Explained variation and degrees of necessity and of sufficiency for competing risks survival data.

In this contribution, the Schemper-Henderson measure of explained variation for survival outcomes is extended to accommodate competing events (CEs) in addition to events of interest. The extension is achieved by moving from the unconditional and conditional survival functions of the original measure to unconditional and conditional cumulative incidence functions, the latter obtained, for example, from Fine and Gray models. In the absence of CEs, the original measure is obtained as a special case. We define explained variation on the population level and provide two different types of estimates. Recently, the authors have achieved a multiplicative decomposition of explained variation into degrees of necessity and degrees of sufficiency. These measures are also extended to the case of competing risks survival data. A SAS macro and an R function are provided to facilitate application. Interesting empirical properties of the measures are explored on the population level and by an extensive simulation study. Advantages of the approach are exemplified by an Austrian study of breast cancer with a high proportion of CEs.

Degrees of necessity and of sufficiency: Further results and extensions, with an application to covid-19 mortality in Austria.

The purpose of this paper is to extend to ordinal and nominal outcomes the measures of degree of necessity and of sufficiency defined by the authors for dichotomous and survival outcomes in a previous paper. A cause, represented by certain values of prognostic factors, is considered necessary for an event if, without the cause, the event cannot develop. It is considered sufficient for an event if the event is unavoidable in the presence of the cause. The degrees of necessity and sufficiency, ranging from zero to one, are simple, intuitive functions of unconditional and conditional probabilities of an event such as disease or death. These probabilities often will be derived from logistic regression models; the measures, however, do not require any particular model. In addition, we study in detail the relationship between the proposed measures and the related explained variation summary for dichotomous outcomes, which are the common root for the developments for ordinal, nominal, and survival outcomes. We introduce and analyze the Austrian covid-19 data, with the aim of quantifying effects of age and other potentially prognostic factors on covid-19 mortality. This is achieved by standard regression methods but also in terms of the newly proposed measures. It is shown how they complement the toolbox of prognostic factor studies, in particular when comparing the importance of prognostic factors of different types. While the full model's degree of necessity is extremely high (0.933), its low degree of sufficiency (0.179) is responsible for the low proportion of explained variation (0.193).

Quantifying degrees of necessity and of sufficiency in cause-effect relationships with dichotomous and survival outcomes.

We suggest measures to quantify the degrees of necessity and of sufficiency of prognostic factors for dichotomous and for survival outcomes. A cause, represented by certain values of prognostic factors, is considered necessary for an event if, without the cause, the event cannot develop. It is considered sufficient for an event if the event is unavoidable in the presence of the cause. Necessity and sufficiency can be seen as the two faces of causation, and this symmetry and equal relevance are reflected by the suggested measures. The measures provide an approximate, in some cases an exact, multiplicative decomposition of explained variation as defined by Schemper and Henderson for censored survival and for dichotomous outcomes. The measures, ranging from zero to one, are simple, intuitive functions of unconditional and conditional probabilities of an event such as disease or death. These probabilities often will be derived from logistic or Cox regression models; the measures, however, do not require any particular model. The measures of the degree of necessity implicitly generalize the established attributable fraction or risk for dichotomous prognostic factors and dichotomous outcomes to continuous prognostic factors and to survival outcomes. In a setting with multiple prognostic factors, they provide marginal and partial results akin to marginal and partial odds and hazard ratios from multiple logistic and Cox regression. Properties of the measures are explored by an extensive simulation study. Their application is demonstrated by three typical real data examples.

FVIII-binding IgG modulates FVIII half-life in patients with severe and moderate hemophilia A without inhibitors.

