(Circulation. 2001;103:e9040.)
© 2001 American Heart Association, Inc.
Cardiovascular News
Racial Differences in Response to Drug for Heart Failure Spark Debate
Two studies in the May 3, 2001, issue of the New England Journal of Medicine show that blacks respond differently to drugs commonly used to treat forms of heart failure. However, 2 editorialists debate the significance of these findings in companion opinion pieces.
One article evaluated the use of ACE inhibitors in patients with heart failure by analyzing data from the Studies of Left Ventricular Dysfunction (SOLVD) prevention and treatment trials (N Engl J Med. 2001;344:1351–1357). These 2 large, randomized studies compared the ACE inhibitor enalapril with placebo in patients with left ventricular dysfunction.
The US and Canadian researchers, who were led by Derek V. Exner, MD, of the University of Calgary, used a matched cohort design in which 4 white patients were matched with each black patient according to trial, treatment assignment, sex, left ventricular ejection fraction, and age. A total of 1196 white patients were matched with 800 black patients. Although the patients had similar demographic and clinical characteristics, the black patients had higher rates of death from any cause (12.2 versus 9.7 per 100 person-years) and of hospitalizations for heart failure (13.2 versus 7.7 per 100 person-years). Enalapril therapy resulted in a 44% reduction in the risk of hospitalization among the white patients, but there was no significant reduction in the risk of hospitalization among black patients. After 1 year of therapy, white patients but not black patients had a significant reduction in systolic blood pressure. Neither group had a significant change in the risk of death after therapy with enalapril.
Another study in the same issue of the journal demonstrated little difference between the races in response to carvedilol, a ß-blocker used in patients with chronic heart failure (N Engl J Med. 2001;344:1358–1365). The study, which was led by Clyde W. Yancy, MD, medical director of the University of Texas Southwestern Medical School/St Paul heart transplant program, evaluated results from the US Carvedilol Heart Failure Trials Program in which 217 black and 877 white and other patients with heart failure were randomly assigned to placebo or carvedilol for as long as 15 months.
A retrospective comparison of the effect of the drug in black versus other patients showed that carvedilol lowered the risk of death from any cause or hospitalization for any reason by 48% in black patients and by 30% in all others. The drug reduced the risk of the heart failure getting worse by 54% in black patients and 51% in others.
In each case, the study leaders thought that their studies could have important clinical implications for treatment with regard to the race of the patient. In an editorial, Robert S. Schwartz, MD, disagrees because, he says, the definition of race itself is so imprecise. "Race is a social construct, not a scientific classification. In a 1999 position paper, the American Anthropological Association stated the following: ‘It has become clear that human populations are not unambiguous, clearly demarcated, biologically distinct groups ... Throughout history, whenever different groups have come into contact, they have interbred. The continued sharing of genetic materials has maintained humankind as a single species ... Any attempt to establish lines of division among biological populations is both arbitrary and subjective’" (N Engl J Med. 2001;344:1392–1393).
In other words, Dr Schwartz wants to know how the authors define someone as black. Can this person have one-quarter white blood or one-half or three-quarters? He deplores the perception of race and its effect on medical care. "It is indisputable that social perceptions of what a person is or is not influence the availability, delivery, and outcome of medical care. It is incontrovertible that these perceptions apply with dismaying regularity to black people and other minorities in the United States." It would be better, he said, to look for valid genetic variation than to chase the red herring of race to determine why drugs work for some patients and not for others.
In a counterpoint editorial, Alastair J.J. Wood, MD, of Vanderbilt University School of Medicine, discusses the rates at which variant alleles appear in people of different races and postulates reasons for the differences in the way people of different races respond to drug therapy (N Engl J Med. 2001;344:1393–1396). "Racial differences in the response to drugs not only have practical importance for the choice and dose of drugs but should also alert physicians to the important underlying genetic determinants of drug response. The logical extension of the studies reported in this issue of the Journal will be the identification of the genetic determinants of the reported racial differences, rather than attention to the external phenotypical manifestation of race."
