk of all‐cause mortality (hazard ratio 0.5, 95% confidence interval 0.3‐0.7, P<0.001), cardiovascular death (hazard ratio 0.4, 95% confidence interval 0.2‐0.7, P<0.001), and sudden cardiac death (hazard ratio 0.2, 95% confidence interval 0.1‐0.6, P=0.004). This was confirmed in competing risk analyses (all P<0.004). No interaction was detected with AS severity (all P>0.1).ConclusionsIn post hoc analyses Bbl therapy did not increase the risk of all‐cause mortality, sudden cardiac death, or cardiovascular death in patients with asymptomatic mild to moderate AS. A prospective study may be warranted to determine if Bbl therapy is in fact beneficial.Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00092677.

Lower Transaortic Flow Rate Is Associated With Increased Mortality in Aortic Valve Stenosis

ObjectivesThe association of transaortic flow rate (FR) with outcomes was tested in 1,661 patients with aortic valve stenosis (AS) in the SEAS (Simvastatin and Ezetimibe in Aortic Stenosis) study. BackgroundLow transaortic flow may complicate grading of AS. However, the association of lower transaortic FR with adverse outcomes has not been reported. MethodsTransaortic FR was calculated from Doppler-derived stroke volume in milliliters divided by systolic ejection time in seconds and considered low if <200 ml/s. The association of transaortic FR with cardiovascular and all-cause mortality during 4.3-year follow-up was tested in time-varying Cox regression models run with aortic valve replacement as competing risk and reported as hazard ratio (HR) and 95% confidence interval (CI). ResultsLow transaortic FR was found in 21% of patients at baseline. Patients with low transaortic FR were older, had lower systemic arterial compliance and left ventricular mass, and included more women and patients with inconsistently graded severe AS and low stroke volume index (<35 ml/m2) (p < 0.01 for all). Low in-study transaortic FR was associated with higher rates of cardiovascular and all-cause mortality both in unadjusted analyses (HR: 2.56 [95% CI: 1.62 to 4.04]; and HR: 1.93 [95% CI: 1.35 to 2.75], respectively; p < 0.001 for both) and after adjustment for age, sex, randomized study treatment, hypertension, stroke volume index <35 ml/m2, LV mass, and mean aortic gradient (HR: 2.79 [95% CI: 1.65 to 4.73]; and HR: 1.90 [95% CI: 1.27 to 2.84], respectively; p < 0.01 for both). ConclusionsIn patients with AS without known cardiovascular disease or diabetes, low transaortic FR was independently associated with higher rates of cardiovascular and all-cause mortality. (An Investigational Drug on Clinical Outcomes in Patients With Aortic Stenosis (Narrowing of the Major Blood Vessel of the Heart) (MK-0653A-043 AM4); NCT00092677)

SuPAR Predicts Cardiovascular Events and Mortality in Patients With Asymptomatic Aortic Stenosis

BackgroundSoluble urokinase plasminogen activator receptor (suPAR) is an inflammatory marker associated with subclinical cardiovascular damage and cardiovascular events. Whether suPAR is of prognostic value in asymptomatic patients with aortic stenosis (AS) remains unknown. MethodsPlasma suPAR levels were measured in 1503 patients with a mean age of 68 years who were recruited in the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study. Cox regression analysis was performed to evaluate associations between suPAR and the composite end points of ischemic cardiovascular events (ICEs), aortic valve events (AVEs), cardiovascular and all-cause mortality after adjusting for traditional cardiovascular risk factors, and allocation to treatment. ResultsThe multivariate adjusted hazard ratio (HR) (95% confidence interval [CI]) per unit log2 ng/mL increase in suPAR was HR, 1.5; 95% CI, 1.2-1.9; P = 0.002 for ICEs; HR, 1.2; 95% CI, 0.9-1.5; P = 0.071) for AVEs; HR, 2.0; 95% CI, 1.2-3.3; P = 0.007) for cardiovascular mortality, and HR, 2.0; 95% CI, 1.4-2.9; P < 0.001 for all-cause mortality. ConclusionsIn patients with mild-moderate AS, suPAR is independently associated with the incidence of ICEs, cardiovascular mortality, and all-cause mortality.