The substantial variability in pharmacokinetic parameters in hemophilia patients A poses a challenge for optimal treatment with factor VIII (FVIII) products. We investigated the effect of FVIII-specific immunoglobulin G (IgG) on FVIII half-life in a cohort of 42 adult patients with severe and moderate hemophilia A without inhibitors. Fifteen (35.7%) of 42 patients tested positive for FVIII-binding IgG with titers ≥1:20 in the initial antibody screen, 9 of these 15 patients had FVIII-specific antibodies with titers ≥1:40, mostly low-to-moderate-affinity IgG1 and IgG3, and 1 had high-affinity IgG4 and later developed low-titer FVIII inhibitors. His brother with low-to-moderate-affinity IgG1 and IgG3 also later developed low-titer FVIII inhibitors. The presence of FVIII-specific IgG subclass titer ≥1:40 antibodies was significantly associated with shorter FVIII half-life (median, 7.8 hours [interquartile range, 6.6-9.2 hours]) vs 10.4 hours [interquartile range, 8.9-13.8 hours]); the regression coefficient adjusted for log age and log von Willebrand factor (VWF) antigen was -0.32 (P = .004), accounting for 16.9% of the observed variability of FVIII half-life in our cohort. Our data indicate a significant contribution of non-neutralizing FVIII-specific IgG to FVIII half-life reduction in hemophilia A patients. Thus, screening for FVIII-specific IgG could be beneficial in tailoring FVIII prophylactic regimens.

Explained variation in shared frailty models.

Explained variation measures the relative gain in predictive accuracy when prediction based on prognostic factors replaces unconditional prediction. The factors may be measured on different scales or may be of different types (dichotomous, qualitative, or continuous). Thus, explained variation permits to establish a ranking of the importance of factors, even if predictive accuracy is too low to be helpful in clinical practice. In this contribution, the explained variation measure by Schemper and Henderson (2000) is extended to accommodate random factors, such as center effects in multicenter studies. This permits a direct comparison of the importance of centers and of other prognostic factors. We develop this extension for a shared frailty Cox model and provide an SAS macro and an R function to facilitate its application. Interesting empirical properties of the variation explained by a random factor are explored by a Monte Carlo study. Advantages of the approach are exemplified by an Austrian multicenter study of colon cancer.

Weight and body mass index (BMI): current data for Austrian boys and girls aged 4 to under 19 years.

BACKGROUND: BMI reference charts are widely used to diagnose overweight, obesity and underweight in children and adolescents. AIM: To provide up-to-date national reference values for Austria. METHODS: A cross-sectional sample of over 14 500 children and adolescents (4-19 years) stratified by provinces according to age- and sex-specific population proportions was drawn via schooling institutions (kindergartens, schools and vocational colleges). The generalized additive models for location, scale and shape were used for a flexible estimation of percentile curves. RESULTS: Austrian boys and girls have higher average weight compared with previous prevalence data. BMI centiles matching BMI values at age 18 years, which are used for defining thinness, overweight and obesity in adults, were calculated. In Austria, using reference values as thresholds, ∼18% of boys and 12% of girls are overweight (with thresholds passing through BMI 25.00-29.99 kg/m(2) in adults) and 5% of boys and 3% of girls are obese (with thresholds passing through BMI ≥30.00 kg/m(2) in adults). CONCLUSION: Overweight and obesity are common in Austria and their prevalence is increasing (using the same IOTF reference for international comparison). Up-to-date national BMI reference values are provided to classify children and adolescents according to the proposed overweight and obesity thresholds.

Estimating the correlation of bivariate failure times under censoring.

The analysis of correlations within pairs of survival times is of interest to many research topics in medicine, such as the correlation of survival-type endpoints of twins, the correlation of times till failure in paired organs, or the correlation of survival time with a surrogate endpoint. The dependence of such times is assumed monotonic and thus quantification by rank correlation coefficients appropriate. The typical censoring of such times requires more involved methods of estimation and inference as have been developed in recent years. The paper focuses on semiparametric approaches, and in particular on the normal copula-based estimation of Spearman correlation coefficients. The copula approach, often presented for a mathematically inclined readership, is reviewed from the viewpoint of an applied statistician. As an alternative to the maximum likelihood methodology for the normal copula approach (NCE) we introduce an iterative multiple imputation (IMI) method which requires only about 0.05% of the computing time of NCE, without sacrificing statistical performance. For IMI, survival probabilities at death or censoring times are first transformed to normal deviates. Then, those deviates that relate to censored times are iteratively augmented, by using conditional multiple imputation, until convergence is obtained for the normal scores rank correlation, which is similar to Spearman's rank correlation. Statistical properties of NCE and IMI are compared by means of a Monte Carlo study and by means of three real data sets, which also give an impression of the typical range of applications, and of their problems.

Austrian height and body proportion references for children aged 4 to under 19 years.

