News from the Transcatheter Cardiovascular Therapeutics meeting (TCT)

Boston Scientific Delivers Drug Stent Trial Data Physicians had expected Boston Scientific’s Taxus IV trial to show a restenosis rate of 9% to perhaps as high as 11% in patients receiving the company's drug-eluting stent. Instead, the in-segment rate was 7.9%, compared with 27% for a control group. In last year’s SIRIUS stent trial by J&J, 8.9% of patients receiving the company’s Cypher drug-eluting stent developed in-segment restenosis. "We're all pleasantly surprised," said Dr. Stephen Ellis of the Cleveland Clinic, who served as the co-principal investigator for Taxus IV. Dr. Ellis went on to say the results should be described as a major step forward in the field. The results are certainly as good as the Cypher results. This will be a highly-competitive stent in the marketplace. It offers an alternative, which is always welcome in medical care. Boston Scientific hopes to receive approval for Taxus IV by year-end, although many analysts think an early 2004 approval is more likely. Boston Scientific coats its Taxus stent with paclitaxel, while J&J coats its Cypher stent with sirolimus. In mid-September, J&J released new drug-eluting stent trials for patients being studied in Europe and Canada, showing a combined restenosis rate of 5.1%. J&J believes that should be the new standard for comparisons, while Boston Scientific contends the apples to apples comparison is its TAXUS IV U.S. trial to SIRIUS’ U.S. trial. Physicians cautioned not to directly compare all of the numbers in Sirius to Taxus IV, but comparisons seemed inevitable. The 7.9% restenosis rate within the segment of blood vessel containing the lesion being stented will get the most attention, since that percentage represents a 70% improvement compared with 27% of patients in the control group who developed restenosis with a bare-metal stent. Of the diabetics receiving Boston Scientific’s drug-eluting stent in the 1,314-patient TAXUS IV trial, 6.4% developed in-segment restenosis after nine months, compared with 18% of diabetics in the SIRIUS study. Diabetics represented 24% of the TAXUS IV patients. Major adverse coronary events, or MACE, rates for TAXUS IV patients treated with a drug-eluting stent came in at 8.5%, compared with 7.1% for those patients treated with J&J’s Cypher stent. However, cardiologists advised that the MACE rates can’t be directly compared because they were calculated differently. Boston Scientific calculated it by using cardiac death, myocardial infarction and target vessel revascularization. J&J, on the other hand, calculated MACE using all deaths, myocardial infarction and target lesion revascularization. Physicians involved with the TAXUS IV trial said the stent proved safe, with no increased risk of stent thrombosis, or blood clots. They added it was effective in a wide range of patients and lesions. Doctors will look at target lesion and target vessel revascularization rates closely. However, TAXUS IV patients treated with a drug-eluting stent had a target lesion revascularization rate of 3% and a target vessel revascularization rate of 4.7%, compared with 4.1% and 8.4%, respectively, for drug-eluting stent patients in the SIRIUS trial. Dr. Gregg Stone, principal investigator for TAXUS IV and a cardiologist at Lenox Hill Heart and Vascular Institute in New York, said that while it isn’t a good idea to compare the trials, the TAXUS IV results really set a new standard. He added, Physicians will weigh it all and make up their own minds based on deliverability and clinical data. Subset Analysis of New SIRIUS Data Shows Consistent Clinical Benefits in Difficult-to-treat Patient Populations Cordis Corporation, a Johnson & Johnson company, reinforced the efficacy of the CYPHER Sirolimus-eluting Coronary Stent with a subset analysis of the New SIRIUS data showing success in even the most difficult-to-treat patient populations. The data were presented during the 15th Transcatheter Cardiovascular Therapeutics (TCT) Symposium. New SIRIUS, representing pooled eight-month angiographic and nine-month clinical follow-up data from the C-SIRIUS (Canadian) and E-SIRIUS (European) trials, set a new benchmark for drug-eluting stent trials with an overall 5.1% binary restenosis rate. Even in the most challenging patients within this study, the CYPHER Stent showed a 10.8% in-segment restenosis rate for diabetics versus 17.6% in the SIRIUS trial and a 7.7% in-segment restenosis rate in the smallest vessels compared to 18.4% in SIRIUS patients, said David Holmes, MD, Professor of Medicine, The Mayo Clinic. According to Dr. Holmes, Adjustments in stent size selection and technique appear to have further optimized restenosis rates for these patients who have traditionally been the most difficult to treat. New SIRIUS represents a combined 452 patient population whose de novo (previously untreated) coronary blockages were randomized to either the CYPHER Stent or Bx VELOCITY® Stent. Admission criteria were extended beyond those of the U.S. SIRIUS trial to include a larger percentage of patients