This week’s issue of Circulation focuses on markers of inflammation and their importance in cardiovascular disease. Paul Ridker, MD, of Harvard Medical School in Boston, Mass, emphasizes in his study that C-reactive protein is an important factor in the development of the Metabolic Syndrome (Circulation. 2003;107:391–397).
The issue also includes the AHA Scientific Statement on Inflammatory Markers and Cardiovascular Disease from the American Heart Association and the US Centers for Disease Control and Prevention (Circulation. 2003;107:499–511).
In addition, this issue inaugurates Circulation’s new section, Mini-Review: Expert Opinions, which is designed to provide assistance to care providers of patients with cardiovascular disease and to stimulate future research on the topic. Dr Ridker’s review of inflammatory markers begins on page 363 of this new section and is followed by a review on page 370 by Circulation board member Edward Yeh, MD, and Circulation editor James T. Willerson, MD, both of the University of Texas Health Science at Houston. The two reviews are followed by an editorial comment by Dean Kereiakes, MD, of the Ohio Heart Health Center and Professor of Clinical Medicine at Ohio State University. Dr Kereiakes is editor of the new section.
An ENCORE Is Possible
Treatment with nifedipine improved coronary endothelial function in patients randomized to receive that treatment as part of the Evaluation of Nefedipine and Cerivastatin On the Recovery of Endothelial Function (ENCORE) study, according to a report in this week’s issue of Circulation (Circulation. 2003;107:422–428).
Writing on behalf of the ENCORE investigators, Thomas F. Luscher, MD, Professor and Head of Cardiology at the University Hospital in Zurich, Switzerland, reported on the trial that randomized 343 patients undergoing percutaneous intervention at 29 centers to cerivistatin alone, nifedipine, a combination of the drugs, or placebo. To identify the degree of constriction in the segments of the coronary artery, researchers infused acetylcholine into coronary segments without angiographically significant coronary artery disease and measured the changes in coronary diameter by quantitative angiography.
Dr Luscher and his colleagues reported that nifedipine, but not cerivistatin, reduced vasoconstriction to acetylcholine in the most constricting segment. They found that analysis of all coronary segments that could be evaluated revealed a reduction of acetylcholine-induced vasoconstriction of 11% in patients receiving both nifedipine and cerivistatin, which lowered low-density lipoprotein cholesterol by 35%.
The authors concluded that this study demonstrated that it is possible to perform multicenter studies on coronary endothelial studies. After 6 months, nifedipine “improved coronary endothelial function in the most constricting segment.” Although the combination treatment tended to improve endothelial function, the difference did not reach statistical significance.
Sirolimus-Eluting Stents Viable After Two Years
The sirolimus-eluting stent set the percutaneous intervention community on its ear two years ago when the startling results were first revealed. Now, researchers have found that the effects of the stents remain steadfast in Brazilian patients two years after implantation. The report of this Brazilian-based study appears in this week’s issue of Circulation (Circulation. 2003;107:381–383).
In this study led by J. Eduardo Sousa, MD, PhD, from the Institute Dante Pazzanese of Cardiology in Sao Paulo, researchers from Brazil, the University of Florida-Shands in Jacksonville, the Thoraxcenter Dijkzigt Unversity Hospital in Rotterdam, the Netherlands, Cordis Col, and the Brigham and Women’s Hospital in Boston, Mass, evaluated the angiographic intravascular ultrasound and clinical outcomes of patients who received the sirolimus-eluting stents two years earlier.
Half of the patients in the study had received the slow-release stent and another half had received the fast-release sent. Twenty-eight patients were available for the follow-up. None of the patients suffered in-stent restenosis. One patient in the fast-release group required revascularization. Target vascular revascularization rate for the entire group was 10% or 3/30.
They found that in-stent neointimal hyperplasia was minimal. The researchers concluded that their small study showed that the stents remain safe and effective for 48 months after implantation, although lumen loss was slightly higher in the fast-release group.
High-Volume Centers: Who Benefits?
Despite recent studies which found that only high-risk patients benefit from referral to high-volume centers, researchers from the Veterans Affairs Outcomes Group in the Department of Veteran Affairs Medical Center in White River Junction, Vermont, reported that there was little difference between high- and low-risk patients in an article published in this week’s issue of Circulation (Circulation. 2003;107: 384–387).