BACKGROUND: Previous studies have demonstrated differences between national and the WHO reference curves in children older than 5 years. Moreover, reference curves for body proportions (sitting height, subischial leg length and their ratio) based on state-of-the-art statistics are not available. AIM: To develop reference curves for height and body proportions for use in Austria and compare the curves with WHO reference curves. To estimate and statistically investigate extreme percentiles. SUBJECTS AND METHODS: A sample of ∼14 500 children between 4-19 years of age was drawn via schooling institutions, stratified by provinces according to age- and sex-specific population proportions. GAMLSS models were used for a flexible estimation of percentile curves. RESULTS AND CONCLUSIONS: After the age of 5 years national reference curves are more suitable than the WHO reference curves for clinical use in Austria. These height curves are very similar to the German reference curves published recently. Therefore, these reference curves for criteria of body proportions are recommended for use in other populations. Further validation studies are needed to establish whether the recently recommended -2.5 and -3.0 SD for height are a sensitive and specific cut-off in the diagnostic work-up for children with a suspected growth disorder using this new Austrian height chart.

Evaluation of diagnostic and treatment approaches towards acute dyspnea in a palliative care setting among medical students at the University of Vienna.

BACKGROUND: Dyspnea is common in advanced cancer patients with opioids as first line treatment. OBJECTIVES: To evaluate the level of knowledge about diagnosis and treatment of dyspnea in palliative care patients among 4th year students. METHODS: A case report was distributed to the students describing acute dyspnea in a lung cancer patient. Students were asked to rank their diagnosis and treatment options by importance. RESULTS: 633 medical students in their 4th year attended a seminar about palliative care. Of these, 423 (77%) completed the case report. The most frequent diagnostic option was measuring patient's oxygen saturation (n = 388), followed by auscultation (n = 339). As treatment options, students chose the delivery of oxygen (n = 393) as most important. The application of opioids was suggested by a total of 138 students. CONCLUSION: Although students did not have practical skills in treating advanced cancer patients with acute dyspnea, 32.6% would suggest an opioid as treatment option.

Natural history of very severe aortic stenosis.

BACKGROUND: We sought to assess the outcome of asymptomatic patients with very severe aortic stenosis. METHODS AND RESULTS: We prospectively followed 116 consecutive asymptomatic patients (57 women; age, 67 + or - 16 years) with very severe isolated aortic stenosis defined by a peak aortic jet velocity (AV-Vel) > or = 5.0 m/s (average AV-Vel, 5.37 + or - 0.35 m/s; valve area, 0.63 + or - 0.12 cm(2)). During a median follow-up of 41 months (interquartile range, 26 to 63 months), 96 events occurred (indication for aortic valve replacement, 90; cardiac deaths, 6). Event-free survival was 64%, 36%, 25%, 12%, and 3% at 1, 2, 3, 4, and 6 years, respectively. AV-Vel but not aortic valve area was shown to independently affect event-free survival. Patients with an AV-Vel > or = 5.5 m/s had an event-free survival of 44%, 25%, 11%, and 4% at 1, 2, 3, and 4 years, respectively, compared with 76%, 43%, 33%, and 17% for patients with an AV-Vel between 5.0 and 5.5 m/s (P<0.0001). Six cardiac deaths occurred in previously asymptomatic patients (sudden death, 1; congestive heart failure, 4; myocardial infarction, 1). Patients with an initial AV-Vel > or = 5.5 m/s had a higher likelihood (52%) of severe symptom onset (New York Heart Association or Canadian Cardiovascular Society class >II) than those with an AV-Vel between 5.0 and 5.5 m/s (27%; P=0.03). CONCLUSIONS: Despite being asymptomatic, patients with very severe aortic stenosis have a poor prognosis with a high event rate and a risk of rapid functional deterioration. Early elective valve replacement surgery should therefore be considered in these patients.

Gene selection in microarray survival studies under possibly non-proportional hazards.

MOTIVATION: Univariate Cox regression (COX) is often used to select genes possibly linked to survival. With non-proportional hazards (NPH), COX could lead to under- or over-estimation of effects. The effect size measure c=P(T(1)

Computed tomography-based evaluation of template (NobelGuide™)-guided implant positions: a prospective radiological study.

