Highlights From ACC
Carotid Artery Stenting Supported By CASES-PMS and CAPTURE 3000 Registry Data
March 14, 2006—Results of postmarketing studies from Cordis Endovascular (a division of Cordis Corporation, a Johnson & Johnson company, Warren, NJ) and from Guidant Corporation (Indianapolis, IN) testing the safety of carotid artery stenting (CAS) in high-risk patients demonstrated that interventionists from multiple specialties who undergo a formalized training program can perform CAS and achieve excellent results. The studies were presented in seperate lectures at the American College of Cardiology’s 55th Annual Scientific Session, which was held on March 11-14 in Atlanta. Theodore L. Schreiber, MD, presented Cordis’s Carotid Artery Stenting With Emboli Protection Surveillance-Post-Marketing Study (CASES-PMS). William A. Gray, MD, presented Guidant’s Carotid Acculink/Accunet Post-Approval Trial to Uncover Unanticipated or Rare Events (CAPTURE 3000) Registry.
CASES-PMS is a multicenter, prospective, single-arm, open-label periapproval study designed to assess the outcomes of stenting with Cordis’s investigational Precise Nitinol Self-Expanding Stent and the company’s investigational Angioguard XP Emboli Capture Guidewire System in the treatment of obstructive artery disease in relation to the outcomes of the pivotal study, Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy (SAPPHIRE). The primary objective of CASES-PMS is to demonstrate that outcomes in a periapproval setting, including use of a detailed training program in CAS for physicians not experienced in CAS, allow outcomes that are similar to those obtained in the pivotal trial setting. According to the company, these initial results both corroborate the findings of the SAPPHIRE study, and demonstrate that formalized training in CAS allows physicians from multiple specialties with prior endovascular experience to perform CAS and obtain outcomes as good as the experts who performed the clinical trials. Cordis Endovascular initiated CASES, its comprehensive training program for physicians and other relevant health care professionals, in 2004. The training includes didactic review, case observations and simulation training, and hands-on experience at the CASES regional education centers across the country.
According to Cordis, the preliminary results from CASES-PMS showed that high surgical-risk patients treated with CAS had 30-day major adverse event (MAE) rates identical with that of patients treated with CAS in SAPPHIRE. The data showed an MAE rate of 4.8% (62/1279) among patients treated with CAS in CASES-PMS compared with 4.8% (8/167) of CAS-treated patients in the randomized arm of the SAPPHIRE trial. Overall, the rate of stroke at 30 days was 3.6% (46/1279), whereas the rate of stroke in patients treated by physicians who completed the entire training program was 3.7% (3/82). CASES-PMS enrolled 1,493 patients at more than 70 sites in the US; preliminary data presented at ACC was on the first 1,279 enrolled patients. The study enrolled high surgical-risk patients with de novo atherosclerotic or postendarterectomy restenotic obstructive lesions in native carotid arteries. Inclusion and exclusion criteria matched those in the SAPPHIRE study. Clinical follow-up was conducted at 30 days, and will be conducted again at 1 year postprocedure. The 30-day assessments include a neurological examination and an evaluation of adverse events. The 30-day MAE rate was defined as the 30-day composite of all death, myocardial infarction, and stroke. Clinical events at 1 year also will be assessed.
In Guidant’s CAPTURE 3000 Registry, Dr. Gray and his colleagues collected data on more than 3,000 patients treated by 240 interventionists at 118 medical centers throughout the US as part of the FDA-required postapproval study of the company’s Rx Acculink carotid stent system and Rx Accunet embolic protection system. According to the company, the goal of the ongoing CAPTURE 3000 Registry is to evaluate rare or unanticipated events among patients treated with carotid stenting using the Acculink/Accunet devices. The present analysis included the first 2,500 patients in the registry. Symptomatic disease was present in 9.3% of patients, 34% had diabetes, and 20% were smokers. Of the physicians, 71% had performed at least 10 carotid stent procedures as the primary operator. At 30 days, death, stroke, or MI had occurred in 5.7% of patients. Among the components of the composite event rate, death had occurred in 1.6%, stroke in 4.2%, and MI in 0.9% patients. Among the cohort of asymptomatic patients (n=2,267), the composite event rate was 4.9%, with death in 1.3%, stroke in 3.5%, and MI in 0.7% of patients. Among the cohort of symptomatic patients (n=233), the composite event rate was 14.2%, with death occuring in 4.3%, stroke in 11.2%, and MI in 2.6% of patients. Event rates were higher in patients aged greater than or equal to 80 years with a composite rate of 8.2%, and death in 2%, stroke in 6.6%, and MI in .5% patients.
