Peripheral Arterial Disease
Conditions
Keywords
Endovascular Intervention, MRI, Ultrasound, Cholesterol Medications, High Cholesterol, Peripheral Arterial disease, Claudication, Leg Pain, Niaspan, Extended Release Niacin, Zetia, Ezetimibe, Simvastatin, Zocor, Atorvastatin, Lipitor
Brief summary
Peripheral arterial disease (PAD) occurs when arteries become narrowed or hardened because of a build-up of plaque or fat deposits. PAD develops most often in arteries in the legs, which can result in reduced blood flow to the legs and feet, occasionally causing leg pain and fatigue. Early identification of PAD and treatment with lifestyle changes or medications can help to keep legs healthy and lower risk for heart attack and stroke, but endovascular or surgical procedures may be necessary for people with severe PAD. Even after endovascular intervention, PAD symptoms must be continually monitored to prevent the development and progression of blockages in the arteries. The best approach for monitoring symptoms is still undetermined. This study will compare the effectiveness of an intensive combination of lipid modifying medications versus standard lipid modifying medications in treating people with significant PAD who have had an endovascular intervention.
Detailed description
PAD occurring in the legs is a serious disease that affects about 8 million people in the United States. A person's risk for PAD increases with age but can also be raised by smoking or having diabetes, high blood pressure, high cholesterol, or heart disease. Symptoms of PAD may include leg cramps or pain while walking, foot pain while resting, and skin wounds or ulcers on feet and toes. However, because only about one in three people with PAD knows to seek treatment for these symptoms, many end up with advanced disease that requires significant medical intervention, such as an endovascular or other surgical procedure to open the blocked arteries. While these procedures are helpful in treating people with severe PAD, lifestyle modifications and certain medications are also needed for long-term management of PAD and improved quality of life. An intensive combination of lipid modifying medications may be superior to standard lipid modifying medications in reducing PAD-associated risk factors and improving overall health in people with PAD. This study will compare the effectiveness of an intensive combination of lipid modifying medications versus standard lipid modifying medications in preventing blockages and re-narrowing of arteries in people with significant PAD who have had an endovascular intervention. Participation in this study will last a minimum of 2 years and a maximum of 5 years. All participants will first undergo baseline assessments that will include a medical history, vascular and physical exam, electrocardiograph (EKG), magnetic resonance imaging (MRI) scan, 3D ultrasound, blood pressure measurement test in the legs, treadmill walking distance test, urine test, blood draw, and questionnaires. A portion of the blood draw will be used for DNA analysis and genetic testing. Participants who have not had an endovascular intervention in the 3 months before study entry will undergo a standard of care percutaneous transluminal angioplasty (PTA) procedure. First these, participants will complete a series of clinical review assessments that will include a review of social, vascular, and clinical history. Next, they will undergo the PTA procedure, which will involve the inflation and deflation of a small balloon in the area of the blocked artery. Additionally, participants may have a metal mesh tube called a stent placed in the blocked area, if deemed necessary by their physicians. All participants will then be assigned randomly to receive standard care plus an intensive combination of lipid modifying medications (Simvastatin, Plavix, aspirin, Ezetimibe, and Niaspan) or standard lipid modifying medications with placebo (Simvastatin, Plavix, aspirin, placebo Ezetimibe, and placebo Niaspan). Participants will take their assigned medications daily for 24 months. Follow-up visits will occur at Day 10; Week 6; and Months, 6, 12, and 24 after beginning the study medications. During follow-up visits, participants will repeat the baseline assessments and the clinical review assessments from the pre-PTA visit. The Week 6 follow-up visit will include only a blood draw, questionnaires, and the clinical review assessments. Participants will also be contacted by phone to check their status every 2 to 3 months during treatment and every 6 months after treatment for up to 3 years.
Interventions
DRUGEzetimibe
Daily dose of 10 mg of Ezetimibe
DRUGNiaspan
Daily dose of 1500 mg of Niaspan
DRUGStatin therapy
Daily dose of 40 mg of Simvastatin (If unable to tolerate Simvastatin, participants will take a daily dose of Atorvastatin.)
BEHAVIORALStandard care
Standard of medical care for PAD
DRUGAspirin
Daily dose of 325 mg of aspirin
DRUGClopidogrel
Daily dose of 75 mg of clopidogrel for 3 months or as recommended by the primary care physician
DRUGPlacebo Niaspan
Daily dose of 1500 mg of placebo Niaspan
Daily dose of 10 mg of placebo Ezetimibe
Participants who have not had an endovascular intervention in the 3 months before study entry will undergo PTA to mechanically open the artery blockages. This procedure will involve the inflation and deflation of a small balloon to open the blocked artery. Additionally, participants may have a metal mesh tube called a stent placed in the blocked area if deemed necessary by their physicians.