OBJECTIVES: This prospective study was intended to evaluate the overall deviation in a clinical treatment setting to provide for quantification of the potential impairment of treatment safety and reliability with computer-assisted, template-guided transgingival implantation. MATERIAL AND METHODS: The patient population enrolled (male/female=10/8) presented with partially dentate and edentulous maxillae and mandibles. Overall, 86 implants were placed by two experienced dental surgeons strictly following the NobelGuide™ protocol for template-guided implantation. All patients had a postoperative computed tomography (CT) with identical settings to the preoperative examination. Using the triple scan technique, pre- and postoperative CT data were merged in the Procera planning software, a newly developed procedure - initially presented in 2007 allowing measurement of the deviations at implant shoulder and apex. RESULTS: The deviations measured were an average of 0.43 mm (bucco-lingual), 0.46 mm (mesio-distal) and 0.53 mm (depth) at the level of the implant shoulder and slightly higher at the implant apex with an average of 0.7 mm (bucco-lingual), 0.63 mm (mesio-distal) and 0.52 mm (depth). The maximum deviation of 2.02 mm was encountered in the corono-apical direction. Significantly lower deviations were seen for implants in the anterior region vs. the posterior tooth region (P<0.01, 0.31 vs. 0.5 mm), and deviations were also significantly lower in the mandible than in the maxilla (P=0.04, 0.36 vs. 0.45 mm) in the mesio-distal direction. Moreover, a significant correlation between deviation and mucosal thickness was seen and a learning effect was found over the time period of performance of the surgical procedures. CONCLUSION: Template-guided implantation will ensure reliable transfer of preoperative computer-assisted planning into surgical practice. With regard to the required verification of treatment reliability of an implantation system with flapless access, all maximum deviations measured in this clinical study were within the safety margins recommended by the planning software.

The estimation of average hazard ratios by weighted Cox regression.

Often the effect of at least one of the prognostic factors in a Cox regression model changes over time, which violates the proportional hazards assumption of this model. As a consequence, the average hazard ratio for such a prognostic factor is under- or overestimated. While there are several methods to appropriately cope with non-proportional hazards, in particular by including parameters for time-dependent effects, weighted estimation in Cox regression is a parsimonious alternative without additional parameters. The methodology, which extends the weighted k-sample logrank tests of the Tarone-Ware scheme to models with multiple, binary and continuous covariates, has been introduced in the nineties of the last century and is further developed and re-evaluated in this contribution. The notion of an average hazard ratio is defined and its connection to the effect size measure P(X

High-density lipoprotein and the risk of recurrent venous thromboembolism.

BACKGROUND: High-density lipoprotein (HDL) protects against arterial atherothrombosis, but it is unknown whether it protects against recurrent venous thromboembolism. METHODS AND RESULTS: We studied 772 patients after a first spontaneous venous thromboembolism (average follow-up 48 months) and recorded the end point of symptomatic recurrent venous thromboembolism, which developed in 100 of the 772 patients. The relationship between plasma lipoprotein parameters and recurrence was evaluated. Plasma apolipoproteins AI and B were measured by immunoassays for all subjects. Compared with those without recurrence, patients with recurrence had lower mean (+/-SD) levels of apolipoprotein AI (1.12+/-0.22 versus 1.23+/-0.27 mg/mL, P<0.001) but similar apolipoprotein B levels. The relative risk of recurrence was 0.87 (95% CI, 0.80 to 0.94) for each increase of 0.1 mg/mL in plasma apolipoprotein AI. Compared with patients with apolipoprotein AI levels in the lowest tertile (<1.07 mg/mL), the relative risk of recurrence was 0.46 (95% CI, 0.27 to 0.77) for the highest-tertile patients (apolipoprotein AI >1.30 mg/mL) and 0.78 (95% CI, 0.50 to 1.22) for midtertile patients (apolipoprotein AI of 1.07 to 1.30 mg/mL). Using nuclear magnetic resonance, we determined the levels of 10 major lipoprotein subclasses and HDL cholesterol for 71 patients with recurrence and 142 matched patients without recurrence. We found a strong trend for association between recurrence and low levels of HDL particles and HDL cholesterol. CONCLUSIONS: Patients with high levels of apolipoprotein AI and HDL have a decreased risk of recurrent venous thromboembolism.

Outcome of watchful waiting in asymptomatic severe mitral regurgitation.

