Atherosclerosis
Conditions
Keywords
plaque, magnetic resonance imaging (MRI), high blood pressure, MI, heart attack, CVA, stroke, PAD
Brief summary
This study is being done to assess the effectiveness of short term (\ 9 months) Aliskiren/Placebo therapy to slow down the progression of atherosclerotic disease in thoracic and abdominal aorta. This will be checked by comparing before and after therapy magnetic resonance imaging (MRI) pictures of the aortic wall. Aliskiren is an FDA approved drug for hypertension but in this study is used for a new indication. Recent studies with animals have shown that Aliskiren therapy reduces the atherosclerotic plaque. Therefore, in this study, the investigators would like to evaluate whether the investigational drug Aliskiren, which is not FDA approved for this indication has the same beneficial effects in people with atherosclerotic disease.
Detailed description
Treatments and Clinic Visits: The 36-week double-blind, randomized treatment phase of the trial is preceded by 2-week single-blind placebo period to assess eligibility into the active treatment period, compliance, and to confirm the baseline blood pressure values of the enrolled subjects. If at the end of the single-blind phase, inclusion criteria will not be met, the participants will not be allowed to continue on to the trial. If they are eligible they will undergo baseline MRI studies after being randomized to either placebo or Aliskiren 150 mg, with an escalation to 300 mg at 2 weeks into treatment. This dose will be maintained for the duration of the trial. After randomization and dose escalation visits (at 2 weeks), patients will return for scheduled clinic visits at weeks 12 and 36. Assessment of routine safety measures including serum creatinine and potassium will be performed at pre-designated visits (randomization, drug escalation and end-of trial). At each study visit, after having the patient in a sitting position for 5 minutes, SBP/diastolic blood pressure will be measured 3 times in accordance with the AHA Committee Report on blood pressure determination. The patient will be then asked to stand for 2 minutes, and a single blood pressure measurement will be measured in the standing position. Evidence of left ventricular hypertrophy (LVH) will be determined using the Romhilt-Estes scoring system at baseline. Specialized measurements of plasma including insulin, glucose measures, adipokines (leptin and adiponectin) and high- sensitivity C-reactive protein (hsCRP) will be performed at randomization and 12 weeks into the trial. Central aortic blood pressure assessment will be performed at randomization and end of trial/exit visits (SphygmoCor CP, AtCor Medical, Itaska, Illinois, USA). Plasma direct renin measurements will be obtained at baseline and 12 weeks in part to assess compliance of patients with their therapy (Diasource, Belgium).
Interventions
DRUGAliskiren
150 mg/300mg
DRUGPlacebo
150mg/300mg
Sponsors
Novartis
Ohio State University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
45 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Patients, both males and females, were eligible if they were ≥ 45 years of age, with previously documented cardiovascular disease, defined as at least one of the following: myocardial infarction (MI), cerebrovascular accident (CVA), coronary bypass surgery and/or percutaneous intervention, peripheral arterial disease (PAD), defined as ankle brachial index (ABI) \<0.9 and/or prior peripheral intervention/surgery. Subjects on angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blockers (ARB) therapy were eligible to participate, provided no dose adjustments were made during the course of the study.
Exclusion criteria
Contraindications to the MRI exam (pacemakers, metallic implants, severe claustrophobia); diagnosis of Type II Diabetes or use of hypoglycemic drugs; uncontrolled hypertension (\>145/90 mm Hg); low density lipoprotein (LDL) of ≥ 130mg/dL; renal insufficiency defined as glomerular filtration rate (GFR) ≤ 40 ml/minute (derived by the Modified Diet in Renal Disease (MDRD) equation); initiation of new therapy with statins, ACEI/ARBs, anti-oxidants, calcium channel blockers, diuretics, β blockers; transient ischemic cerebral attack during the prior 6 months; history of allergy to renin inhibitors; unstable cardiac syndromes; symptomatic arrhythmias; history of malignancy including leukemia and lymphoma (but not basal cell skin cancer, cured squamous cell cancer and localized prostate cancer) and history of allergy to renin inhibitors.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Normalized Total Aortic Wall Volume (TWV) Between the Trial Arms at the End of the Treatment | Baseline and end of treatment ( 17 to 36 weeks) | All patients underwent imaging using a 3T, MRI system. The MRI sequence method used for wall depiction was a 3D, fat suppressed, dark blood, turbo spin echo sequence with variable flip angles (SPACE). Following co-registration of pre and post treatment MR images, and generation of MPR sections, images were magnified, contrast adjusted and patient/exam identifier information was removed and replaced by pre-assigned code to blind images for measurements. An experienced observer performed manual measurements of lumen and lumen plus wall areas by delineating the inner border and the outer border of the vessel wall in each cross-section image of the aorta. Using an approach similar to intravascular atheroma volume calculations, normalized total aortic wall volume (TWV) for thoracic region, abdominal region and total aorta for each patient and each exam was generated. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in the Percentage Wall Volume (PWV) Between Baseline and End of Treatment | Baseline and end of treatment ( 17 to 36 weeks) | Using an approach similar to intravascular atheroma volume calculations, percentage wall volume (PWV) for thoracic region, abdominal region and total aorta for each patient and each exam was generated. and a difference between baseline and end of treatment was calculated. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Resting Diastolic Blood Pressure | baseline to end of treatment ( up to 36 weeks) | Difference between end of treatment and baseline in resting diastolic blood pressure |
Countries
United States
Participant flow
Recruitment details
Participants recruited from The Ohio State Medical Center and Columbus surrounding area between April 2009 to December 2011.