with small vessels and long lesions, as well as more patients with clinical profiles including smokers and previous heart attacks. The use of multiple stents and overlapping stents was also more common among New SIRIUS patients, while the use of IIB/IIIA inhibitors was significantly lower as compared to SIRIUS patients. Six Month Data from The Medicines Company’s REPLACE-2 Trial of Angiomax (Bivalirudin) Released at TCT Lower Mortality in Angiomax® Group Reduced Bleeding, Shortened Treatment and Lower Costs Findings from 30-Day Analysis Reinforced The Medicines Company announced that six month results of the landmark REPLACE-2 clinical trial included numerically lower death rates in the Angiomax randomized patients as compared to patients randomized to heparin with glycoprotein IIb/IIIa inhibitors. REPLACE-2 principal investigator, A. Michael Lincoff, MD, of The Cleveland Clinic, described a 30% relative risk reduction in 6-month death rates from 1.35% to 0.95% comparing heparin and GPIIb/IIIa inhibitor to Angiomax randomized groups (odds ratio 0.70 with 95% confidence interval 0.43-1.14). These new six-month data reinforce the primary 30-day data conclusions. The 30-day follow-up data demonstrated that Angiomax is as effective as heparin given with GP IIb/IIIa inhibitors, superior to historical results for heparin alone and easier to use, safer, with less cost. The 31 to 183-day follow-up data demonstrated that patients randomized to heparin with GPIIb/IIIa inhibitor and Angiomax experienced practically the same rates of myocardial infarction (1.5%) and revascularization (9%). For this follow-up period, the combined event rate for death, myocardial infarction and revascularization was 11% in both groups. Dr. Rick McClure, The Medicines Company’s VP of Endovascular Medicine, commented, It’s clear that we can now minimize bleeding risk without increasing risk of ischemic complications either short or long-term. The finding of lower death rates reinforces our view that minor differences in CKMB elevations between heparin with GPIIb/IIIa inhibitor and Angiomax-randomized groups at 30 days were inconsequential. Further, the mortality results provide strong evidence that Angiomax is substantially better than heparin and should replace heparin in coronary angioplasty. REPLACE-2 was a 6,002 patient (intent to treat), randomized, double-blind trial conducted at 233 clinical sites in the United States, Canada, Western Europe and Israel. The REPLACE-2 study was designed to evaluate whether patients in the trial receiving bivalirudin plus provisional GP IIb/IIIa inhibitors would have outcomes that were superior to, a heparin historical control arm (based on heparin event rates from prior angioplasty trials). The REPLACE-2 study was also designed to evaluate whether patients in the randomized trial receiving bivalirudin plus provisional GP IIb/IIIa inhibitors would have outcomes that were non-inferior to patients in the trial receiving heparin plus GP IIb/IIIa inhibitors. There is an additional pre-specified analysis of the death endpoint at one-year follow-up. The Medicines Company expects that the one-year data will be presented during the American Heart Association’s Scientific Sessions in November. Vulnerable Plaque Study Shows Correlation Between Lipid-Rich Plaques and Heart Attacks in Cath Lab Patients Guidant Corporation announced additional findings of a study utilizing optical coherence tomography (OCT) to examine highly detailed images of complex coronary lesions in patients with coronary artery disease. OCT provides resolution 10 times greater than intravascular ultrasound. Results of the Guidant-supported study, which was conducted at Massachusetts General Hospital (MGH) in Boston, Mass., were presented by Dr. Ik-Kyung Jang at the annual Transcatheter Cardiovascular Therapeutics (TCT) conference. Dr. Jang reported that lipid-rich plaque and thrombus as detected by OCT occur more frequently in patients with an acute coronary syndrome, including patients who present with heart attack and unstable angina, than occur in patients with stable angina. These statistically significant findings are the first that confirm previously published findings from human autopsies correlating the prevalence of lipid and thrombus in plaques of patients dying of acute coronary syndromes. Last year Dr. Jang presented preliminary data from the MGH-Guidant study, which demonstrated that OCT is able to successfully detect morphological characteristics of coronary lesions that have been associated with heart attacks, including lipid pools and their thin fibrous caps that are susceptible to rupture. To date, Dr. Jang has successfully used OCT in 88 patients with no procedure-related complications. In the past, our knowledge of the pathophysiology of coronary artery disease has been principally based on pathology studies, because, before OCT, there was no reliable method for studying minute details of coronary plaques in living persons, said Ik-Kyung Jang, MD, PhD, interventional cardiologist at MGH, associate professor of medicine at Harvard Medical