On the one hand, Dr Wood speaks of the identification of the genetic determinants of reported racial differences. On the other, Dr Schwartz warns that race is a very imprecise term and that one cannot catalogue the medical treatment of a patient based on the color of his or her skin. Both views deserve careful attention.
First Meeting of Federal Stem Cell Approval Panel Canceled by National Institutes of Health
The first meeting of the committee charged with reviewing the first applications from scientists seeking federal funds for research with pluripotent embryonic stem cells was abruptly canceled by Ruth Kirschstein, PhD, acting director of the National Institutes of Health, according the Washington Post in its April 21, 2001, edition.
Dr Kirshstein halted the meeting 1 week before the panel was to convene because of a request from officials in the Department of Health and Human Services (HHS), according to the Post report. The delay in beginning approval for the research results from a disagreement over whether federal money can be used for such work. Research with human embryonic stem cells has the promise of curing many human ills because, theoretically, almost any kind of tissue can be grown from such cells. However, such research has sparked controversy because the cells from which cultures are grown come from human embryos that were created in fertility clinics but are no longer slated for use.
The controversy began during the Clinton Administration. The lawyer for HHS during that time said the use of federal funds for stem cell work was legal, but current HHS Secretary Tommy G. Thompson has ordered a review of that decision. The Post quoted HHS spokesman Bill Hall as saying, "The bottom line is the department felt that it makes the most sense to hold off until the guidelines review that the department is doing is complete."
Hall told the Post that there is no timetable for completion of that review. According to the Association of American Medical Colleges, Secretary Thompson told the Senate subcommittee on Labor, HHS, and Education that the review should be completed in another 6 weeks. Secretary Thompson has not stated his view on the use of stem cells publicly, but President Bush has said he does not believe federal money should be used for research on cells from human embryos or aborted fetuses. The National Institutes of Health has said it would not fund research using the latter source of cells.
In the meantime, researchers and patients have joined together with scientific societies and universities to advocate for stem cell work. The Coalition for the Advancement of Medical Research seeks to ensure "that federal funding will be available for stem cell research using fertilized eggs developed for in vitro fertilization and that the current federal guidelines overseeing the research are retained."
In an editorial in the journal Science, David Baltimore, president of the California Institute of Technology in Pasadena, California, and Irving L. Weissman, professor of pathology and developmental biology at Stanford University, wrote: "Although the forces that science brings to this field are powerful, the future of embryonic stem cell research will largely be determined by other interests: politics, organized religion, commerce, the legal community, and patient advocacy groups ... Plainly, scientists alone should not make decisions about the ethical conduct of their work or about its social applications. It is appropriate that governments, with appropriate public input, define the societal interest in particular lines of research. But in making those policies, the state should minimize purely political considerations and be mindful of the separation of church and state. The wrong action here could close the door to an important avenue of scientific and clinical discovery" (Science. 2001;292:601).
Early Discharge After Coronary Artery Bypass: Does It Really Save Time and Money?
"Fast-tracking" patients after coronary artery bypass surgery may get them out of the hospital faster, but they are more likely to end up in extended care facilities or to be readmitted to the hospital than those who stay in acute care facilities longer, said researchers from the Department of Cardiothoracic Surgery at the Boston Medical Center and the Boston University School of Medicine.
In the study published in the May issue of the Journal of Thoracic and Cardiovascular Surgery (2001;121:943–950), researchers led by Harold L. Lazar, MD, compared the course of recovery for 407 patients who underwent bypass grafting in 1990 with 379 patients who underwent the procedure in 1998, when early extubation and other fast-track procedures were common. They found that patients in the 1998 cohort were more likely to have class IV angina, undergo urgent or emergency surgery, and have lower ejection fractions than the group from the earlier time period. However, the 1998 patients spent less time on ventilator support and had a shorter average length of stay. The 1990 group stayed in the hospital an average of 9.2±4.3 days, and the 1998 group stayed 5.4±2.5 days.