“The transfer of carotid stenting technology from clinical trial sites to clinical practice sites appears to have been successful with the same, or even better, outcomes in the clinical setting,” commented Dr. Gray.
On March 17, Guidant announced that the first patient has been enrolled in the company-sponsored CAPTURE 2 postapproval study of CAS with the Acculink/Accunet systems in high-surgical risk patients. A key objective of the study is to gather additional and more extensive clinical data to extend Medicare coverage of carotid stenting to a broader group of patients. The study will include up to 10,000 patients at 400 US centers. According to the company, data from CAPTURE 2 will provide a deeper and broader understanding of carotid stenting in real-world clinical settings with physicians who enter Guidant’s training program with varying levels of experience, and will examine outcomes in both symptomatic and asymptomatic patients. The study will use an innovative electronic data capture system to collect the rate of death, stroke, and MI at 30 days after the procedure. Guidant will work with Dartmouth Medical School and the CMS to link to the Medicare database to collect 1-year patient outcomes. An executive committee made up of physicians from multiple specialties will oversee the trial.
ASTEROID Trial Shows Intensive Statin Therapy May Regress Arterial Plaque
March 13, 2006—The ASTEROID (A Study To Evaluate the Effect of Rosuvastatin On Intravascular Ultrasound-Derived Coronary Atheroma Burden) Trial demonstrated that very intensive cholesterol lowering with a statin drug can regress the build-up of plaque in the coronary arteries. According to investigators, this finding has never before been observed in a study using statin drugs. Previous research had indicated that intensive statin therapy could prevent the progression of coronary atherosclerosis, or arterial plaque build-up, but not actually reduce disease burden. The ASTEROID data was presented by Steven E. Nissen, MD, at the American College of Cardiology’s 55th Annual Scientific Session, which was held on March 11-14 in Atlanta. The Journal of the American Medical Association published the results (2006;295:1556-1565).
The ASTEROID trial was conducted at 53 community and tertiary care centers in the US, Canada, Europe, and Australia. The goal of the trial was to evaluate the effect of treatment with intensive statin therapy on IVUS-assessed atherosclerosis disease progression among patients with angiographic coronary disease. All patients were treated with 40 mg of rosuvastatin in an open-label manner (n=507). Patients underwent IVUS of a single vessel that had not been intervened upon at baseline. Patients then underwent follow-up IVUS at
24 months to evaluate the change in atherosclerosis, which was assessed by a core lab in a time-sequence blinded manner. A total of 349 patients had baseline and follow-up IVUS.
LDL levels were reduced from 130.4 mg/dL at baseline to a mean of 60.8 mg/dL during the study, with 75% of patients achieving an LDL <70 mg/dL. HDL levels were increased from 43.1 mg/dL at baseline to 49 mg/dL. The coprimary endpoint of change in percent atheroma volume was reduced by a mean of .98%. Regression in percent atheroma volume was observed in 63.6% of patients and progression in 36.4%. The other coprimary endpoint, change in nominal atheroma volume in the 10-mm subsegment with the greatest disease severity at baseline, was also reduced by mean of -6.1 mm3. Total atheroma volume was also reduced at follow-up by a mean of -14.7 mm3. IVUS results were similar in the prespecified subgroups. Adverse events leading to study drug discontinuation included musculoskeletal complaints (3.7%) and cardiovascular disorders (4.3%). There were no cases of rhabdomyolysis.
The investigators concluded that among patients with angiographic coronary disease, treatment with intensive statin therapy with 40 mg of rosuvastatin was associated with atherosclerosis regression on IVUS at 2-year follow up. Previous IVUS studies showed a reduction in atherosclerosis progression with intensive statin therapy compared to a more moderate lipid-lowering regimen. However, the present study is the first large-scale study to demonstrate atherosclerosis regression with intensive statin therapy. The authors attribute the regression to the very large reductions in LDL and increases in HDL. However, regression in atheroma volume in the most diseased 10-mm subsegment was observed even in patients with an average LDL of 100 mg/dL (-6.9 mm3) and those with an average HDL <35 mg/dL (-5.9 mm3). The impact of aggressive lipid lowering on clinical events was not fully evaluated in this trial.