School, and principal investigator for the study. OCT has the most extensive clinical experience of all the invasive modalities being studied today for vulnerable plaque. Now that we are detecting lesion-structure differences in different patient subsets, we will want to move on to prospective studies, such as a natural history study. OCT has now been shown to detect the features of plaques that may cause heart attacks. These findings support the concept that OCT could be used to identify such plaques before they rupture. This could make prevention of heart attacks a reality, said James E. Muller, MD, director of the Center for Integration of Medicine and Innovative Technology (CIMIT) vulnerable plaque program at MGH and the Harvard Medical School. A natural history study is the single most important development needed to move the vulnerable plaque field forward. What we learn from that may someday enable cardiologists to detect in the cath lab signals of those lesions with the highest risk of rupture. The OCT system used in the study was developed at Wellman Laboratories of Photomedicine, based at Massachusetts General Hospital within the Department of Dermatology at Harvard Medical School. The co-principal investigators of the study were Brett Bouma, PhD, and Guillermo Tearney, MD, PhD, assistant professors at Massachusetts General Hospital conducting research at Wellman Laboratories. ENDEAVOR I Clinical Study Demonstrates Positive Results of Medtronic Endeavor Drug Eluting Stent in Reducing Restenosis The principal investigator for the ENDEAVOR I Clinical Trial reported positive four-month results of the study at the Transcatheter Cardiovascular Therapeutics (TCT) annual symposium. The ENDEAVOR I clinical trial, sponsored by Medtronic, Inc., is a prospective, multi-center trial which is assessing the safety and efficacy of the Endeavor Drug Eluting Stent for the treatment of de novo coronary lesions in native coronary arteries with a diameter of 3.0 mm to 3.5 mm. The ENDEAVOR I clinical study is the first in a three-phase study designed to collect substantial data on Medtronic’s Endeavor Drug Eluting Stent for the safe and effective reduction of restenosis. The principal investigator for ENDEAVOR I is Professor Ian Meredith, MD, Monash Medical Centre, Melbourne, Australia. The 100-patient study began in January 2003 and is being conducted at sites in Australia and New Zealand. The primary endpoints presented today are the major adverse cardiac event (MACE) rate at 30 days and angiographic late lumen loss at four months. The remaining endpoints for ENDEAVOR I include Target Vessel Failure (TVF) and Target Lesion Revascularization (TLR) at nine months and late loss at 12 months. Additional four-month data from ENDEAVOR I includes a TLR rate of 1.0 percent and a four month MACE rate of 2.0 percent. Prof. Meredith said, The study's primary endpoints included a 1.0 percent MACE rate at 30 days and four-month late lumen loss by QCA of 0.20 mm in segment. These results, combined with the fact that there was a four-month 2.1 percent binary restenosis rate and a four-month TLR rate of 1.0 percent, shows that the Endeavor stent utilized in the trial brings a complementary combination of drug, stent, and polymer together to produce compelling results. Finally, the extensive IVUS follow up in this trial shows excellent lumen preservation from beginning to end, with only 4.5 percent neointimal volume loss. The Medtronic Endeavor Drug Eluting Stent system being tested utilizes the drug ABT-578, a patent-protected compound licensed to Medtronic from Abbott Laboratories. ABT-578 is designed to inhibit smooth muscle cell proliferation by blocking the function of the cell cycle regulatory protein, mTOR. By inhibiting the mTOR function, ABT-578 permits the cell to return to normal function versus causing cell death. Medtronic also licenses from Abbott the rights to phosphorylcholine coating (PC Technology), a polymer copy of the outside surface of a red blood cell, which mimics the structure of the natural cell membrane and is designed to reduce the body's response to implanted devices. The PC polymer is designed to serve as the delivery matrix, which controls the elution, or release, of ABT-578 directly into the arterial wall. The PC coating has six years of European clinical experience dating from 1997. Medtronic’s drug eluting stent utilizes the company’s original Driver coronary stent, which has CE Mark approval in Europe for treating large and small vessels. The Driver coronary stent is made of a cobalt-based alloy that is designed to be stronger and denser than earlier stainless steel stents. This original alloy is also designed to allow for thinner struts, a lower profile and better deliverability in the vessel without compromising radial strength and visibility. Medtronic anticipates that the Driver coronary stent will be approved in the U.S. in the fall of 2003. Medtronic intends to provide the Endeavor Drug Eluting Stent on rapid exchange, over-the-wire and Multi-Exchange delivery platforms. Medtronic is the only company to