High sensitivity C reactive protein as a prognostic marker in patients with mild to moderate aortic valve stenosis during lipid-lowering treatment: an SEAS substudy

AimsTo assess the prognostic importance of high-sensitive C reactive protein (hsCRP) in patients with mild to moderate aortic valve stenosis during placebo or simvastatin/ezetimibe treatment in Simvastatin and Ezetimibe in...

Ezetimibe: rescued by randomization (clinical and mendelian).

Since its market launch in the early 2000s, ezetimibe has had a stormy history of acceptance and use by the clinical community. Ezetimibe’s initial approval by regulatory bodies was based primarily on its low side effect profile together with its ability to consistently reduce low-density lipoprotein (LDL) cholesterol by ≈20% either as monotherapy or as an additive to statin therapy. Notably, approval was granted despite the absence from ezetimibe’s portfolio of studies, demonstrating reductions in hard clinical cardiovascular outcomes, such as myocardial infarction or stroke. By 2006, ezetimibe accounted for >15% of all prescriptions for lipid-lowering medications in the United States,1 reflecting that era’s stout faith in the reliability of LDL cholesterol as a surrogate marker for clinical end points, together with practitioners’ positive real-world experiences with ezetimibe’s biochemical efficacy and good tolerability. It was tacitly anticipated that the pending cardiovascular outcome studies would be positive, eventually vindicating the early confidence that clinicians placed in the drug. However, the waters grew rough for ezetimibe in 2008. First, the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) trial conducted for 24 months in 720 patients with familial hypercholesterolemia showed that combined therapy with ezetimibe and simvastatin did not significantly change carotid intima–media thickness when compared with simvastatin alone, despite decreased levels of LDL cholesterol.2 Next, the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial conducted for 52 months in 1873 elderly nondiabetic patients with aortic stenosis showed that ezetimibe plus simvastatin did not reduce the composite outcome of combined aortic valve events and ischemic events.3 To add insult to injury, the 2009 Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol-6-HDL and LDL Treatment Strategies in Atherosclerosis (ARBITER 6-HALTS) study demonstrated that when combined with a statin, extended-release niacin caused a significant …

Resting heart rate and risk of adverse cardiovascular outcomes in asymptomatic aortic stenosis: The SEAS study

BackgroundAn elevated resting heart rate (RHR) may be an early sign of cardiac failure, but its prognostic value during watchful waiting in asymptomatic aortic stenosis (AS) is largely unknown. MethodsRHR was determined by annual ECGs in the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study of asymptomatic mild-to-moderate AS patients. Primary endpoint in this substudy was major cardiovascular events (MCEs) and secondary outcomes its individual components. Multivariable Cox-models using serially-measured RHR were used to examine the prognostic impact of RHR per se. Results1563 patients were followed for a mean of 4.3years (6751 patient-years of follow-up), 553 (35%) MCEs occurred, 10% (n=151) died, including 75 cardiovascular deaths. In multivariable analysis, baseline RHR was independently associated with MCEs (HR 1.1 per 10min−1 faster, 95% CI: 1.0–1.3) and cardiovascular mortality (HR 1.3 per 10min−1 faster, 95% CI: 1.0–1.7, both p≤0.03). Updating RHR with annual in-study reexaminations, time-varying RHR was highly associated with excess MCEs (HR 1.1 per 10min−1 faster, 95% CI: 1.1–1.3) and cardiovascular mortality (HR 1.4 per 10min−1 faster, 95% CI: 1.2–1.7, both p≤0.006). The association of RHR with MCEs and cardiovascular mortality was not dependent on atrial fibrillation status (both p≥0.06 for interaction). ConclusionsRHR is independently associated with MCEs and cardiovascular death in asymptomatic AS (Clinicaltrials.gov; unique identifier NCT00092677).

