Effects of Rosuvastatin on Progression of Stenosis in Adult Patients With Congenital Aortic Stenosis (PROCAS Trial)

doi:10.1016/j.amjcard.2011.03.032

The American Journal of Cardiology

Volume 108, Issue 2, 15 July 2011, Pages 265-271

https://doi.org/10.1016/j.amjcard.2011.03.032 Get rights and content

Recent trials have failed to show that statin therapy halts the progression of calcific aortic stenosis (AS). We hypothesized that statin therapy in younger patients with congenital AS would be more beneficial, because the valve is less calcified. In the present double-blind, placebo-controlled trial, 63 patients with congenital AS (age 18 to 45 years) were randomly assigned to receive either 10 mg of rosuvastatin daily (n = 30) or matched placebo (n = 33). The primary end point was the progression of peak aortic valve velocity. The secondary end points were temporal changes in the left ventricular mass, ascending aortic diameter, and N-terminal pro-brain natriuretic peptide (NT-proBNP). The median follow-up was 2.4 years (interquartile range 1.9 to 3.0). The mean increase in peak velocity was 0.05 ± 0.21 m/s annually in the rosuvastatin group and 0.09 ± 0.24 m/s annually in the placebo group (p = 0.435). The annualized change in the ascending aorta diameter (0.4 ± 1.7 mm with rosuvastatin vs 0.5 ± 1.6 mm with placebo; p = 0.826) and left ventricular mass (1.1 ± 15.8 g with rosuvastatin vs −3.7 ± 30.9 g with placebo; p = 0.476) were not significantly different between the 2 groups. Within the statin group, the NT-proBNP level was 50 pg/ml (range 19 to 98) at baseline and 21 pg/ml (interquartile range 12 to 65) at follow-up (p = 0.638). NT-proBNP increased from 40 pg/ml (interquartile range 20 to 92) to 56 pg/ml (range 26 to 130) within the placebo group (p = 0.008). In conclusion, lipid-lowering therapy with rosuvastatin 10 mg did not reduce the progression of congenital AS in asymptomatic young adult patients. Interestingly, statins halted the increase in NT-proBNP, suggesting a potential positive effect of statins on cardiac function in young patients with congenital AS.

Section snippets

Methods

The PROCAS study was a prospective, double-blind, randomized, placebo-controlled, multicenter trial that evaluated the effect of rosuvastatin on the progression of asymptomatic congenital AS in young adult patients. The study was conducted at 6 tertiary referral centers for congenital heart disease in The Netherlands and Belgium. Enrollment occurred from December 2005 to December 2007. The intended follow-up duration was 3 years. Annually, patients underwent transthoracic echocardiography,

Results

From December 2005 to December 2007, 242 patients were assessed for eligibility to participate in the PROCAS trial (Figure 1). The main reason for refusal was the burden of taking medication for 3 years. The main reasons for not meeting the inclusion criteria were young women considering pregnancy, previous AVR, and severe aortic regurgitation. The median follow-up was 2.4 years (interquartile range 1.9 to 3.0). The baseline characteristics of the 2 treatment groups were well balanced (Table 1),

Discussion

The present small, prospective, double-blind, randomized, placebo-controlled multicenter PROCAS trial could not detect a significant effect of rosuvastatin on the progression of congenital AS in asymptomatic adult patients aged 18 to 45 years. Also, rosuvastatin did not have a significant effect on the progression of ascending aorta diameter, LV mass, or AVR-free survival. The results of the PROCAS trial have confirmed and extended the findings of the Scottisch Aortic Stenosis and Lipid

Acknowledgment

We thank Elini R. Andrinopoulou, BSc, for her support in data analysis.

References (19)

H. Baumgartner et al.
Echocardiographic assessment of valve stenosis: EAE/ASE recommendations for clinical practice
J Am Soc Echocardiogr
(2009)
R.B. Devereux et al.
Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy findings
Am J Cardiol
(1986)
E. Abergel et al.
Which definition for echocardiographic left ventricular hypertrophy?
Am J Cardiol
(1995)
W. Dichtl et al.
Prognosis and risk factors in patients with asymptomatic aortic stenosis and their modulation by atorvastatin (20 mg)
Am J Cardiol
(2008)
I. Hamilton-Craig et al.
At sea with SEAS: the first clinical endpoint trial for ezetimibe, treatment of patients with mild to moderate aortic stenosis, ends with mixed results and more controversy
Heart Lung Circ
(2009)
L.M. Moura et al.
Rosuvastatin affecting aortic valve endothelium to slow the progression of aortic stenosis
J Am Coll Cardiol
(2007)
E.T. Van de Velde et al.
An initiative towards a national registry and DNA-bank of patients with congenital heart disease in the Netherlands: rationale, design, and first results
Eur J Epidemiol
(2005)
L.F. Hiratzka et al.
ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM guidelines for the diagnosis and management of patients with Thoracic Aortic Disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, American Association for Thoracic Surgery, American College of Radiology, American Stroke Association, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of Thoracic Surgeons, and Society for Vascular Medicine
Circulation
(2010)
P. Hildebrandt et al.
Amino-terminal pro-B-type natriuretic peptide testing to assist the diagnostic evaluation of heart failure in symptomatic primary care patients
Am J Cardiol
(2008)

There are more references available in the full text version of this article.

