(Circulation. 2000;101:e9036.)
© 2000 American Heart Association, Inc.
Cardiovascular News
Clopidogrel-Associated Thrombotic Thrombocytopenic Purpura Identified
The drug clopidogrel has been associated with 11 cases of thrombotic thrombocytopenic purpura, a finding that has prompted physicians to warn their peers about the risk to patients. The study, which is scheduled to appear in the June 15 issue of the New England Journal of Medicine, was posted early on the journal’s website (www.nejm.org) because of its clinical implications, a rare waiving of the Ingelfinger Rule against early publication (Thrombotic thrombocytopenic purpura associated with clopidogrel. N Engl J Med. 2000).
"The view was that it was a very benign drug," said Marc Feldman, MD, a coauthor of the story and an associate professor of medicine at the University of Texas Medical School at San Antonio. "This is not a benign drug, and physicians shouldn’t put patients on it and forget about it." He said the finding did not mean that physicians should stop prescribing clopidogrel because the drug is an important therapeutic tool. Nor do the study’s authors want patients to stop taking the drug. "The risk of having an acute myocardial infarction by stopping far outweighs the risk of thrombotic thrombocytopenia purpura" said Dr Feldman.
The finding is of interest because, since it received Food and Drug Administration approval in late 1997, clopidogrel has become more popular for use than a similar drug, ticlopidine, which was also associated with development of thrombotic thrombocytopenic purpura. However, in 20 000 patients in phase 3 clinical trials of clopidogrel, no incidences of this complication were reported. In contrast, the incidence of thrombotic thrombocytopenic purpura in patients treated with ticlopidine was estimated at between 1 in 1600 patients to 1 in 5000 patients treated with the drug. More than 3 million patients have received clopidogrel worldwide.
Both clopidogrel and ticlopidine have been prescribed for the prevention of stroke and thrombosis in patients who have received coronary artery stents and in patients with peripheral vascular disease or acute cardiac ischemia. The lead author of the article was Charles L. Bennett, MD, PhD, an associate professor at Northwestern University School of Medicine in Chicago and director of the Health Services Working Group at the Robert H. Lurie Comprehensive Cancer Center, which is also in Chicago.
The 11 patients in the study were identified through the surveillance activities of medical directors of blood banks, hematologists, and the drug’s manufacturers, Sanofi-Synthelabo and Bristol-Myers Squibb. To be included, patients had to have previously taken or still be taking clopidogrel at the time of diagnosis.
In analyzing the demographics of the patients, the researchers found that 6 had received the drug for coronary artery disease; 3 of these 6 patients were given the drug after the placement of a coronary artery stent. Five patients were also taking the cholesterol-lowering drugs atorvastatin and simvastatin. Three patients had received atenolol long-term, and one was on long-term cyclosporine because the patient had undergone kidney-pancreas transplantation.
The disease manifested itself with thrombocytopenia and microangiopathic hemolytic anemia. Platelet counts were <20 000 cells/mm3 in 10 patients, and hematocrit values were <24% in 8 patients. Seven patients had neurological changes. Four patients had renal insufficiency, and 2 patients had evidence of acute liver injury.
All patients received plasma exchange. The symptoms resolved in 10, but the number of plasma exchanges needed to achieve resolution varied from 1 to 30. One patient died after 4 days of plasma exchange. One patient suffered 2 recurrences, and another had 3. In the patient with 3 relapses, the third occurred 7 months after the onset of the first course of the disease.
The cases of the disease in those who received clopidogrel occurred
within 2 weeks after treatment began for 10 of the 11 patients, whereas
those who received ticlopidine developed the problem after 2 to 12
weeks of treatment. Plasma exchange seemed more effective in the
ticlopidine-treated patients, with 
7 exchanges required for a
response and no relapses. However, only 57% of patients with the
disease associated with ticlopidine received plasma exchange because
the disease was not promptly identified in all patients.
Among those who received plasma exchange, 18% of those who had received ticlopidine died and 9% of those who had clopidogrel-associated disease died. The overall mortality for ticlopidine-associated disease was 33%, in part because of the lower rates of plasma exchange in that group.
The authors noted that in one patient, "thrombotic thrombocytopenic purpura appeared to be induced by atorvastatin and one patient had a recurrence during treatment with atorvastatin... The possibility that cholesterol-lowering drugs and clopidogrel may have adverse pharmacologic interactions in some patients deserves further study."
