Acute Coronary Artery Syndrome
Conditions
Keywords
plaque, LDL, statin, endothelial, apheresis, acute coronary artery syndrome
Brief summary
The purpose of this randomized, multi-site, clinical trial is to determine whether intensive therapy consisting of cholesterol-lowering statin drugs plus apheresis to cleanse the blood of low-density lipoprotein (LDL) cholesterol is more effective than statin therapy alone in reducing plaque volume in heart arteries of patients who have already suffered an acute coronary syndrome (ACS). The study will also investigate whether this intensive approach can help increase the presence of endothelial progenitor cells (EPC), stem cells that have been shown to reduce cardiovascular (CV) events in ACS patients. This study has two phases and FDA approval for phase II has been received and all information has been updated to reflect PREMIER Phase II.
Detailed description
Using statins to lower blood cholesterol, and specifically LDL, is well established as a long-term strategy to reduce CVs and even death. But the most intensive pharmacologic lipid-lowering therapy with statins, though proven superior to standard dose regimens, is still associated with an unacceptably high rate of recurrent CV events early after an ACS. This study hypothesizes that for ACS patients undergoing percutaneous coronary intervention (PCI), intensive lipid-lowering therapy consisting of statins and LDL-apheresis (ILLT) will significantly reduce the total coronary atheroma volume of vulnerable plaque and augment mobilization of peripherally circulating EPC colony forming units, compared to guideline statin monotherapy (SMT). ILLT will lead to fewer CV events for these patients. Patients presenting at four VA sites with ACS will be screened and consented before undergoing uncomplicated PCI (balloons or stents) and intravascular ultrasound with virtual histology (IVUS-HS). They will then be randomized into the ILLT arm or SMT arm of the study. The ILLT group will receive one treatment of LDL-apheresis plus a daily oral 40- 80mg dose of Atorvastatin or equivalent statin; the SMT group will only get 40-80mg Atorvastatin or equivalent. Patients will again undergo IVUS-HS 12 weeks after enrollment to measure atheroma volume; EPC level will also be checked. The three-year duration of the study includes 24 months of accrual, six months of follow-up, and 12 months of study closure and data analysis. A two-sample t-test of mean difference with 90% power and 0.65 Cohen's D effect size provides a total sample size estimate of 102. Counting 20% drop-out rate, the sample size increases to 128. The recent FDA recommendations regarding the design of the study have been included in the revised study protocol: 1. The safety data will be submitted to the FDA. 2. Patients will be randomized to both LDL-apheresis and an oral daily dose of 40-80mg Atorvastatin or equivalent statin (Intensive LDL-lowering therapy/ILLT) or a daily dose of 40-80mg of Atorvastatin or equivalent statin without LDL-apheresis (standard statin monotherapy/SMT) following an uncomplicated PCI.
Interventions
The intensive LDL-lowering therapy uses LDL-apheresis in addition to the standard statin therapy. The device used in this study is the LIPOSORBER LA-15 System, manufactured by Kaneka Pharma America LLC. A filter separates plasma from whole blood, the Liposorber -columns remove LDL from the plasma. The system recombines plasma and blood cells and returns them into the patient's body. This procedure typically takes about 3 hours. The procedure provides an immediate reduction in a patient's lipid levels. A single apheresis treatment can lower LDL by more than 80%, but levels return to baseline within 3 weeks.
The standard statin therapy of 40-80mg oral daily dose of Atorvastatin or other equivalent types of statin to lower LDL in blood for both randomized groups.
Sponsors
VA Office of Research and Development
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
31 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Willing and able to provide informed consent (including HIPAA) * Age \>30 years * Presenting with acute coronary syndrome (ACS), manifested as unstable angina or non-ST-elevation myocardial infarction * Referred for clinically-indicated, non-emergent (the procedure is not required to be performed within 3 hours after patient presentation) coronary angiography and PCI with Intravascular Ultrasound with Virtual Histology (IVUS-VH) of target coronary artery for ACS * Successful placement of two large bore IV cannulas in bilateral upper extremities * Fasting (12 hrs.) LDL 70mg/dl while on less than or equal to 80mg Atorvastatin or equivalent dose of other statin, performed at time of admission or prior to PCI.