Pre-assignment details
187 participants screened; 116 did not meet inclusion criteria or meet exclusion criteria; 71 randomized.
Participants by arm
| Arm | Count |
|---|---|
| Aliskiren Aliskiren will be administered for 2 weeks at 150mg/day oral pill, followed by 34 weeks oral therapy with 300mg/day | 34 |
| Placebo Placebo (sugar pill) built to mimic both the 150mg Aliskiren tablet ( administered for the first 2 weeks) and the 300mg Aliskiren tablet ( administered for the rest of treatment period) | 37 |
| Total | 71 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Failure to make contact | 0 | 1 |
| Overall Study | Withdrawal by Subject | 5 | 1 |
Baseline characteristics
| Characteristic | Placebo | Aliskiren | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 24 Participants | 17 Participants | 41 Participants |
| Age, Categorical Between 18 and 65 years | 13 Participants | 17 Participants | 30 Participants |
| Age, Continuous | 64.5 years STANDARD_DEVIATION 8.9 | 63.9 years STANDARD_DEVIATION 11.5 | 64.18 years STANDARD_DEVIATION 10.17 |
| Region of Enrollment United States | 37 participants | 34 participants | 71 participants |
| Sex: Female, Male Female | 3 Participants | 9 Participants | 12 Participants |
| Sex: Female, Male Male | 34 Participants | 25 Participants | 59 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 1 / 34 | 0 / 37 |
| serious Total, serious adverse events | 0 / 34 | 0 / 37 |
Outcome results
Primary
Change in Normalized Total Aortic Wall Volume (TWV) Between the Trial Arms at the End of the Treatment
All patients underwent imaging using a 3T, MRI system. The MRI sequence method used for wall depiction was a 3D, fat suppressed, dark blood, turbo spin echo sequence with variable flip angles (SPACE). Following co-registration of pre and post treatment MR images, and generation of MPR sections, images were magnified, contrast adjusted and patient/exam identifier information was removed and replaced by pre-assigned code to blind images for measurements. An experienced observer performed manual measurements of lumen and lumen plus wall areas by delineating the inner border and the outer border of the vessel wall in each cross-section image of the aorta. Using an approach similar to intravascular atheroma volume calculations, normalized total aortic wall volume (TWV) for thoracic region, abdominal region and total aorta for each patient and each exam was generated.
Time frame: Baseline and end of treatment ( 17 to 36 weeks)
Population: 3 MRI data sets were not analyzable ( low quality images), and 23 post-treatment MRI not obtained ( \<17 weeks on drug when trial terminated owing to ALTITUDE results)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aliskiren | Change in Normalized Total Aortic Wall Volume (TWV) Between the Trial Arms at the End of the Treatment | 5.31 mm3 | Standard Deviation 6.57 |
| Placebo | Change in Normalized Total Aortic Wall Volume (TWV) Between the Trial Arms at the End of the Treatment | 0.15 mm3 | Standard Deviation 4.39 |
p-value: <0.03195% CI: [0.85, 9.47]t-test, 2 sided
Secondary
Change in the Percentage Wall Volume (PWV) Between Baseline and End of Treatment
Using an approach similar to intravascular atheroma volume calculations, percentage wall volume (PWV) for thoracic region, abdominal region and total aorta for each patient and each exam was generated. and a difference between baseline and end of treatment was calculated.
Time frame: Baseline and end of treatment ( 17 to 36 weeks)
Population: 3 MRI not analyzable, 23 final MRI not obtained due to trial termination
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aliskiren | Change in the Percentage Wall Volume (PWV) Between Baseline and End of Treatment | 3.37 Percentage of the Outer Wall Volume | Standard Deviation 2.96 |
| Placebo | Change in the Percentage Wall Volume (PWV) Between Baseline and End of Treatment | 0.97 Percentage of the Outer Wall Volume | Standard Deviation 2.02 |
p-value: 0.04195% CI: [0.44, 4.36]t-test, 2 sided
Other Pre-specified
Change From Baseline in Resting Diastolic Blood Pressure
Difference between end of treatment and baseline in resting diastolic blood pressure
Time frame: baseline to end of treatment ( up to 36 weeks)
Population: Intent to treat analysis including only participants who had at least one post-baseline assesment
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Aliskiren | Change From Baseline in Resting Diastolic Blood Pressure | -3.88 mm Hg |
| Placebo | Change From Baseline in Resting Diastolic Blood Pressure | -2.32 mm Hg |