“This regimen significantly lowered bad cholesterol, and surprisingly, markedly increased good cholesterol levels,” commented Dr. Nissen. “We conclude that very low LDL levels (below current guidelines), when accompanied by raised HDL, can regress, or partially reverse, the plaque buildup in the coronary arteries.”
CHARISMA Raises Questions of Efficacy of Clopidogrel
March 12, 2006—Deepak L. Bhatt, MD, FACC, presented the findings of the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) study at the American College of Cardiology’s (ACC’s) 55th Annual Scientific Session, which was held on March 11-14 in Atlanta. The results will be published in The New England Journal of Medicine. The conclusion of CHARISMA, an international study of more than 15,000 high-risk patients, was that the addition of clopidogrel to standard, low-dose aspirin failed to significantly reduce the combined rate of death, heart attack, or stroke. However, in an unexpected finding, patients with established cardiovascular disease did benefit from dual antiplatelet therapy, whereas patients with multiple risk factors alone may have experienced some harm.
According to the ACC, CHARISMA enrolled 15,603 patients who had either documented cardiovascular disease or only multiple risk factors for future atherosclerosis. Patients were randomly assigned to 75 mg of clopidogrel daily or placebo, in addition to low-dose aspirin. The results showed that, in the overall population of patients, clopidogrel plus aspirin had no significant effect on clinical outcomes after a median follow-up of 28 months. The combined rate of cardiovascular death, heart attack, or stroke was 7.3% in the group randomly assigned to placebo plus aspirin, versus 6.8% in the patients assigned to clopidogrel plus aspirin, a difference that was not statistically significant. When clinical outcomes included not only cardiovascular death, heart attack, or stroke, but also hospitalization for an ischemic event, clopidogrel reduced the combined risk from 17.9% in the placebo group to 16.7% in the clopidogrel group, a difference that was statistically significant. Furthermore, when the analysis was limited to the 12,153 patients with established cardiovascular disease—excluding those with risk factors only—clopidogrel reduced the combined rate of cardiovascular death, heart attack, or stroke from 7.9% in the placebo group to 6.9% in the clopidogrel group, a statistically significant difference. Investigators observed no significant increase in severe bleeding in patients with established cardiovascular disease. By comparison, clopidogrel did not improve outcomes in patients with risk factors only, and may even have increased the risk of severe bleeding and mortality, the investigators noted.
“These results are intriguing,” commented Dr. Bhatt. “They suggest that combination antiplatelet therapy might be useful in a large, new group of patients—those with established cardiovascular disease—but offers no benefit whatsoever in patients only having risk factors for developing vascular disease.”
In a related story, the ACC issued a Public Health Alert on March 16 warning physicians and patients of the dangers of stopping clopidogrel therapy for patients with stents and certain other conditions. The ACC is concerned that recent media reports regarding the results of the CHARISMA Trial may be misinterpreted by patients with coronary stents and other conditions, causing these patients to inappropriately stop taking the anticlotting drug. The ACC noted that although the CHARISMA trial showed no benefit to combining clopidogrel and aspirin, this study does not invalidate use of the drug for approved indications, such as stenting. The public health alert warned that discontinuation of clopidogrel in patients with recently placed stents can cause clot formation within the stent, resulting in serious harm or death.
BASKET LATE Findings Suggest Clopidogrel Is Prematurely Stopped in Patients With DESs
March 14, 2006—Data from the Basel Stent Cost Effectiveness Trial (BASKET), a randomized study that compared bare-metal and drug-eluting stents, was evaluated by Matthias E. Pfisterer, MD, and colleagues to determine the risk of late stent thrombosis after discontinuation of clopidogrel. Investigators were concerned that physicians might be stopping the antiplatelet therapy too soon after treatment with a drug-eluting stent. The new analysis, known as Late Clinical Events Related to Late Stent Thrombosis After Stopping Clopidogrel (BASKET LATE), focused on 746 patients from the BASKET study who experienced no cardiac complications within the first 6 months of stent implantation and were advised to discontinue clopidogrel at that time. Investigators continued to follow-up with these patients for another 12 months. The BASKET LATE follow-up study determined the comparative rates of late stent thrombosis in patients treated with bare-metal and drug-eluting stents and the clinical consequences of this complication, including cardiac death, heart attack, and the need for a procedure to re-establish blood flow through the stented artery. Dr. Pfisterer presented the findings at the American College of Cardiology’s 55th Annual Scientific Session, which was held on March 11-14 in Atlanta.
