The Potential of Rosuvastatin and Candesartan to Retard the Progression of Aortic Stenosis - Full Text View

Sponsors and Collaborators:	Helsinki University AstraZeneca
Information provided by:	Helsinki University
ClinicalTrials.gov Identifier:	NCT00699452

Purpose

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.

Condition	Intervention	Phase
Aortic Valve Stenosis	Drug: rosuvastatin Drug: candesartan Drug: rosuvastatin and candesartan Drug: placebo	Phase III

Drug Information available for: Rosuvastatin Rosuvastatin calcium Candesartan cilexetil CV 11974

U.S. FDA Resources

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

Further study details as provided by Helsinki University:

Primary Outcome Measures:

The degree of inflammation in stenotic aortic valves [ Time Frame: 3-5 months ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

The degree of calcification, lipid accumulation, and fibrosis in stenotic aortic valves [ Time Frame: 3-5 months ] [ Designated as safety issue: No ]

Estimated Enrollment:	120
Study Start Date:	June 2008
Estimated Study Completion Date:	December 2013
Estimated Primary Completion Date:	December 2011 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
1: Active Comparator Rosuvastatin 10 mg/d for 2 weeks, then 20 mg/d until surgery (approximately 3 months)	Drug: rosuvastatin Rosuvastatin 10 mg/d for 2 weeks, then 20 mg/d until surgery (approximately 3 months)
2: Active Comparator Candesartan 8 mg/d for two weeks, then 16 mg/d until valve replacement surgery (approximately 3 months)	Drug: candesartan Candesartan 8 mg/d for two weeks, then 16 mg/d until valve replacement surgery (approximately 3 months)
3: Active Comparator 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: 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)
4: Placebo Comparator Placebo	Drug: placebo placebo

Detailed Description:

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.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

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)

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00699452

Contacts

Contact: Markku Kupari, MD, PhD	358-9-4717-2441	markku.kupari@hus.fi
Contact: Satu Helske, MD, PhD	358-9-681-411	satu.helske@wri.fi

Locations

Finland
Division of Cardiology, Helsinki University Central Hospital	Recruiting
Helsinki, Finland, 00029
Contact: Markku Kupari, MD, PhD 358-9-4717-2441 markku.kupari@hus.fi
Contact: Satu Helske, MD, PhD 358-9-681-411 satu.helske@wri.fi
Principal Investigator: Markku Kupari, MD, PhD

Sponsors and Collaborators

Helsinki University

AstraZeneca

Investigators

Principal Investigator:

Markku Kupari, MD, PhD

Division of Cardiology, Helsinki University Central Hospital

More Information

Responsible Party:	Division of Cardiology, Helsinki University Central Hospital ( Markku Kupari )
Study ID Numbers:	ROCK-AS
Study First Received:	June 16, 2008
Last Updated:	June 17, 2008
ClinicalTrials.gov Identifier:	NCT00699452
Health Authority:	Finland: National Agency for Medicines

Keywords provided by Helsinki University:

aortic stenosis
valve
rosuvastatin
candesartan

Study placed in the following topic categories:

Candesartan cilexetil
Pathological Conditions, Anatomical
Rosuvastatin
Heart Diseases
Candesartan
Disease Progression

Constriction, Pathologic
Aortic valve stenosis
Angiotensin II
Aortic Valve Stenosis
Heart Valve Diseases

Additional relevant MeSH terms:

Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antilipemic Agents
Enzyme Inhibitors
Cardiovascular Agents
Anticholesteremic Agents
Antihypertensive Agents

Hydroxymethylglutaryl-CoA Reductase Inhibitors
Pharmacologic Actions
Angiotensin II Type 1 Receptor Blockers
Therapeutic Uses
Cardiovascular Diseases
Ventricular Outflow Obstruction

ClinicalTrials.gov processed this record on January 16, 2009