offer the Zipper Multi-Exchange Delivery Platform. The Multi-Exchange technology combines over-the-wire and rapid exchange formats onto a single delivery platform. The Zipper MX offers short wire compatibility, over-the-wire deliverability and permits the changing of wires without catheter removal. ENDEAVOR I four-month results were released at TCT with the patient follow-up continuing to 12 months. The remaining endpoints for ENDEAVOR I include TVF and TLR at nine months and late loss at 12 months. The ENDEAVOR II Pivotal Clinical Trial began in July 2003. ENDEAVOR II is a randomized, double-blind trial that will evaluate the safety and efficacy of the Endeavor Drug Eluting Stent compared to the Driver bare metal stent and will support product approvals in various countries. The primary endpoint of the study is TVF at nine months. ENDEAVOR II includes approximately 1,200 patients enrolled at approximately 96 hospitals in 21 countries throughout Europe, the Middle East, Asia-Pacific and Canada. Medtronic anticipates completion of patient enrollment in ENDEAVOR II by the end of 2003. ENDEAVOR III is a randomized trial that will evaluate the safety and efficacy of the Endeavor Drug Eluting Stent as compared to the Cypher Sirolimus-eluting stent marketed by Cordis Corporation, a Johnson & Johnson company. This proposed study will include an estimated 480 patients and has a primary endpoint of late lumen loss by QCA at eight months. Medtronic anticipates starting enrollment in this study by the end of 2003. Guidant Reports Positive Results of Two Everolimus Eluting Coronary Stent Clinical Trials FUTURE I and II Trials Utilize Everolimus with Bioabsorbable Polymer Guidant Corporation reported positive results from two clinical trials evaluating an everolimus eluting coronary stent with a bioabsorbable polymer vs. a metallic stent platform in de novo lesions in native coronary arteries. Findings were presented at the 15th Annual Transcatheter Cardiovascular Therapeutics (TCT) Conference in Washington, D.C. Results from the two trials show that the everolimus eluting stent with bioabsorbable polymer was safe, and effective in reducing tissue proliferation in the stent following implantation. Fully adjudicated results reported from six-month follow-up of FUTURE II, a prospective, randomized, multi-center double-blinded trial of a bioabsorbable polymer and everolimus eluting stent in 21 patients, confirmed the six-month results of the FUTURE I clinical trials presented earlier this year. FUTURE II, which included a more complex patient group than FUTURE I, met its primary safety endpoint, with a 4.8 percent major adverse cardiac events (MACE) rate in the everolimus eluting stent arm at six months. Angiographic endpoint results were positive, with zero percent (0/21) in-stent restenosis (re-narrowing) in the everolimus arm vs. 19.4 percent (7/36) in the metallic control arm. The everolimus eluting stent significantly reduced in-stent tissue proliferation compared to control with a late loss of 0.12 mm. The company also presented preliminary 12-month clinical follow-up for the FUTURE I clinical trial, a prospective, randomized, single-blinded trial evaluating the safety of an everolimus eluting stent in 27 patients. Both the safety and efficacy results from FUTURE I at six months were sustained at 12-month follow-up. Twenty-four patients who had received the everolimus eluting stent were evaluated at 12 months. No new MACE occurred between six and 12 months, with no incidence of repeat intervention required. Preliminary angiographic analysis of eight patients showed no new binary restenosis events. In six patients who underwent follow-up intravascular ultrasound (IVUS), the results were consistent with six-month results demonstrating minimal luminal volume obstruction. In August 2003 Guidant submitted the first module of the application for CE Mark approval to European regulatory authorities to support approval of Guidant’s CHAMPION drug eluting stent system with a bioabsorbable polymer and everolimus. The submission included the positive six-month data from the FUTURE I clinical trial. BLAZE Trial Studied FilterWire EZ Embolic Protection System Boston Scientific Corp. announced final results from its BLAZE clinical trial, which studied the Company's FilterWire EZ Embolic Protection System. The objective of the registry trial was to establish the safety and efficacy of the FilterWire EZ system during balloon angioplasty or stenting procedures in the treatment of saphenous vein grafts (SVGs). The system, a low-profile embolic filter mounted on a guide wire that captures embolic debris during cardiovascular interventions, has been granted CE Mark in Europe for multiple indications, including peripheral, coronary/SVG and carotid vessels. The FilterWire EZ system is pending FDA 510(k) clearance in the U.S. Results were presented by the study’s U.S. Principal Investigator, David Cox, MD, of Presbyterian Healthcare, Charlotte, North Carolina. The BLAZE multi-center registry trial studied 107 patients at 17 U.S. and seven European sites. The