The study population was composed of 21% ST elevation MI patients, 37% unstable angina, and 42% stable angina. Multivessel disease was present in 67%, and the culprit artery was the left anterior descending in 51% of patients. An average of 1.9 stents was used per patient. Principal findings showed that in the year following clopidogrel discontinuation, the primary composite endpoint of cardiac death or MI occurred significantly more frequently in the drug-eluting stent group (4.9% vs 1.3%). Nonfatal MI was also higher in the drug-eluting stent group (4.1% vs 1.3%) and cardiac death trended higher (1.2% vs 0%). There was no difference in restenosis-driven target vessel revascularization (4.5% vs 6.7%). Late stent thrombosis (combination of angiographic document thrombosis and thrombotic clinical events) occurred in 2.6% of the drug-eluting stent group and 1.3% of the bare-metal stent group. The median time of the late thrombotic event was 116 days after clopidogrel discontinuation, but events occurred throughout the 1-year follow up. Among patients with coronary artery disease treated with PCI, use of a drug-eluting stent was associated with significantly higher rates of cardiac death or MI compared with bare-metal stents in the year following clopidogrel discontinuation.
According to the investigators, many trials have demonstrated a reduction in target lesion revascularization with drug-eluting stents compared with bare metal stents in recent years, but none has ever demonstrated an effect on the hard endpoints of death or MI. The present study showed a more than three-fold increase in death or MI with drug-eluting stents in the year after clopidogrel discontinuation. Clopidogrel is generally prescribed for the first 6 months following stent placement, along with aspirin indefinitely. These BASKET LATE data suggest the 6-month antiplatelet regimen of clopidogrel may not be long enough to provide adequate protection from late thrombosis with drug-eluting stents. The investigators noted that it is unknown if a better strategy would be a longer duration of clopidogrel, a more potent antiplatelet drug, or a different drug elution or kinetic pattern on the stents. Further study on late thrombotic events with drug-eluting stents is strongly warranted given these findings, the investigators said.
MIST Study Misses Endpoint But Shows Benefits of PFO Closure for Migraine Relief
March 13, 2006—Results from the Migraine Intervention with StarFlex Technology (MIST) trial, a study to evaluate the effectiveness of patent foramen ovale (PFO) closure for the sole purpose of relieving migraines, failed to meet the study’s endpoints of eliminating 40% of migraines at 6 months, but showed positive treatment effects. The study was presented by co-Principal Investigators Peter Wilmshurst, MD, and Andrew Dowson, MD, at the Innovation in Intervention: i2 Summit 2006 held in conjunction with the American College of Cardiology’s 55th Annual Scientific Session, which was held on March 11-14 in Atlanta.
To definitively determine whether PFO repair can eliminate migraines, the MIST trial studied patients with severe, frequent migraines and a medium-to-large PFO, randomly assigning them to PFO closure or a sham intervention. Fifteen medical centers in the UK participated in the study. The study screened 432 migraine-with-aura patients for a PFO and enrolled 147 patients. All patients in the MIST study had general anesthesia and transesophageal echocardiography before randomization to determine the presence and size of the PFO. Patients who were assigned to the sham intervention awoke from anesthesia with a cut in the groin just as treated patients did. To further avoid the possibility of a placebo effect or bias in determining the effect of PFO closure on migraine frequency and severity, all patients were evaluated at monthly intervals over 6 months by neurologists who were unaware of the patients’ group assignments.
The MIST trial was sponsored by NMT Medical, Inc. (Boston, MA), the manufacturer of the StarFlex septal repair implant technology that was used exclusively in the trial. According to NMT, MIST is the first prospective, randomized, double-blind study to evaluate the effect of PFO closure on migraine headaches. A significant finding in the MIST study is that more than 60% of those screened had a right-to-left shunt. Of those patients, almost 40% had a moderate or large PFO, six times greater than the general population. As reported at the i2 Summit, the MIST results indicated an approximate 37% reduction in migraine burden (number of headaches multiplied by the length, in hours of headache) in those patients who received a StarFlex implant and a 17% reduction in those who received the sham procedure and no implant. This represents a statistically significant treatment effect. It also was reported that this variance appears to increase over time. The company expressed disappointment that MIST failed to meet its endpoints but stated that because the study was designed to help demonstrate clinical relevancy and not to obtain a specific regulatory approval, it will prove useful by providing the company and investigators with significant data that will be incorporated into the MIST II and MIST III studies.
