Primary Investigator: Richard Webel, MD
Study Coordinator: Kathy Belew, RN
Status: Active - open to enrollment
Study Title: A 104-week, randomized, double-blind, placebo-controlled, parallel-group, multicenter study to evaluate the efficacy of aliskiren on the progression of atherosclerosis in patients with coronary artery disease when added to optimal background therapy (AQUARIUS)
Purpose: This study is being conducted to assess the effect of aliskiren on both the rate of plaque progression in the coronary arteries and cardiovascular endpoints in patients with CAD and blood pressure in the pre-hypertensive (high normal) range. This study is being conducted as a proof-of concept study utilizing intravascular ultrasound (IVUS) as a surrogate efficacy endpoint.
1. Male and female patients >/=35 years of age who are scheduled to undergo a coronary catheterization procedure for a clinically indicated reason.
2. Patients with or without current treatment for hypertension must have a msSBP >/=125 and for those patients receiving treatment for hypertension, every effort should be made by the investigator to have the patient on a stable dose (defined as dose unchanged for >/=1 week) of medication prior to visit.
3. Patients must have at least two of the following risk factors:
· History of prior myocardial infarction (MI), acute coronary syndrome (ACS) or previous coronary or peripheral revascularization.
· No prior treatment with a statin drug. If the patient has been previously treated at any time with a statin medication, it must be for a period of
· HDL < 40 mg/dL for men or <50 mg/dL for women OR triglycerides > 150 mg/dL at visit 1.
· Microalbuminuria (defined as UACR >/= 30 mg/g and <300 mg/g) OR macroalbuminuria (defined as UACR >/=300mg/g and < 3000mg/g) at visit 1.
· Age > 55 years.
· Diagnosis of diabetes mellitus based on medical history, concomitant diabetic medications being taken at study entry, OR a fasting plasma glucose(FPG) >/=126mg/dL (7.0mmol/l) or non-fasting plasma glucose >/= 200 mg/dl (11.1 mmol/L) or HbA1c > 6.0% at visit 1.
· Current smoking within four weeks of visit 1 or at visit 1.
· History of LVH documented by ECG, echocardiogram or MRI performed.
· Elevated hs-CRP >/= 2.0 mg/L (0.2mg/dL) at visit 1, which in the opinion of the investigator, is not related to an underlying inflammatory condition or concomitant medication.
· Patients must meet all of the following criteria at the qualifying coronary catheterization procedure:
© Entire coronary circulation: angiographic evidence of coronary heart disease as defined by at least one lesion in any of the three major native coronary arteries that has >20% reduction in lumen diameter by angiographic visual estimation or prior history of PTCA. This vessel need not be the target coronary artery for IVUS. Any vessel with previous PTCA may not be used as the target coronary artery.
© Left main coronary artery: must not have >50% reduction in lumen diameter by visual angiographic estimation.
© Target coronary artery:
a. must be accessible to the IVUS catheter.
b. must have a <50% reduction in lumen diameter by angiographic visual estimation throughout a segment of at least 40 mm in length (the "target segment"). A lesion of up to 60% stenosis is permitted, distal to the target segment. A single branch of the target vessel may have a narrowing up to but <70% by visual estimation as long as the target segment contains no lesion >50%, provided that the branch in question is not a target for percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) surgery.
c. has not undergone prior PCI or CABG surgery.
d. the target vessel is not currently a candidate for intervention or a likely candidate for intervention over the next 24 months.
e. the target vessel may not be a bypass graft.
f. the target vessel may not be a bypassed vessel.
g. the target vessel may not be the culprit vessel for a previous MI.
Patients with any of the following at visit 1 (unless otherwise stated) will be excluded from participation in the study.
1. Baseline IVUS study determined to be of unacceptable quality by the IVUS Core laboratory.
2. Patients requiring treatment with any two of the following classes of medications at visit 1 or visit 2: ACEIs, ARBs, aldosterone receptor blockers or a direct renin inhibitor.
3. Patients with clinically significant heart disease, which in the opinion of the Investigator is likely to require coronary bypass surgery, PCI in the target vessel, surgical repair, ventricular assist device placement, cardiac transplantation, or require intra-aortic balloon pump support during the duration of the study.
4. Previous or current diagnosis of heart failure (NYHA Class IV) or a documented left ventricular ejection fraction (LVEF) of <25%.
5. Patients with evidence of cardiac electrophysiologic instability including a history of uncontrolled ventricular arrhythmias, uncontrolled atrial fibrillation/flutter or uncontrolled supraventricular tachycardias with a ventricular response heart rate of >100 beats per minute at rest within four weeks prior to visit 1.
6. Coronary artery bypass graft surgery.
7. Evidence of renal impairment.
8. History or evidence of a secondary form of hypertension.
9. Known Keith-Wagener grade III or IV hypertensive retinopathy.
10. History of hypertensive encephalopathy, cerebrovascular accident or transient ischemic cerebral attack (TIA) within 12 months of study entry.
11. Second or third degree heart block without a pacemaker.
12. Serum sodium < 135 mEq/ L (mmol/L) at visit 1.
13. Serum potassium > 5.0 mEq/L (mmol/L) at visit 1.
14. Any medical or surgical condition which might significantly alter the absorption, distribution, metabolism or excretion of medication including, but not limited to any of the following:
a. History of small or large bowel resection (excluding appendectomy), or gastric surgery for weight control (e.g., gastric bypass, Lap-Band, etc.).
b. Currently active gastritis, duodenal or gastric ulcers.
c. Any gastrointestinal bleeding during the 3 months prior to visit 1.
d. Any history of pancreatic injury, pancreatitis, or evidence of impaired pancreatic function/injury as indicated by an abnormal lipase or amylase in the 12 months prior to visit 1.
e. Current treatment with cholestyramine or colestipol resins.
15. Evidence of hepatic disease as determined by any one of the following: ALT or AST values exceeding 3 x ULN at visit 1, a history of hepatic encephalopathy, a history of esophageal varices, or a history of portocaval shunt.
16. History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past five years regardless of whether there is evidence of local recurrence or metastases.
17. History of hypersensitivity to any of the study drugs or to drugs belonging to the same therapeutic class as the study drugs.
18. Concurrent treatment with cyclosporine or quinidine at visit 1 or during the trial.
19. History or evidence of drug or alcohol abuse within the last 12 months.
20. Previously treated with aliskiren at any time prior to visit 1.
21. Pregnant or nursing (lactating) women.
22. Women of child-bearing potential (WOCBP), defined as all women physiologically capable of becoming pregnant, including women whose career, lifestyle, or sexual orientation precludes intercourse with a male partner and women whose partners have been sterilized by vasectomy or other means, UNLESS they are using two birth control methods.
23. Any surgical or medical condition, which in the opinion of the investigator, may place the patient at higher risk from his/her participation in the study, or is likely to prevent the patient from complying with the requirements of the study or completing the study.
24. Use of other investigational drugs, excluding drug eluting stents, at the time of enrollment, or within 30 days or five half-lives of enrollment, whichever is longer.
25. History of noncompliance to medical regimens or unwillingness to comply with the study protocol.
26. Any condition that in the opinion of the investigator or the Novartis Medical Monitor would confound the evaluation and interpretation of efficacy and/or safety data.
27. Persons directly involved in the execution of this protocol.
1. Determine if patient fits major study criteria.
2. Determine if patient is interested in joining a clinical trial.
3. Call Kathy Belew (beeper 573-499-8063) and/or on-call research nurse (on-call beeper 573-499-8084) or Dr. Webel to complete screening of patient.