However, although the 1998 group left the hospital earlier, only 56.7% of them were discharged home, but 97% of the 1990 group went home directly from the hospital. In fact, 43.3% of the 1998 patients were sent from the hospital to extended care facilities, whereas only 2.9% of the 1990 patients were. In addition, patients in the 1998 group were more likely to be readmitted to the hospital than the 1990 group (5.3% versus 0.5%).
The researchers concluded that although fast-track protocols and early extubation may result in patients leaving the hospital sooner, the result is actually increased use of outpatient nursing services and extended care facilities. In some cases, patients find themselves leaving the hospital only to return.
Food and Drug Administration Issues Warning About 2 Endovascular Grafts for Repair of Abdominal Aortic Aneurysms
The US Food and Drug Administration (FDA) has issued a "Dear Colleague" letter warning physicians of problems with 2 endovascular grafts that are used to treat infrarenal abdominal aortic aneurysms. Included in the April 27, 2001, letter is a caution for physicians to be careful in their use of endovascular repair of abdominal aortic aneurysms.
In a letter signed by David W. Feigal, Jr, MD, MPH, director of the Center for Devices and Radiological Health of the FDA, the agency urges physicians to stay informed about changes in the procedure and devices for it. "Endovascular repair of abdominal aortic aneurysm is a new and evolving technology ... Anticipate that there will be changes and improvements as more clinical experience accumulates with this class of devices," Dr Feigal wrote.
"We recommend that you carefully follow the device manufacturer’s most recent warnings, precautions, and instructions regarding patient selection and device use. Make sure that all implanted patients are carefully followed and undergo periodic follow-up imaging. Patients who are unlikely to adhere to the manufacturer’s graft follow-up recommendations may be poor candidates for endovascular repair, even if they are otherwise suitable. Problems that are identified through follow-up imaging may be amenable to further endovascular repair (eg, additional stent placement) or might require conversion to open aneurysm resection. Report problems you encounter with the use of these devices, as well as adverse events, to the manufacturer and to the FDA."
Two devices about which the agency issued warnings were the Ancure Endograft System (Guidant Endovascular Solutions) and AneuRx Stent Graft System (Medtronic AVE), both of which were approved for marketing in the United States in September 1999. The Ancure system has a flexible, unsupported fabric graft prosthesis actively fixed in place on the ends by wire hooks that penetrate the vascular tissue, the FDA reported. Guidant, the manufacturer, halted production of the device on March 16, 2001, and recalled all existing inventory. Later, according to the FDA, the company said that they had failed to report many device malfunctions and adverse events, including severe vessel damage associated with problems in deploying the device.
The company also told the FDA that there had been manufacturing changes not reported to the federal agency as required and that an internal audit had revealed problems with their complaint handling and manufacturing quality systems, as well as with documentation procedures and training. An FDA review of the company’s plan for correcting the problems is underway.
The AneuRx System has a fabric graft supported along its
entire length by a series of metal rings sutured to the graft. The
graft is held in place by the radial force applied by the rings to the
patient’s aorta. According to the letter, the "FDA is concerned
about reports of 
25 aneurysm ruptures, as well as other
serious adverse events, in patients who have received AneuRx. Factors
thought to be associated with the adverse events, including
aneurysm ruptures, include: suboptimal placement of the graft;
endoleak (inadequate proximal seal, collateral vessel retrograde flow,
persistent perigraft flow); migration of the main body of the device as
well as any attachment cuffs, possibly associated with continuing
aortic dilatation; problems with device integrity due to metal frame
fractures, suture breaks, or fabric tears; and aneurysm
anatomy."
The agency is working with Medtronic AVE, the manufacturer, to obtain data that will understand how these problems affect the overall risk/benefit assessment of the product.
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