Official Title: “The Potential of Rosuvastatin and Candesartan to Retard the Progression of Aortic Stenosis Influences of Medical Therapy to the Atheroinflammatory Process in Stenotic Aortic Valves”

The present study defines a blinded, randomized, placebo-controlled, prospective study, the aim of which is to determine the influence of intensive statin therapy, using rosuvastatin (target dose 20 mg), and effective treatment with AT-1R antagonist, using candesartan (target dose 16 mg) on stenotic aortic valves. We will specifically quantify whether these drugs attenuate the key pathogenic mechanisms of aortic valve stenosis, namely inflammation, fibrosis, elastin degradation, calcification, and neovascularization.

Study Type: Interventional

Study Design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator), Placebo Control, Parallel Assignment, Safety/Efficacy Study

Study Primary Completion Date: December 2011

We will include in the study 120 consecutive patients with clinically significant, symptomatic aortic stenosis referred to the Helsinki University Central Hospital for consideration of valve replacement surgery.Patients who can be put on the hospital's normal waiting list for elective angiography (i.e who do not need urgent surgery) and who give their informed consent, will be randomized into four groups to start therapy with rosuvastatin (10 mg/d for 2 weeks, and then 20 mg/d until surgery) or candesartan (8 mg/d for 2 weeks, and then 16 mg/d until surgery), a combined rosuvastatin and candesartan therapy, or placebo. On average, the overall duration of the drug intervention will be 3 months, i.e. the average time in our institution from referral to surgery. In addition, patients (n=50) undergoing aortic valve replacement surgery due to aortic regurgitation caused by dilation of the aortic root will be included. This population consists of both patients with early sclerotic, i.e.

pre-stenotic, changes in their aortic valves (n=30) and of patients without any sclerotic or stenotic changes in their aortic valves (n=20). The group with sclerotic changes in their aortic valves (n=30) will be divided into two groups to receive both rosuvastatin (10 mg/d fro 2 wk and thereafter 20 mg/d until surgery) and candesartan (8 mg/d 2 wk, and then 16 mg/d until surgery) (n=15), or placebo + placebo (n=15).The removed aortic valves will be examined utilizing real-time PCR, autoradiography, fluorometry, immunohistochemistry, double immunofluorecence, confocal microscopy, and enzyme immunoassays. With these techniques, several markers of inflammation, calcification, fibrosis, and the amount of lipid accumulation and oxidation of LDL in the valves will be examined.

Intervention(s) in this Clinical Trial

• Drug: rosuvastatin
  • Rosuvastatin 10 mg/d for 2 weeks, then 20 mg/d until surgery (approximately 3 months)
• Drug: candesartan
  • Candesartan 8 mg/d for two weeks, then 16 mg/d until valve replacement surgery (approximately 3 months)
• Drug: rosuvastatin and candesartan
  • Combination therapy: Rosuvastatin 10 mg/d for 2 weeks, then 20 mg/d and candesartan 8 mg/d for two weeks, then 16 mg/d until valve replacement surgery (approximately 3 months)
• Drug: placebo
  • placebo

Arms, Groups and Cohorts in this Clinical Trial

• Active Comparator: 1
  • Rosuvastatin 10 mg/d for 2 weeks, then 20 mg/d until surgery (approximately 3 months)
• Active Comparator: 2
  • Candesartan 8 mg/d for two weeks, then 16 mg/d until valve replacement surgery (approximately 3 months)
• Active Comparator: 3
  • Combination therapy: Rosuvastatin 10 mg/d for 2 weeks, then 20 mg/d and candesartan 8 mg/d for two weeks, then 16 mg/d until valve replacement surgery (approximately 3 months)
• Placebo Comparator: 4
  • Placebo

Primary Measures

• The degree of inflammation in stenotic aortic valves
  • Time Frame: 3-5 months
    Safety Issue?: No

Secondary Measures

• The degree of calcification, lipid accumulation, and fibrosis in stenotic aortic valves
  • Time Frame: 3-5 months
    Safety Issue?: No

Inclusion Criteria:

• 120 consecutive patients with clinically significant, symptomatic aortic stenosis referred to the Helsinki University Central Hospital for consideration of valve replacement surgery.

Exclusion Criteria:

• Individuals with past myocardial infarction, more than mild mitral valve disease, or previous cardiac surgery will be excluded.
• Patients with heart failure who need urgent surgery or those with hypotension (systolic blood pressure below 110 mm Hg) will be excluded.
• Patients already taking ACE inhibitors, AT-1R antagonists, or statins will be excluded from the study population.
• Other exclusion criteria include the following:
• Complicated diabetes
• Primary cardiomyopathy
• History of statin induced myopathy, or serious hypersensitivity reaction to other
• HMG-CoA reductase inhibitors (statins) including rosuvastatin
• Pregnant women, women who are breast feeding, and women of childbearing potential who are not using chemical or mechanical contraception or have a positive serum pregnancy test
• History of malignancy (unless a documented disease free period exceeding 5-years is present) with the exception of basal cell or squamous cell carcinoma of the skin. Women with a history of cervical dysplasia would be permitted to enter the study provided they had 3 consecutive clear Papanicolaou (Pap) smears
• Hypothyroidism (TSH 1.5xULN)
• Abnormal liver function tests
• Patients on concomitant therapy with gemfibrozil or cyclosporine
• History of alcohol or drug abuse within the last 5 years (this may affect compliance)
• Current active liver disease (ALT/SGPT >2xULN or severe hepatic impairment (to protect patient safety as directed on the labels of currently approved statins)
• Unexplained creatine kinase (CK 3xULN) (To protect patient safety)
• Serum creatinine >176 umol/L (2.0mg/dL)
• Participation in another investigational drug study less than 4 weeks before enrolment in the study, or according to subjects local ethics committee requirements where a larger period is stipulated (to avoid potential misinterpretation of overlapping adverse events)

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Helsinki University

Overall Clinical Trial Officials and Contacts

Markku Kupari, MD, PhD Principal Investigator Division of Cardiology, Helsinki University Central Hospital  

Overall Contact: Markku Kupari, MD, PhD 358-9-4717-2441 markku.kupari@hus.fi

Information obtained from ClinicalTrials.gov on September 05, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00699452

Study ID Number: ROCK-AS

ClinicalTrials.gov Identifier: NCT00699452

Health Authority: Finland: National Agency for Medicines