“With no prior randomized, double-blind study to draw from, MIST was designed and primary endpoints were selected based upon a review and analysis of several previously reported device observational and migraine drug studies,” commented Dr. Wilmshurst. “Consistent with what was reported in the observational studies, we selected a challenging primary endpoint of 40% elimination in migraine headache at 6 months in the treatment group. Preliminary analysis of MIST data did not satisfy that endpoint; however, we are seeing a significant treatment effect and promising trend to support PFO closure with StarFlex as a treatment option for certain types of migraine.”
STENT Registry Shows Taxus Results Favorable vs Cypher in Patients With Diabetes
March 29, 2006—Boston Scientific Corporation (Natick, MA) announced that 9-month data from the Strategic Transcatheter Evaluation of New Therapies (STENT) Registry was presented by Charles . Simonton, MD, at the Innovation in Intervention: i2 Summit 2006 held in conjunction with the American College of Cardiology’s 55th Annual Scientific Session, which was held on March 11-14 in Atlanta.
Dr. Simonton is chairman of the executive steering committee for the STENT group. STENT is the first US multicenter prospective registry initiated to evaluate the long-term efficacy and safety of paclitaxel- and sirolimus-eluting coronary stents among real-world patients and clinical situations.
The STENT Registry is a study of 5,566 patients at eight coronary centers in the US who received either the company’s Taxus Express2 paclitaxel-eluting coronary stent system or a Cypher sirolimus-eluting stent system (Cordis Corporation, a Johnson & Johnson company, Miami, NJ). The registry included 1,680 diabetic patients, nearly 500 of whom were insulin-treated diabetics. According to Boston Scientific, the results demonstrated a numerical trend toward improved survival and a lower overall Major Adverse Cardiac Events (MACE) rate among insulin-treated diabetic, for those patients who received a Taxus stent system versus those who received a Cypher stent system. In the less complex noninsulin treated diabetic population, the stents showed equal performance.
Among the study's diabetic patients, the Taxus system was used in more complex lesions than Cypher. The Taxus patients had a slightly higher ACC risk score, smaller vessels, and longer lesions than Cypher patients. Despite the higher complexity of the Taxus patients, the results favored the Taxus over the Cypher in each of the study's MACE categories for insulin-treated diabetics. In these patients, the MACE rate was a composite of death (2.1% for Taxus vs 5.7% for Cypher), MI (1.3% for Taxus vs 1.9% for Cypher), and target vessel revascularization (3.4% for Taxus vs 4.2% for Cypher). The overall MACE rate in these patients also trended in favor of Taxus (6% vs 10.7% for Cypher).
TriActiv FX System Reduces MACE Rates in ASPIRE Study
March 10, 2006—Kensey Nash Corporation (Exton, PA) announced that its TriActiv FX Embolic Protection System achieved a 3.2% major adverse cardiac event (MACE) rate in the company’s Angioplasty in SVGs with Post Intervention Removal of Embolic Debris (ASPIRE) Study. ASPIRE studied the effectiveness of the TriActiv FX to reduce MACE during the treatment of diseased saphenous vein grafts (SVG). The company believes that the 3.2% rate is the lowest recorded to date from a sizable multicenter study of the SVG population, and is less than half of the next-best data set widely quoted by the cardiology community. The rate of heart attacks in the ASPIRE study, included as part of the MACE rate, was 2.2%, which is a 67% reduction in the rate seen in the next-best embolic protection device’s data set. Procedure times were on average 15 minutes below the control cohort of the other embolic protection systems, the company noted. ASPIRE was a multicenter, prospective registry that enrolled more than 100 patients, and was designed to support US regulatory clearance of the TriActiv FX System for a saphenous vein graft indication. The company submitted a 510(k) application to FDA in January. The ASPIRE data were presented at the 55th Annual Scientific Session of the American College of Cardiology, which was held on March 11-14 in Atlanta.