Velocity ratio predicts outcomes in patients with low gradient severe aortic stenosis and preserved EF

ObjectiveTo evaluate the usefulness of velocity ratio (VR) in patients with low gradient severe aortic stenosis (LGSAS) and preserved EF.BackgroundLGSAS despite preserved EF represents a clinically challenging entity. Reliance on...

Incidence of Cancer and Mortality in Patients from the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) Trial

The Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) clinical trial, including 1,873 patients found an increased risk for cancer with lipid-lowering therapy with ezetimibe/simvastatin 10/40 mg/day, relative to placebo. In a registry-based follow-up study over 21 months from the conclusion of the SEAS trial, new incident cancer and total mortality were investigated in the SEAS study cohort from Denmark, Finland, Norway, Sweden, and the United Kingdom. Among 1,359 subjects eligible for follow-up (73% of the original total cohort), 1,194 had no history of cancer (primary follow-up cohort). New cancers and deaths were identified in the national cancer and mortality registries and classified by an Expert Review Committee. Data were analyzed using Cox proportional-hazards models of new cancers and mortality during follow-up according to treatment group assigned in the SEAS base study and with age, gender, smoking history, and previous cancers as covariates. The primary follow-up cohort had 12 patients with new cancers in the ezetimibe/simvastatin group and 22 in the placebo group (hazard ratio 0.55, 95% confidence interval 0.27 to 1.11), indicating no significant difference between the treatment groups. During follow-up, 43 patients assigned to ezetimibe/simvastatin and 33 assigned to placebo died (hazard ratio 1.29, 95% confidence interval 0.82 to 2.03). In conclusion, in this registry-based observational follow-up study of the original SEAS study patient population, treatment with ezetimibe/simvastatin was not associated with an increased risk for cancer or mortality in the 21-month period after the completion of the original SEAS study.

Stroke in patients with aortic stenosis: the Simvastatin and Ezetimibe in Aortic Stenosis study.

There are limited data on risk stratification of stroke in aortic stenosis. This study examined predictors of stroke in aortic stenosis, the prognostic implications of stroke, and how aortic valve replacement (AVR) with or without concomitant coronary artery bypass grafting influenced the predicted outcomes. Patients with mild-to-moderate aortic stenosis enrolled in the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study. Diabetes mellitus, known atherosclerotic disease, and oral anticoagulation were exclusion criteria. Ischemic stroke was the primary end point, and poststroke survival a secondary outcome. Cox models treating AVR as a time-varying covariate were adjusted for atrial fibrillation and congestive heart failure, hypertension, age≥75 years, diabetes mellitus, stroke/transient ischemic attack, vascular disease, age 65-74 years and female sex (CHA2DS2-VASc) scores. One thousand five hundred nine patients were followed for 4.3±0.8 years (6529 patient-years). Rates of stroke were 5.6 versus 21.8 per 1000 patient-years pre- and post-AVR; 429 (28%) underwent AVR and 139 (9%) died. Atrial fibrillation (hazard ratio [HR], 2.7; 95% confidence interval [CI], 1.1-6.6), CHA2DS2-VASc score (HR 1.4 per unit; 95% CI, 1.1-1.8), diastolic blood pressure (HR, 1.4 per 10 mm Hg; 95% CI, 1.1-1.8), and AVR with concomitant coronary artery bypass grafting (HR, 3.2; 95% CI, 1.4-7.2, all P≤0.026) were independently associated with stroke. Incident stroke predicted death (HR, 8.1; 95% CI, 4.7-14.0; P<0.001). In patients with aortic stenosis not prescribed oral anticoagulation, atrial fibrillation, AVR with concomitant coronary artery bypass grafting, and CHA2DS2-VASc score were the major predictors of stroke. Incident stroke was strongly associated with mortality. http://www.clinicaltrials.gov. Unique identifier: NCT00092677.