Atorvastatin for Preventing Occlusion and Restenosis After Intracranial Artery Stenting
Information source: Jinling Hospital, China
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: CVD
Intervention: atorvastatin (Drug)
Phase: Phase 4
Status: Active, not recruiting
Sponsored by: Jinling Hospital, China Official(s) and/or principal investigator(s): Xinfeng Liu, MD, Study Chair, Affiliation: Department of Neurology, Jinling Hospital, Nanjing University School of Medicine
Summary
Severe intracranial atherosclerosis with concomitant stenosis is responsible for
approximately 10% of all strokes. Retrospective studies have indicated that up to 50% of
patients with a recently symptomatic intracranial stenosis experience recurrent ischemic
events. Due to the high stroke risk, patients with high grade 70% symptomatic intracranial
stenosis represent the main target group for endovascular treatment. Atorvastatin is widely
used in the treatment of hyperlipidemia, especially after acute myocardial infarction.
High-dose atorvastatin has been known to stop the progression of atherosclerosis and to
decrease the levels of inflammatory markers. Several recent clinical trials have proved
atorvastatin can reduce restenosis after stent implantation in coronary artery. But the
feasibility of atorvastatin in preventing restenosis in patients with intracranial stenting
has not been evaluated. The purpose of this prospective, randomized, single-blinded trial is
to evaluate the effect of atorvastatin 80 mg daily in preventing restenosis and related
vascular events in patients with intracranial stent implantation.
Clinical Details
Official title: Phase 4 of Atorvastatin for Preventing Occlusion and Restenosis After Intracranial Artery Stenting
Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Single Blind (Investigator), Primary Purpose: Treatment
Primary outcome: Target lesion failure
Secondary outcome: Clinical endpointAngiographic follow-up In-segment binary restenosis rate 12 months after the index procedure Effects of atorvastatin on blood lipid and inflammatory levels Effects of atorvastatin treatment on neurological function outcomes
Detailed description:
Severe intracranial atherosclerosis with concomitant stenosis is responsible for
approximately 10% of all strokes. In Asian populations intracranial stenoses are even the
most commonly found vascular lesions. Retrospective studies indicated that up to 50%
patients with recently symptomatic intracranial stenosis experienced recurrent ischemic
events. The risk of recurrent stroke increases with the aggravation of intracranial artery
stenosis. In Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) trial, 14% and 23% of
the patients with TIA or stroke attributable to high-grade intracranial stenosis had further
ipsilateral ischemic stroke over the next year despite best medical treatments. If
percentage of intracranial stenosis exceeded 70%, the stroke risk went up to 20% in the
first year. These results spurred the enthusiasm for endovascular approaches, including
percutaneous transluminal balloon angioplasty (PTA) and stenting to treat this potentially
harmful disease. Due to the high stroke risk, patients with high-grade ≥70% symptomatic
intracranial stenosis represent the main target group for endovascular treatment.
Endovascular management of intracranial arthrosclerosis is, however, associated with an
appreciable number of potential complications, including local thrombosis, thromboembolism
and, especially, restenosis and in-stent occlusion. To date, the reported 1-year restenosis
rates after intracranial stenting in case series and small trials have varied widely,
ranging from less than 10% in some to more than 50% in others. According to a recent review,
the overall 1-year restenosis rate of intracranial stenting was 25%, and the in-stent
occlusion rate was nearly 10%. These relatively high rates of restenosis and re-occlusion
after procedure have raised the question about whether stenting improves the natural course
of intracranial atherosclerosis.
Compared with the relatively good durability of angioplasty and stenting procedures within
the extracranial carotid artery, the high incidence of restenoses appears to be a major
drawback of intracranial stenting. Recent studies suggested that especially younger patients
treated with self-expandable stents within the anterior circulation have a higher risk for
this complication. Considering about 33% of restenoses were symptomatic (TIA or stroke),
decreasing restenosis rates after intracranial stenting became the key issue for improving
the clinical feasibility of this treatment strategy.
Animal studies have indicated that statins can inhibit platelet aggregation and release of
platelet-derived mediators, reduce inflammatory responses of vascular wall, improve artery
endothelial function, all of which may contribute to decrease proliferative responses after
stent implantation. These profiles make statin optimal for preventing restenosis or
occlusion after intracranial stenting, but this strategy has not been tested by clinical
trials to date, although statin has been proved by several recent clinical trials to be
efficacious in preventing restenosis after stent implantation in coronary arteries.
The initial attempts to lower restenosis rates after coronary balloon angioplasty have
failed to demonstrate beneficial effects of statin therapy, although the FLuvastatin
Angioplasty REstenosis (FLARE) trial reported a reduction in mortality and myocardial
infarction in the fluvastatin treatment patients. Subsequent studies, however, did confirm
that statin therapy can decrease restenosis rates and the related ischemic events after
stent implantation in patients with coronary artery diseases. Unlike chronic vessel
shrinkage may account for ≥70% of recurrence rates after balloon angioplasty, restenosis
after coronary stent implantation is entirely due to neointimal proliferation. Experimental
studies have shown that statins are capable of inhibiting intimal proliferation after
arterial injury. Results from other studies suggested that statins interfere with
proliferative responses after coronary stent implantation in humans. Statin therapy was
associated not only with a significant reduction in late lumen loss, but also with a greater
net gain after coronary stent implantation. Thus, the discrepancy of the effects of statin
therapy on restenosis development after balloon angioplasty compared with coronary stent
implantation may be easily reconciled by the different mechanisms underlying the recurrence
of luminal narrowing.