In this study led by Philip P. Goodney, MD, of the White River Junction, Vermont, Center, researchers studied operative mortality among patients undergoing CABG, aortic valve replacement, mitral valve replacement, and elective abdominal aortic aneurysmal repair. All reports were contained in the 1994–1999 national Medicare database. Patients were divided into two groups—those in the highest 25th percentile of predicted risk and those in the lowest 75th percentile of risk. The researchers then compared the mortality of patients who underwent the surgery at very high-volume hospitals and very low-volume hospitals.
They found that greatest volume-related differences in mortality did occur in patients at highest risk, but they also found volume-related differences in lower-risk patients. The researchers concluded that, “Although the merits of volume-based referral initiatives can be debated on many grounds, there seems to be little rationale for restricting these initiatives to high-risk patients.”
They also noted: “Pointing to the magnitude of observed volume-outcome associations, proponents argue that these initiatives could potentially avert thousands of surgical deaths, and that, at the very least, patients should be informed about the importance of volume for some procedures. Opponents point out that the potential benefits of volume-based referral initiatives come at the cost of disrupting traditional referral lines for tens or even hundreds of thousands of patients. Some indirect effects of these policies could be harmful for both patients and small hospitals. Our study does not address these basic tradeoffs. However, it does suggest that restricting volume-based referral initiatives to high-risk patients is unlikely to be an easy solution to this policy dilemma.”
Health Spending Rises at Record Rate
Health spending in 2001 reached new heights, growing 8.7% over the year before. It was an increase close to double digits and was not equaled in the 1990s. Overall, US health expenditures reached $1.42 trillion in 2001—an average of $5035 per person, according to a report from the Centers for Medicare and Medicaid Services.
“While still the greatest in the world, our healthcare system is stretched and stressed to the point of nearly breaking,” Health and Human Services Secretary Tommy G. Thompson said in a released statement. “We have launched a series of town hall meetings across America to listen to Americans and develop solutions to rising health costs and other challenges. What will emerge from these meetings will be a series of legislative proposals and pilot projects that can be adopted by states to strengthen our healthcare system.”
More information on the report can found on the site of the journal Health Affairs at http://www.healthaffairs.org/ readeragent.php?ID=/usr/local/apache/sites/healthaffairs. org/htdocs/Library/v22n1/s19.pdf, where the report by Katharine Levit, Cynthia Smith, Cathy Cowan, Helen Lazenby, Art Sensenig, and Aaron Catlin was published.
FDA Suspends 27 Gene Therapy Trials After Second Illness
Responding to reports that a second child in a French gene therapy trial had developed a condition similar to leukemia, the US Food and Drug Administration abruptly suspended 27 gene therapy studies involving hundreds of patients.
In an agency “talk paper” on the January 14, 2003, action, FDA officials called the halt “temporary.” The action was taken against those trials that use a retroviral vector, which integrates into the cell’s genome. The decision to halt the trials was taken after a second child who had participated in a French gene therapy study designed to treat severe combined immune deficiency had developed a leukemia-like condition. This child and another child who had developed the disease in August had both been successfully treated for the inherited X-linked disorder that had left them without an immune system.
Infants that are born with X-linked SCID completely lack white blood cells. Without treatment, they often die within the first year of life from complications of infectious ailments. Before gene therapy, the only treatment was a bone marrow transplant, with all its attendant risks and difficulties in finding a matched donor.
The French trial had had early successes, with 9 of 11 patients treated responding well to the treatment in which a normal gene is inserted into the blood stem cells of the patients. The risk that a gene might integrate itself into a spot on the genome where it might activate a cancer-causing gene had always been recognized, but these cases were the first to be identified.
The FDA noted that it did not know of any similar cases in trials in the United States that were using a retroviral vector. After the first French case in August, the FDA stopped enrollment of human subjects in three US studies that most closely resembled that in France.
The agency noted: “The temporary hold reflects FDA’s appreciation that some of these trials involve patient populations and gene therapy products that may be appropriate to continue after they are updated to reflect this new risk information. FDA will consider and evaluate specific requests for clinical indications for fatal or life-threatening disorders for which there are no viable alternative treatments.”
However, officials noted, sponsors of trials will have to inform potential patients of the adverse events in the French trials and must have an active plan to monitor subjects for similar diseases in their study. The agency plans to hold an advisory committee meeting in late February to discuss the adverse event and the issue of retroviral gene therapy in general.