Exclusion criteria
* Known allergy to aspirin, clopidogrel, statins, or iodinated contrast * Positive pregnancy test, planning to become pregnant, or breast-feeding * Coexisting conditions that limit life expectancy to less than six months or affect patient compliance * Uncontrolled fasting (12 hrs.) triglyceride levels ( 500mg/dl) * Already participating in an investigational device or drug study * History of heparin induced thrombocytopenia (HIT) * Persons with estimated glomerular filtration rate (eGFR) of less than 45 ml/min * ST-elevation myocardial infarction at admission * Abnormal liver function test (LFT) at time of admission or prior to PCI with abnormal LFT defined as any liver transaminases (ALT or AST) 3 times the upper limit of the normal laboratory reference * Pre-PCI or post-PCI left ventricular ejection fraction \<25% by echo or cardiac catheterization done after admission * Pre-PCI, intra-PCI, or post-PCI hemodynamic instability with hypotension * Pre-PCI, intra-PCI, or post-PCI cardiac arrest * Pre-PCI or post-PCI acute heart failure with or without pulmonary edema * Intra-PCI or post-PCI sustained ventricular tachycardia * Complicated PCI, defined as PCI with any of the vascular access complications (large hematoma with lump \> 5 cm or requiring medical treatment; arteriovenous (AV) fistula; pseudo aneurysm requiring treatment; retroperitoneal bleeding), or PCI with any of the procedural complications (abrupt vessel closure; no-reflow phenomenon; new angiographic thrombus; new major dissection with reduced flow; catheter-related thrombus), or PCI requiring further medical treatments (urgent coronary artery bypass graft (CABG); endotracheal intubation; unplanned in-aortic balloon pump; left ventricular assist device (LVAD); covered stent; unplanned temporary pacemaker wire; administration of inotropes; cardiopulmonary resuscitation (CPR)) , or PCI resulting in clinical events (death; stroke; myocardial infarction; stent thrombosis) during or within 24 hours after the index PCI * Post-PCI ongoing chest pain * Post-PCI severe groin pain and hematoma \> 5cm in diameter * Persons whose hemoglobin is less than 9 grams following the index PCI/IVUS procedure, or who experience a drop in hemoglobin of greater than or equal to 2 grams following the procedure * Not able to comply with study protocol as determined by the investigators
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in the Total Atheroma Volume From Baseline to 12 Weeks | 12 weeks | The primary effectiveness outcome measure was the change in the total atheroma volume within a ≥ 20 mm long segment of the target coronary artery from baseline to 12 weeks post-PCI. The measurement was done via IVUS-VH at 2 time points (baseline during index PCI and 90-day follow-up). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in % Necrotic Core Component of Atheroma | 12 weeks | The %NC component of atheroma were obtained via IVUS-VH at 2 time points (baseline during index PCI and 90-day follow-up). |
| Endothelial Progenitor Cell Colony Forming Units/ml of Peripheral Blood Across Time | 12 weeks | The cell culture assay and quantification of circulating EPC-CFU were performed for patients recruited at the Dallas VA center only. The assay were done at 4 time points (pre-PCI, post-PCI, 30-day follow-up, and 90-day follow-up). |
| Major Adverse CV Events | 6 months | The number of patients who experienced major adverse cardiovascular endpoints (MACE) including death, myocardial infarction, coronary revascularization, and stroke during the follow-up periods. |
Countries
United States
Participant flow
Recruitment details
Subject recruitment for Phase II pivotal study started on March 30, 2015, and the first participant was randomized on April 9, 2015. The recruitment period stopped in July 2017. For all 4 participating sites, Dallas, Nashville, Oklahoma City, and Denver randomized 80, 5, 38, and 6 participants, respectively.