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Baylor College of Medicine
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
HEALTH_SERVICES_RESEARCH
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Symptoms consistent with calf claudication and described as life style limiting * Objective evidence of peripheral artery disease (PAD): Ankle brachial index less than 0.9 OR other hemodynamic or imaging modalities confirming significant PAD * Baseline imaging reveals superficial femoral artery (SFA) disease starting at least 5 cm from the origin of the SFA * Agrees to be available for follow-up and is able to participate in all study testing procedures * Weight and/or body characteristics that will allow testing with MRI * No known contraindication to lipid lowering agents * Serum creatinine level less than 2.5 mg/dL * Scheduled to undergo or has already undergone an endovascular intervention of a de novo lesion in the SFA with an anticipated result that would satisfy hemodynamic stability OR is medically managed and does not require an intervention at this time * Compressible arteries (if not, has toe brachial index \[TBI\] less than 0.7) * Has/had an A, B, C lesion amendable to a catheter based therapy (prior bypass is acceptable)
Exclusion criteria
* Non-atherosclerotic disease that is responsible for claudication * Unstable cardiac disease (e.g., unstable angina, heart attack within the 30 days before study entry, uncontrolled coronary heart failure, poorly controlled hypertension \[systolic blood pressure greater than 180 mmHg and/or diastolic blood pressure greater than 100 mmHg\], ventricular arrhythmias) * Pancreatitis * Documented hypercoagulable state * Clinically severe diabetic neuropathy * Rest pain, gangrene, or tissue loss * Active peptic ulcer disease or a recent gastrointestinal bleed that would prohibit the use of an anti-platelet (aspirin/Plavix) * Untreated or unsuccessfully controlled psychiatric disease * Chronic hepatic disease determined by aspartate transaminase (AST) and/or alanine transaminase (ALT) more than 3 times upper limit of normal (ULN) and/or total bilirubin more than 2 times ULN * Creatine phosphokinase (CPK) more than 3 times ULN (may be repeated once before patient is excluded) * Active gout symptoms or a uric acid level greater than 1.3 times ULN * Untreated hypothyroidism * Allergy to Plavix, nickel, titanium, niacin, Ezetimibe, statins, or their derivatives * Participated in another interventional study within the 30 days before study entry * Scheduled to undergo planned synchronous bilateral percutaneous transluminal angioplasty (PTA) procedures * Requires an above the ankle amputation * Scheduled to undergo elective surgery within 30 days after the PTA procedure * Has an implanted pacemaker, defibrillator, neural stimulator, brain clip, insulin pump, cochlear implant, or any other predetermined radiographic finding that would exclude MRI testing * Has claustrophobia that would prevent MRI testing * Recent drug or alcohol abuse history (less than 6 months before study entry) or is currently using or abusing excessive alcohol or drugs (excessive alcohol will be defined as greater than 14 drinks per week) * Past recipient of a cardiac, kidney, liver, lung, or other organ transplant (skin grafts are acceptable)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Effect of Intensive Lipid Modification Medication Therapy on Progression of Atherosclerosis and Restenosis of Femoral Arteries Measured Using High Resolution Magnetic Resonance Imaging (MRI) to Examine the Femoral Artery for Progression of Atherosclerosis | Measured at baseline and 24 Months | The primary outcome variable was the change in superficial femoral artery (SFA) wall volume over 24-months, as determined by MRI. The 24-month changes in SFA lumen and SFA total vessel volumes were also analyzed. Analysis details: A total of 102 patients were randomized. 87 patients completed baseline MRI. Between randomization and the baseline visit, 1 patient withdrew from the study, 8 patients opted out from baseline imaging, and 6 additional patients declined blood collection at baseline. The multilevel models (primary endpoint) used all available imaging data (n=91), including patients who only completed baseline imaging (n=20) or completed at least 2 imaging visits other than baseline (n=4). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Total Cholesterol (mg/dl) From Baseline to Month 12 | Measured at baseline and 12 months | Lipids: Total cholesterol (mg/dl); Lipid Data at 12-Months (change from baseline) \[mg/dl\]. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Triple Therapy Participants will receive standard of medical care and treatment with intensive lipid modification using a statin plus Ezetimibe and Niaspan.
Ezetimibe: Daily dose of 10 mg of Ezetimibe
Niaspan: Daily dose of 1500 mg of Niaspan
Statin therapy: Daily dose of 40 mg of Simvastatin (If unable to tolerate Simvastatin, participants will take a daily dose of Atorvastatin.)