Elevated LDL cholesterol levels increase platelet and red-cell aggregability, and thrombosis
is believed to have a decisive role in the process of restenosis and in-stent occlusion.
Lowering LDL cholesterol levels decreases rates of restenosis in the rat-carotid model,
whereas treatment with statin decreases the progression of disease in the rabbit-iliac model
independently of an effect on LDL cholesterol. In contrast, in the
overstretched-swine-coronary model, no relation between either LDL cholesterol or statin and
restenosis was observed. An attempt was made to resolve these conflicts with a prospective
clinical study in which 157 patients were treated with or without statin. The results
indicated that the rate of restenosis was 12 percent with and 44 percent without statin.
More than one study also identified the diagnosis of hypercholesterolemia at the time of
coronary stent implantation as a major independent predictor for reduced recurrence rates.
But a recent study indicated that statin therapy was associated with a comparable reduction
of restenosis rates in patients with average serum cholesterol levels at baseline, suggest
that the observed effects are not only due to reduced serum cholesterol levels, but also may
be related to the non-lipid anti-atherosclerotic properties of statins.
Since the efficacy of high dose statin in preventing restenosis after coronary artery
stenting has been confirmed by several clinical trials, it is reasonable to presume that
high-dose statin is also efficacious in preventing restenosis and in-stent occlusion after
intracranial stenting, because these two vasculatures share very similar anatomical
profiles. The present study is aimed to evaluate the preventive effects of atorvastatin 80
mg daily in decreasing restenosis in a consecutive series of patients undergoing
intracranial stent implantation at a single center. The hypotheses of this study is that
patients with atorvastatin therapy is associated with improved clinical outcome and reduced
restenosis rates 12 months after intracranial stent implantation than patients without
atorvastatin therapy.
Eligibility
Minimum age: 18 Years.
Maximum age: N/A.
Gender(s): Both.
Criteria:
Inclusion Criteria:
- 1: Clinical inclusion criteria
1. Subject is ≥18 years old
2. Eligible for percutaneous endovascular intervention
3. Documented severe (70%) symptomatic intracranial stenosis
4. Acceptable candidate for intracranial stenting
5. Subject (or legal guardian) understands the study requirements and the treatment
procedures and provides written Informed Consent before any study-specific tests
or procedures are performed
6. Subject willing to comply with all specified follow-up evaluations
- 2: Angiographic Inclusion Criteria
1. Target lesion located in intracranial internal artery, intracranial vertebral
artery, basilar artery or middle cerebral artery
2. Target lesion must be symptomatic
3. Target lesion diameter stenosis ≥70%
4. Reference vessel diameter (RVD): ≥2. 0 mm to ≤6. 0 mm
5. Cumulative target lesion length (area to be treated must be completely coverable
by one study stent) ≤30 mm
6. Target lesion is presumed accessible by endovascular treatment.
7. One non target lesion may be treated in a non target vessel
8. Non-target lesion in non-target vessel must be treated with a commercially
available stent.
9. Treatment of a non target lesion (if performed) must be deemed a clinical
angiographic success, without requiring use of unplanned additional stent(s).
10. Treatment must be completed prior to treatment of target lesion
Exclusion Criteria:
- Contraindication to ASA, or to both clopidogrel and ticlopidine
- Known hypersensitivity to atorvastatin
- Known allergy to stainless steel
- Known allergy to platinum
- Previous treatment of the target vessel with angioplasty
- Previous treatment of the target vessel with stent
- Previous treatment of any non target vessel with stent within 9 months of the index
procedure
- Planned endovascular treatment to post index procedure
- Planned or actual target vessel treatment with an unapproved device, directional or
rotational intracranial atherectomy, laser, cutting balloon or transluminal
extraction catheter immediately prior to stent placement
- Cerebral infarction within 1 month prior to the index procedure
- Myocardial infarction within the past 1 month
- Uncontrollable malignant hypertension (>180/110 mmHg) before procedure
- Acute or chronic renal dysfunction (creatinine > 2. 0 mg/dl or 177 μmol/l)
- Anticipated treatment with atorvastatin or other statins during the 12 months after
the index procedure
- Any prior true anaphylactic reaction to contrast agents; defined as known
anaphylactoid or other non-anaphylactic allergic reactions to contrast agents that
cannot be adequately pre-medicated prior to the index procedure
- Leukopenia (leukocyte count < 3. 5 × 109/liter)
- Thrombocytopenia (platelet count < 100,000/mm3)
- Thrombocytosis (> 750,000/mm3)
- Seizure 12 months before procedure
- Intracranial tumor
- Active peptic ulcer or active gastrointestinal (GI) bleeding
- Male or female with known intention to procreate within 12 months after the index
procedure
- Positive pregnancy test within 7 days before the index procedure, or lactating
- Life expectancy of less than 24 months due to other medical conditions
- Co-morbid condition(s) that could limit the subject's ability to comply with study
follow-up requirements or impact the scientific integrity of the study
- Currently participating in another investigational drug or device study
- Current treatment, or past treatment within 6 months with atorvastatin or other
statins
Locations and Contacts
Department of Neurology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu 210002, China
Additional Information
Starting date: January 2011
Last updated: February 7, 2014
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