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More vigilant assessment of AS is required because symptoms from progression of AS can easily be confused with symptoms from inadequate dialysis. Compared with previous outcome studies of AS in normal kidney function,28,29 our data show a higher incidence of clinical outcomes. In particular, there is a high rate of hospital admission because of heart failure.
This study aimed to investigate the progression of mild-to-moderate aortic stenosis (AS) in patients with end-stage renal disease (ESRD) and determine its metabolic and hemodynamic contributors and clinical outcomes. A total of 74 patients with ESRD (50 men, age 72 ± 11 years) with mild-to-moderate AS were compared with 79 age- and gender-matched controls with normal kidney function. Clinical, laboratory, and echocardiographic features and clinical outcomes including aortic valve (AV) intervention, hospitalization due to heart failure, and cardiovascular death were analyzed. Patients with ESRD were divided into 2 subgroups according to their rate of AV area changes (group 1 [n = 28], rapid progression; and group 2 [n = 46], slow progression). Progression in the degree of AS was noted in 38% of patients with ESRD and 18% of controls (p <0.01) during comparable echocardiographic follow-up durations (29 ± 15 vs 27 ± 24 months, respectively, p = 0.57). In ESRD, patients in group 1 were older (p <0.01) with higher baseline log parathyroid hormone (p <0.01) and larger stroke volume (p = 0.03) than those in group 2. During clinical follow-up (48 ± 23 months), patients in group 1 showed poorer clinical outcomes than those in group 2 and controls (log-rank p <0.01). Age, left atrial volume index ≥42 ml/m², and annual increases of peak pressure gradient across the AV (mm Hg/year) demonstrated additive predictive values for prognosis. AS in ESRD progresses in an accelerated manner along with higher metabolic and hemodynamic loads on AV compared with those with normal kidney function. Accelerated progression of mild-to-moderate AS in ESRD results in poor prognosis.
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A recent meta-analysis, which pooled the results of the four randomized trials, confirmed the equivocal results [55]. In the PROCAS (Progression of Stenosis in Adult Patients with Congenital Aortic Stenosis) trial [56], investigators analyzed the possible efficacy of statin therapy on AS in a group of patients that were underrepresented in the aforementioned clinical studies, those with congenital AS. It was theorized that “upstream” anti-inflammatory effects of statins may provide more benefit in this younger population of patients, in whom there is often less calcification, and more anatomic stress contributing to the stenotic burden [57].
The 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, better known as ‘statins’, are amongst the most widely used medications in the world. They have become a pivotal component in the primary and secondary prevention of coronary artery and vascular disease. However, a growing amount of evidence has suggested that statins also possess strong pleiotropic effects irrespective of their lipid-lowering properties, which include enhancement of endothelial function, anti-inflammatory and anti-atherothrombotic properties, and immunomodulation. The following provides a comprehensive and updated review of the clinical evidence regarding the pleiotropic effects of statins in cardiovascular disorders and their potential therapeutic benefits.
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: This study was supported by ZonMW, The Netherlands, project number 92003405. Roche Diagnostics, Inc., Basel, Switzerland, provided kits to determine the NT-proBNP levels. No relation with the industry exists.

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Valvular heart diseaseEffects of Rosuvastatin on Progression of Stenosis in Adult Patients With Congenital Aortic Stenosis (PROCAS Trial)

Section snippets

Methods

Results

Discussion

Acknowledgment

J Am Soc Echocardiogr

Am J Cardiol

Am J Cardiol

Am J Cardiol

Heart Lung Circ

J Am Coll Cardiol

An initiative towards a national registry and DNA-bank of patients with congenital heart disease in the Netherlands: rationale, design, and first results

Eur J Epidemiol

Circulation

Amino-terminal pro-B-type natriuretic peptide testing to assist the diagnostic evaluation of heart failure in symptomatic primary care patients

Am J Cardiol

Valvular heart disease
Effects of Rosuvastatin on Progression of Stenosis in Adult Patients With Congenital Aortic Stenosis (PROCAS Trial)