Standard care: Standard of medical care for PAD
Aspirin: Daily dose of 325 mg of aspirin
Clopidogrel: Daily dose of 75 mg of clopidogrel for 3 months or as recommended by the primary care physician
Inclusion criteria were life-style-limiting claudication consistent with Fontaine Stage IIa/IIb or angiographically confirmed Trans-Atlantic Inter-Society Consensus A-C lesions in the SFA. | 47 |
| Mono Therapy Participants will receive standard of medical care and treatment with standard lipid modifying medications plus placebo Ezetimibe and placebo Niaspan.
Statin therapy: Daily dose of 40 mg of Simvastatin (If unable to tolerate Simvastatin, participants will take a daily dose of Atorvastatin.)
Standard care: Standard of medical care for PAD
Aspirin: Daily dose of 325 mg of aspirin
Clopidogrel: Daily dose of 75 mg of clopidogrel for 3 months or as recommended by the primary care physician
Placebo Niaspan: Daily dose of 1500 mg of placebo Niaspan
Placebo Ezetimibe: Daily dose of 10 mg of placebo Ezetimibe
Inclusion criteria were life-style-limiting claudication consistent with Fontaine Stage IIa/IIb or angiographically confirmed Trans-Atlantic Inter-Society Consensus A-C lesions in the SFA. | 48 |
| Total | 95 |
Baseline characteristics
| Characteristic | Triple Therapy | Total | Mono Therapy |
|---|---|---|---|
| Age, Continuous | 62.1 years STANDARD_DEVIATION 7.8 | 63.0 years STANDARD_DEVIATION 7.5 | 63.9 years STANDARD_DEVIATION 7.1 |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 13 Participants | 17 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 32 Participants | 76 Participants | 44 Participants |
| Region of Enrollment United States | 47 participants | 95 participants | 48 participants |
| Sex: Female, Male Female | 4 Participants | 6 Participants | 2 Participants |
| Sex: Female, Male Male | 43 Participants | 89 Participants | 46 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 4 / 47 | 4 / 48 |
| other Total, other adverse events | 10 / 47 | 8 / 48 |
| serious Total, serious adverse events | 7 / 47 | 4 / 48 |
Outcome results
Primary
Effect of Intensive Lipid Modification Medication Therapy on Progression of Atherosclerosis and Restenosis of Femoral Arteries Measured Using High Resolution Magnetic Resonance Imaging (MRI) to Examine the Femoral Artery for Progression of Atherosclerosis
The primary outcome variable was the change in superficial femoral artery (SFA) wall volume over 24-months, as determined by MRI. The 24-month changes in SFA lumen and SFA total vessel volumes were also analyzed. Analysis details: A total of 102 patients were randomized. 87 patients completed baseline MRI. Between randomization and the baseline visit, 1 patient withdrew from the study, 8 patients opted out from baseline imaging, and 6 additional patients declined blood collection at baseline. The multilevel models (primary endpoint) used all available imaging data (n=91), including patients who only completed baseline imaging (n=20) or completed at least 2 imaging visits other than baseline (n=4).
Time frame: Measured at baseline and 24 Months
Population: Multilevel models were used to describe changes over time in the MRI outcome variables and to compare the drug therapy groups. The advantage of multilevel models is the capability to use data with missing or irregularly timed observations, due to death or loss to follow-up, on the outcome variable.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Triple Therapy | Effect of Intensive Lipid Modification Medication Therapy on Progression of Atherosclerosis and Restenosis of Femoral Arteries Measured Using High Resolution Magnetic Resonance Imaging (MRI) to Examine the Femoral Artery for Progression of Atherosclerosis | 58.1 mm^3, at 24-months | Standard Error 5.5 |
| Mono Therapy | Effect of Intensive Lipid Modification Medication Therapy on Progression of Atherosclerosis and Restenosis of Femoral Arteries Measured Using High Resolution Magnetic Resonance Imaging (MRI) to Examine the Femoral Artery for Progression of Atherosclerosis | 60.5 mm^3, at 24-months | Standard Error 5.1 |
Secondary
Change in Total Cholesterol (mg/dl) From Baseline to Month 12
Lipids: Total cholesterol (mg/dl); Lipid Data at 12-Months (change from baseline) \[mg/dl\].
Time frame: Measured at baseline and 12 months
Population: All values are medians and interquartile range (IQR). P-values were calculated with the KruskaleWallis rank test.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Triple Therapy | Change in Total Cholesterol (mg/dl) From Baseline to Month 12 | -30.0 mg/dl |
| Mono Therapy | Change in Total Cholesterol (mg/dl) From Baseline to Month 12 | -7.5 mg/dl |