Pre-assignment details
There were 270 subjects consented and enrolled into the study before entering catheterization lab to have the PCI procedure, but 141 subjects were not randomized to treatment assignments with the major exclusion reason as not able to comply with study protocol based on the inclusion/exclusion criteria.
Participants by arm
| Arm | Count |
|---|---|
| Intensive LDL-lowering Therapy (ILLT) Patient of acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) is randomized to LDL-apheresis in addition to the standard statin therapy of an oral daily dose of 40-80mg of Atorvastatin or equivalent. The device used in this study is the LIPOSORBER LA-15 System, manufactured by Kaneka Pharma America LLC. A filter separates plasma from whole blood, the Liposorber -columns remove LDL from the plasma. The system recombines plasma and blood cells and returns them into the patient's body. This procedure typically takes about 3 hours. The procedure provides an immediate reduction in a patient's lipid levels. A single apheresis treatment can lower LDL by more than 80%, but levels return to baseline within 3 weeks. | 63 |
| Standard Statin Monotherapy (SMT) Patient of acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) is randomized to an oral daily dose of 40-80mg of Atorvastatin or equivalent without LDL-apheresis. | 66 |
| Total | 129 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 1 | 0 |
| Overall Study | Lost to Follow-up | 2 | 2 |
| Overall Study | no visit due to illness | 2 | 1 |
| Overall Study | Refuse Follow-up Visit | 1 | 5 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Standard Statin Monotherapy (SMT) | Intensive LDL-lowering Therapy (ILLT) | Total |
|---|---|---|---|
| Age, Continuous | 67.3 years STANDARD_DEVIATION 7.7 | 64.2 years STANDARD_DEVIATION 9.4 | 65.8 years STANDARD_DEVIATION 8.7 |
| Diastolic BP | 77.0 mmHg STANDARD_DEVIATION 13.1 | 78.7 mmHg STANDARD_DEVIATION 13.1 | 77.8 mmHg STANDARD_DEVIATION 13.1 |
| Heart Rate | 71.8 beats/min STANDARD_DEVIATION 13.6 | 79.0 beats/min STANDARD_DEVIATION 16 | 75.3 beats/min STANDARD_DEVIATION 15.2 |
| Height | 70.0 inches STANDARD_DEVIATION 2.9 | 69.9 inches STANDARD_DEVIATION 2.7 | 70.0 inches STANDARD_DEVIATION 2.8 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 14 Participants | 13 Participants | 27 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 | 52 Participants | 48 Participants | 100 Participants |
| Region of Enrollment United States | 66 Participants | 63 Participants | 129 Participants |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 2 Participants |
| Sex: Female, Male Male | 65 Participants | 62 Participants | 127 Participants |
| Smoker Current | 14 Participants | 16 Participants | 30 Participants |
| Smoker Former | 40 Participants | 31 Participants | 71 Participants |
| Smoker Never | 12 Participants | 16 Participants | 28 Participants |
| Systolic BP | 141.8 mmHg STANDARD_DEVIATION 23.9 | 140.0 mmHg STANDARD_DEVIATION 22.1 | 140.9 mmHg STANDARD_DEVIATION 22.9 |
| Weight | 221.7 pounds STANDARD_DEVIATION 46.7 | 225.0 pounds STANDARD_DEVIATION 56.7 | 223.3 pounds STANDARD_DEVIATION 51.6 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 63 | 0 / 66 |
| other Total, other adverse events | 42 / 63 | 39 / 66 |
| serious Total, serious adverse events | 28 / 63 | 28 / 66 |
Outcome results
Primary
Change in the Total Atheroma Volume From Baseline to 12 Weeks
The primary effectiveness outcome measure was the change in the total atheroma volume within a ≥ 20 mm long segment of the target coronary artery from baseline to 12 weeks post-PCI. The measurement was done via IVUS-VH at 2 time points (baseline during index PCI and 90-day follow-up).