BACKGROUND: The management of asymptomatic severe mitral regurgitation remains controversial. The aim of this study was to evaluate the outcome of a watchful waiting strategy in which patients are referred to surgery when symptoms occur or when asymptomatic patients develop left ventricular (LV) enlargement, LV dysfunction, pulmonary hypertension, or recurrent atrial fibrillation. METHODS AND RESULTS: A total of 132 consecutive asymptomatic patients (age 55+/-15 years, 49 female) with severe degenerative mitral regurgitation (flail leaflet or valve prolapse) were prospectively followed up for 62+/-26 months. Patients underwent serial clinical and echocardiographic examinations and were referred for surgery when the criteria mentioned above were fulfilled. Overall survival was not statistically different from expected survival either in the total group or in the subgroup of patients with flail leaflet. Eight deaths were observed. Thirty-eight patients developed criteria for surgery (symptoms, 24; LV criteria, 9; pulmonary hypertension or atrial fibrillation, 5). Survival free of any indication for surgery was 92+/-2% at 2 years, 78+/-4% at 4 years, 65+/-5% at 6 years, and 55+/-6% at 8 years. Patients with flail leaflet tended to develop criteria for surgery slightly but not significantly earlier. There was no operative mortality. Postoperative outcome was good with regard to survival, symptomatic status, and postoperative LV function. CONCLUSIONS: Asymptomatic patients with severe degenerative mitral regurgitation can be safely followed up until either symptoms occur or currently recommended cutoff values for LV size, LV function, or pulmonary hypertension are reached. This management strategy is associated with good perioperative and postoperative outcome but requires careful follow-up.

Gene expression profiling: does it add predictive accuracy to clinical characteristics in cancer prognosis?

It is widely accepted that gene expression classifiers need to be externally validated by showing that they predict the outcome well enough on other patients than those from whose data the classifier was derived. Unfortunately, the gain in predictive accuracy by the classifier as compared to established clinical prognostic factors often is not quantified. Our objective is to illustrate the application of appropriate statistical measures for this purpose. In order to compare the predictive accuracies of a model based on the clinical factors only and of a model based on the clinical factors plus the gene classifier, we compute the decrease in predictive inaccuracy and the proportion of explained variation. These measures have been obtained for three studies of published gene classifiers: for survival of lymphoma patients, for survival of breast cancer patients and for the diagnosis of lymph node metastases in head and neck cancer. For the three studies our results indicate varying and possibly small added explained variation and predictive accuracy due to gene classifiers. Therefore, the gain of future gene classifiers should routinely be demonstrated by appropriate statistical measures, such as the ones we recommend.

Hypertrophy of the breast: a problem of beauty or health?

BACKGROUND: Despite the complex health burden for women with breast hypertrophy, medical directors of health insurance companies are not convinced that this procedure is of medical benefit for patients. Therefore, coverage of cost by the health insurance companies is no longer guaranteed. The purpose of this study is to evaluate the influence of breast weight on the physical and psychological morbidity of women and to prove the medical necessity of reduction mammaplasty. METHODS: We performed a cohort study of 50 women with various breast sizes, a mean age of 28 years (range 20-40 years), and a body mass index (BMI) <25. Breast weight was measured, the spine was investigated by magnetic resonance imaging (MRI), and a spine score of clinical symptoms was assessed. The Beck Depression Inventory (BDI) was used to evaluate psychological impairment. Pathological findings have been correlated with breast weight, and the risk of developing a morphological or psychological disorder independence of the breast weight was calculated. RESULTS: The incidence of degenerative spine disorders and the extent of depressive symptoms are correlated with increasing breast weight. CONCLUSIONS: The data show that high breast weight has a negative influence on the physical and psychological morbidity of women. This objective evidence in support of the medical necessity of reduction mammaplasty should guide managed care organizations' methods for determining coverage for reduction mammaplasty.

Asymptomatic Severe Aortic Stenosis in the Elderly.