primary safety endpoint of the study was the cumulative incidence of MACE (Major Adverse Cardiac Events), defined as death, Q-wave or non Q-wave myocardial infarction (MI), emergent coronary artery bypass surgery (CABG), or target vessel revascularization (TVR) at 30 days post-procedure. In the BLAZE study, the incidence of MACE at 30 days was 5.6%, compared to 9.9% in the FIRE study for FilterWire EX system. New Cardiovascular Results Supporting Broad Indications in Atherosclerosis, Including Vulnerable Plaque Miravant Medical Technologies, a pharmaceutical development company specializing in PhotoPoint® photodynamic therapy (PDT), announced new preclinical results in cardiovascular disease, presented by Ron Waksman, MD. The results indicate that PhotoPoint PDT may provide benefit in a wide range of coronary and peripheral atherosclerotic disease indications, including diffuse disease, long lesions and life-threatening vulnerable plaque. In preclinical atherosclerosis models at 28-days post-treatment, there was a 23-44% decrease in plaque areas (p less than 0.03), which suggests that PhotoPoint PDT may significantly reduce vessel blockage by decreasing the atherosclerotic plaque burden. Furthermore, following PhotoPoint treatment, the macrophage cells characteristic of vessel inflammation were almost completely eliminated and were replaced by smooth muscle cells typical of arteries free of disease. This suggests that PhotoPoint PDT may also stabilize rupture-prone vulnerable plaque, the most dangerous form of atherosclerosis. The experimental studies were conducted under the direction of Dr. Waksman, Professor of Medicine (Cardiology), Georgetown University and Associate Chief of Cardiology at the Washington Hospital Center, who stated, It appears that PhotoPoint PDT may have the potential to turn back the clock by reducing atherosclerotic burden, attenuating inflammation and allowing vessels to return to a more normal cellular state. Furthermore, this therapy may enable us to treat long lengths of arteries not currently addressed by drug-eluting stents. Miravant is currently developing PhotoPoint PDT as a minimally invasive interventional procedure for the treatment of such at-risk patients. The catheter-based treatment uses a systemic light-reactive drug in combination with low power light to selectively treat the lesion site. Recent studies have also indicated that vulnerable plaque causes 60-80% of fatal heart attacks. AVI BioPharma Reports Positive Phase II Clinical Results in Restenosis AVI BioPharma, Inc., reported positive Phase II clinical trial data on its NEUGENE® antisense drug Resten-NG®. The multicenter clinical trial evaluated the safety and effectiveness of Resten-NG in patients at high risk of cardiovascular restenosis following angioplasty and stent placement. Resten-NG inhibits the expression of the c-myc gene, which plays a key role in the development of the pathology leading to restenosis. Fifty-seven patients were enrolled in the trial, the AVAIL study, and were randomized into three groups: a control arm, a subtherapeutic dose (3 mg) treatment arm, and a therapeutic dose (10 mg) treatment arm. Patients in the therapeutic dose and subtherapeutic dose treatment arms received the drug via a coronary delivery catheter directly to the site of angioplasty and stent placement. The primary efficacy endpoint was angiographic analysis at six months. The restenosis rate was 33.3 percent in both the control and subtherapeutic dose treatment arms, and 8.3 percent in the therapeutic dose treatment arm. This 75 percent reduction in the rate of restenosis was statistically significant (p=0.02). The secondary endpoint of the study was late loss, which is the decrease in vessel lumen diameter at six months. The therapeutic dose treatment arm showed a significant reduction of late loss and lesion length compared with the control arm and the subtherapeutic treatment arm. There were no increases in toxicity or adverse events in either of the treatment arms. The therapeutic dose treatment arm also experienced a lower rate of target lesion revascularization than the other arms. Nicholas Kipshidze, MD, PhD, of Lenox Hill Hospital in New York, said, The patients treated in this trial were at high risk for restenosis, giving us the ability to evaluate efficacy with a small sample size. The data indicate Resten-NG provided a substantial and statistically significant benefit for these high-risk patients. In August, AVI initiated a Phase II clinical study of Resten-NG delivered using AVI’s proprietary microbubble delivery system. The study will evaluate efficacy and safety of Resten-NG delivered systemically with AVI’s microbubble preparation, compared with angioplasty and stent placement alone. Successful systemic delivery of Resten-NG could make the drug available for broad application with stent placement and for multiple applications after angioplasty. AVI plans to initiate a Phase III clinical trial in Europe with Resten-NG on a stent platform around the end of this year.

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