Time frame: 12 weeks
Population: Reported results are based on observed data from participants who had primary outcome measured.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intensive LDL-lowering Therapy (ILLT) | Change in the Total Atheroma Volume From Baseline to 12 Weeks | -7.63 mm^3 | Standard Deviation 23.78 |
| Standard Statin Monotherapy (SMT) | Change in the Total Atheroma Volume From Baseline to 12 Weeks | -3.10 mm^3 | Standard Deviation 17.74 |
p-value: 0.2533t-test, 2 sided
Secondary
Change in % Necrotic Core Component of Atheroma
The %NC component of atheroma were obtained via IVUS-VH at 2 time points (baseline during index PCI and 90-day follow-up).
Time frame: 12 weeks
Population: Reported results are based on observed data from participants who had secondary outcome measured.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intensive LDL-lowering Therapy (ILLT) | Change in % Necrotic Core Component of Atheroma | 0.44 percentage of atheroma component | Standard Deviation 6.81 |
| Standard Statin Monotherapy (SMT) | Change in % Necrotic Core Component of Atheroma | 0.94 percentage of atheroma component | Standard Deviation 9.89 |
p-value: 0.779t-test, 2 sided
Secondary
Endothelial Progenitor Cell Colony Forming Units/ml of Peripheral Blood Across Time
The cell culture assay and quantification of circulating EPC-CFU were performed for patients recruited at the Dallas VA center only. The assay were done at 4 time points (pre-PCI, post-PCI, 30-day follow-up, and 90-day follow-up).
Time frame: 12 weeks
Population: Reported results are based on observed data from participants who had secondary outcome measured. This outcome was captured for Dallas site only.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Intensive LDL-lowering Therapy (ILLT) | Endothelial Progenitor Cell Colony Forming Units/ml of Peripheral Blood Across Time | baseline pre-PCI | 11.85 colonies/ml | Standard Deviation 9.24 |
| Intensive LDL-lowering Therapy (ILLT) | Endothelial Progenitor Cell Colony Forming Units/ml of Peripheral Blood Across Time | baseline post-PCI | 15.30 colonies/ml | Standard Deviation 10.96 |
| Intensive LDL-lowering Therapy (ILLT) | Endothelial Progenitor Cell Colony Forming Units/ml of Peripheral Blood Across Time | 30-day | 21.60 colonies/ml | Standard Deviation 14.78 |
| Intensive LDL-lowering Therapy (ILLT) | Endothelial Progenitor Cell Colony Forming Units/ml of Peripheral Blood Across Time | 90-day | 16.32 colonies/ml | Standard Deviation 13.29 |
| Standard Statin Monotherapy (SMT) | Endothelial Progenitor Cell Colony Forming Units/ml of Peripheral Blood Across Time | 90-day | 15.06 colonies/ml | Standard Deviation 14.33 |
| Standard Statin Monotherapy (SMT) | Endothelial Progenitor Cell Colony Forming Units/ml of Peripheral Blood Across Time | baseline pre-PCI | 11.99 colonies/ml | Standard Deviation 11.37 |
| Standard Statin Monotherapy (SMT) | Endothelial Progenitor Cell Colony Forming Units/ml of Peripheral Blood Across Time | 30-day | 20.40 colonies/ml | Standard Deviation 17.87 |
| Standard Statin Monotherapy (SMT) | Endothelial Progenitor Cell Colony Forming Units/ml of Peripheral Blood Across Time | baseline post-PCI | 17.89 colonies/ml | Standard Deviation 16.91 |
p-value: 0.4549Mixed Models Analysis
Secondary
Major Adverse CV Events
The number of patients who experienced major adverse cardiovascular endpoints (MACE) including death, myocardial infarction, coronary revascularization, and stroke during the follow-up periods.
Time frame: 6 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intensive LDL-lowering Therapy (ILLT) | Major Adverse CV Events | 5 Participants |
| Standard Statin Monotherapy (SMT) | Major Adverse CV Events | 2 Participants |
p-value: 0.2663Fisher Exact