Short Term Statin Treatment and Endothelial Dysfunction Due to Ischemia and Reperfusion Injury - Full Text View

Sponsor:	Radboud University
Information provided by:	Radboud University
ClinicalTrials.gov Identifier:	NCT00987974

Purpose

Rationale:

Apart from their cholesterol lowering effects, statins have cholesterol‐independent pleiotropic actions, such as upregulation of 5'‐ectonucleotidase and up‐regulation of NO‐synthase that may increase tolerance against ischemia‐reperfusion injury (IR‐injury). Several animal studies have shown reduction of IR‐injury as a result of statin treatment in both the heart and the kidney. Recently the investigators have shown, using Annexin A5 targeting after voluntary ischemic exercise to assess IR‐injury, a protective effect of a 7 day oral rosuvastatin treatment. A three day treatment with atorvastatin however failed to reduce annexin targeting.

Assessment of the flow mediated dilation of the brachial artery as measure of endothelial (dys)function, is a validated model to research effects of possible protective strategies and perform mechanistic experiments on IR‐injury in humans in vivo.

The investigators hypothesize that pretreatment with statins can increase endothelial tolerance against ischemia and reperfusion injury.

Objective:

To study the protective effect of pretreatment (both 3 day and 7 day) with rosuvastatin and atorvastatin on flow mediated dilation after 15 minutes ischemia and 15 minutes reperfusion.

Study design: placebo‐controlled randomised double‐blind trial

Study population: Healthy volunteers, age 18‐50

Intervention: Treatment with either rosuvastatin 20 mg, atorvastatin 80mg or placebo during either 3 or 7 days

Main study parameters: Difference in flow mediated dilation before and after 15 minutes ischemia.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: Treatment with rosuvastatin or atorvastatin is not expected to harm the volunteers. Most reported side effects of rosuvastatin and atorvastatin are gastro‐intestinal complains and myalgia. The volunteers will not benefit directly from participating in this study.

Condition	Intervention	Phase
Ischemia Reperfusion Injury Endothelial Dysfunction	Drug: rosuvastatin Drug: atorvastatin 3 days Drug: placebo Drug: rosuvastatin 7 days Drug: atorvastatin 7 days Drug: placebo 7 days	Phase IV

Study Type:	Interventional
Study Design:	Prevention, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Parallel Assignment, Efficacy Study
Official Title:	Short Term Statin Treatment and Endothelial Dysfunction Due to Ischemia and Reperfusion Injury

Resource links provided by NLM:

MedlinePlus related topics: Statins

Drug Information available for: Atorvastatin Atorvastatin calcium Rosuvastatin calcium Rosuvastatin

U.S. FDA Resources

Further study details as provided by Radboud University:

Primary Outcome Measures:

Difference in flow mediated dilation before and after 15 minutes ischemia [ Time Frame: 30 minutes ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Ecto‐5'‐nucleotidase activity and lipid profile after statin therapy [ Time Frame: 3-7 days ] [ Designated as safety issue: No ]

Estimated Enrollment:	48
Study Start Date:	September 2009
Estimated Study Completion Date:	April 2010
Estimated Primary Completion Date:	February 2010 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
rosuvastatin 3days: Experimental 8 Subjects will use rosuvastatin 20 mg/day for 3 days	Drug: rosuvastatin rosuvastatin 20 mg/day for 3 days.
atorvastatin 3 days: Active Comparator 8 Subjects will use atorvastatin 80 mg/day for 3 days.pj	Drug: atorvastatin 3 days atorvastatin 80 mg/day for 3 days.
placebo 3days: Placebo Comparator 8 Subjects will use placebo for 3 days.	Drug: placebo placebo for 3 days.
rosuvastatin 7 days: Experimental 8 Subjects will use rosuvastatin 20 mg/day for 7 days.	Drug: rosuvastatin 7 days rosuvastatin 20 mg/day for 7 days
atorvastatin 7 days: Active Comparator 8 Subjects will use atorvastatin 80 mg/day for 7 days.	Drug: atorvastatin 7 days atorvastatin 80 mg/day for 7 days.
placebo 7 days: Placebo Comparator 8 Subjects will use placebo for 7 days.	Drug: placebo 7 days placebo 7 days

Eligibility

Ages Eligible for Study:	18 Years to 50 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	Yes

Criteria

Inclusion Criteria:

Age 18‐50
Written informed consent

Exclusion Criteria:

Smoking
History of any cardiovascular disease
Hypertension (in supine position: systole >140 mmHg, diastole >90 mmHg)
Diabetes Mellitus (fasting glucose >7.0 mmol/L or random glucose >11.0 mmol/L)
Hyperlipidaemia (fasting total cholesterol >5.5 mmol/L or random cholesterol >6.5 mmol/L)
Alanine amino transferase >90 U/L
Creatine kinase >440 U/L
Raised rhabdomyolysis risk
- GFR <60 ml/min
- Overt clinical signs of hypothyroidism
- Myopathy in family history
- Alcohol abuse
Concomitant chronic use of medication
Participation to any drug‐investigation during the previous 60 days as checked with VIP check.
Professional athletes

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00987974

Contacts

Contact: C. Wouters, MD MSc	+31 24 3616723	c.wouters@cardio.umcn.nl
Contact: G. Rongen, MD PhD	+31 24 3616723	g.rongen@pharmtox.umcn.nl

Locations

Netherlands
RUNMC	Recruiting
Nijmegen, Netherlands, 6500HB
Sub-Investigator: C. Wouters, MD MSc
Principal Investigator: G Rongen, MD PhD

Sponsors and Collaborators

Radboud University

More Information

Publications:

Meijer P, Oyen WJ, Dekker D, van den Broek PH, Wouters CW, Boerman OC, Scheffer GJ, Smits P, Rongen GA. Rosuvastatin increases extracellular adenosine formation in humans in vivo: a new perspective on cardiovascular protection. Arterioscler Thromb Vasc Biol. 2009 Jun;29(6):963-8. Epub 2009 Apr 9.

Kharbanda RK, Peters M, Walton B, Kattenhorn M, Mullen M, Klein N, Vallance P, Deanfield J, MacAllister R. Ischemic preconditioning prevents endothelial injury and systemic neutrophil activation during ischemia-reperfusion in humans in vivo. Circulation. 2001 Mar 27;103(12):1624-30.

Responsible Party:	RUNMC ( G. Rongen )
Study ID Numbers:	FMD01
Study First Received:	September 30, 2009
Last Updated:	October 28, 2009
ClinicalTrials.gov Identifier:	NCT00987974 History of Changes
Health Authority:	Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)

Keywords provided by Radboud University:

ischemia reperfusion injury
endothelial dysfunction
statins
rosuvastatin

atorvastatin
placebo
ecto-5'-nucleotidase
flow mediated dilation

Additional relevant MeSH terms:

Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antilipemic Agents
Vascular Diseases
Enzyme Inhibitors
Ischemia
Anticholesteremic Agents
Hydroxymethylglutaryl-CoA Reductase Inhibitors

Pharmacologic Actions
Pathologic Processes
Rosuvastatin
Postoperative Complications
Therapeutic Uses
Cardiovascular Diseases
Atorvastatin
Reperfusion Injury

ClinicalTrials.gov processed this record on February 08, 2010