OBJECTIVES: This study sought to assess the natural history and optimal timing of surgery in elderly patients with severe asymptomatic aortic stenosis (AS). BACKGROUND: AS is increasingly diagnosed in an aging population, and large numbers of elderly patients are undergoing aortic valve procedures. However, the average age of patients represented in most natural history studies on AS is between 60 and 70 years. METHODS: A total of 103 consecutive patients >70 years of age (51 female; mean age 77 ± 5 years) with asymptomatic severe AS (peak aortic jet velocity [AV-Vel] 4.7 ± 0.6 m/s) were prospectively followed. RESULTS: During follow-up, 91 events occurred, including an indication for aortic valve replacement in 82 patients and cardiac deaths in 9, respectively. Event-free survival was 73%, 43%, 23%, and 16% at 1, 2, 3, and 4 years, respectively. Physical mobility was impaired in 29% of the patients, and symptom onset was severe (New York Heart Association functional class ≥III) in 43% of those who developed symptoms. Patients with AV-Vel ≥5.0 m/s had event-free survival rates of 21% and 6% at 2 and 4 years, respectively, compared with 57% and 23% for patients with AV-Vel <5.0 m/s (p < 0.001). Seventy-one patients underwent aortic valve replacement, and post-operative survival was 89% and 77% after 1 and 3 years, respectively. CONCLUSIONS: In elderly patients with severe but asymptomatic AS, mild symptoms may be difficult to detect, particularly when mobility is impaired and severe symptom onset is common, warranting close clinical follow-up. Furthermore, a very high event rate can be expected, and cardiac deaths are not infrequent. Thus, elective aortic valve procedures may be considered in selected elderly patients at low procedural risk.

Role of a heart valve clinic programme in the management of patients with aortic stenosis.

AIMS: We sought to assess the efficacy of a heart valve clinic (HVC) follow-up programme for patients with severe aortic stenosis (AS). METHODS AND RESULTS: Three hundred and eighty-eight consecutive patients with AS (age 71 ± 10 years; aortic-jet velocity 5.1 ± 0.6 m/s) and an indication for aortic valve replacement (AVR) were included. Of these, 290 patients presented with an indication for surgery at their first visit at the HVC and 98 asymptomatic patients who had been enrolled in an HVC monitoring programme developed indications for surgery during follow-up. Time to symptom detection was significantly longer in patients that presented with symptoms at baseline (352 ± 471 days) than in patients followed in the HVC (76 ± 75 days, P < 0.001). Despite being educated to recognize and promptly report new symptoms, 77 of the 98 patients in the HVC programme waited until the next scheduled consultation to report them. Severe symptom onset (NYHA or CCS Class ≥III) was present in 61% of patients being symptomatic at the initial visit and in 34% of patients in the HVC programme (P < 0.001). CONCLUSION: Delays in referral and symptom reporting as well as symptom denial are common in patients with AS. These findings support the concept of risk stratification to identify patients who may benefit from elective surgery. A structured HVC programme results in the detection of symptoms at an earlier and less severe stage and thus in an optimized timing of surgery.

Statins but not angiotensin-converting enzyme inhibitors delay progression of aortic stenosis.

BACKGROUND: Recently, statins and angiotensin-converting enzyme inhibitors (ACEIs) have been shown to slow aortic valve calcium accumulation. Although several studies also suggest that statins may reduce the hemodynamic progression of aortic stenosis (AS), no data are available for ACEIs or the combination of both. METHODS AND RESULTS: A total of 211 consecutive patients (aged 70+/-10 years, 104 females) with native AS, defined by a peak velocity >2.5 m/s (valve area 0.84+/-0.23 cm(2), mean gradient 42+/-19 mm Hg), with normal left ventricular function and no other significant valvular lesion who were examined between 2000 and 2002 and who had 2 echocardiograms separated by at least 6 months were included. Of these, 102 patients were treated with ACEIs, 50 patients received statins, and 32 patients received both. Hemodynamic progression of AS was assessed and related to medical treatment. Annualized increase in peak aortic jet velocity for the entire study group was 0.32+/-0.44 m x s(-1) x y(-1). Progression was significantly lower in patients treated with statins (0.10+/-0.41 m x s(-1) x y(-1)) than in those who were not (0.39+/-0.42 m x s(-1) x y(-1); P<0.0001). This effect was observed both in mild-to-moderate and severe AS. ACEI use, however, did not significantly affect hemodynamic progression (P=0.29). Furthermore, ACEIs had no additional effect on AS progression when given in combination with statins (0.11+/-0.42 versus 0.08+/-0.43 m x s(-1) x y(-1) for combination versus statin only; P=0.81). Cholesterol levels did not correlate with hemodynamic progression either in the group receiving statins or in the group that did not. CONCLUSIONS: ACEIs do not appear to slow AS progression. However, statins significantly reduce the hemodynamic progression of both mild-to-moderate and severe AS, an effect that may not be related to cholesterol lowering.