The authors said physicians must be aware of the risk. "The development of cardiac or neurologic changes after initiation of clopidogrel therapy may be mistakenly attributed to the underlying condition for which it was prescribed," they wrote. "Physicians should be aware of the possibility of thrombotic thrombocytopenic purpura among patients who are receiving clopidogrel."
The next step might be a randomized trial comparing the drugs ticlopidine and clopidogrel to determine the comparative effectiveness and the rate of side effects for each, said Dr Feldman. One problem with both drugs is that the most serious side effect—thrombotic thrombocytopenic purpura—was diagnosed by hematologists and not the cardiologists who prescribed it. Without direct knowledge of the side effects, cardiologists cannot make an informed choice about how to use the drug. Dr Feldman said he expects more cases of clopidogrel-associated thrombotic thrombocytopenic purpura will surface in the wake of the journal report.
Surprising Fiber Result
Going against conventional wisdom, 2 studies in the April 20 issue of the New England Journal of Medicine cast considerable doubt on the premise that a high-fiber diet can reduce the growth of precancerous colorectal polyps. The 2 studies, the Polyp Prevention Trial (N Engl J Med. 2000;342:1149–1155) and the Wheat Bran Fiber Study (N Engl J Med. 2000;342:1156–1162), ended with results that researchers called "disappointing" because they demonstrated no benefit from a high-fiber diet.
"Polyps are a point where we can intervene to prevent colorectal cancer," explained Arthur Schatzkin, PhD, DrPH, chief of the National Cancer Institute’s Nutritional Epidemiology Branch and a lead investigator in the Polyp Prevention Trial. "These trials were done to test whether dietary change could prevent these people (who had already had a polyp removed) from getting more polyps and thereby reduce their risk of colorectal cancer. We were surprised and disappointed to find that the dietary changes made in these studies did not decrease the number of new polyps the participants developed... Although we still have a ways to go to prove that dietary change can prevent colorectal cancer, there is a great deal of evidence that adopting a diet low in animal fat, high in whole grains, and rich in vegetables and fruit can improve one’s overall health and reduce the risk of chronic disease."
In the Polyp Prevention Trial, 2079 men and women who had had 
1
polyps removed were randomized to 1 of 2 groups. One group received
intensive counseling to adopt a low-fat, high-fiber,
fruit-and-vegetable–enriched eating plan. The other received a
standard brochure on healthy eating. The participants followed the 2
eating plans for 4 years. In the Wheat Bran Fiber Study, 1429 men and
women from the greater Phoenix, Ariz, area who had had 1 polyps
removed within the prior 3 months were randomized to 1 of 2 groups. One
ate a wheat bran fiber cereal supplement that was high in fiber and one
had a similar supplement that was lower in fiber. They stayed on the
plans for 3 years.
In neither study was there a significant difference between the 2 groups of patients. However, the authors of each study theorized that a longer period on the diet might have an effect. Colorectal cancer takes decades to develop, and 3 to 4 years might not be enough to make a difference in the disease. Researchers in both studies emphasized that there continue to be good reasons to eat a high-fiber diet, including a reduction in the risk of developing heart disease, high blood pressure, and hypertension.
Gene Therapy Works for 2 Cases of Severe Combined Immune Deficiency
Two infants, aged 8 and 11 months, underwent successful gene therapy in France to correct a defect in their immune system that kept them tied to sterile "bubble" environments (Science. 2000;288:669–672). The infants both suffered from SCID X1, a single gene defect present at birth.
Their disease was very similar to that which kept Houston’s Bubble Boy David imprisoned in a sterile environment for all but the last few days of his life. David died in 1984 at the age of 12.
The gene therapy provided the 2 children with a normal copy of the gene that is defective in SCID X1. In these cases, the normal gene rapidly proliferated throughout the children’s bodies, restoring their immune system.
The children’s bone marrow was harvested, and stem cells were sorted out. These stem cells were bathed in a growth factor in containers coated with a fibronectin fragment that encourages efficient gene transfer. Then, the cells were infected with a retrovirus that carried the replacement gene. After repeating the infecting process for 3 days, the scientists, led by Alain Fischer, MD, of the Hospital Necker in Paris, infused the bone marrow containing the replacement gene back into the boys. Within 15 days, the scientists detected new cells containing the corrected version of the gene.
Dr Fischer said the success seems to stem from the disease itself. Cells containing the normal copies of the gene seem to have a significant selective advantage over those with the aberrant form. According to the researchers, the 2 young patients are out of their protective isolation and are living at home with what seem to be good immune systems. They are enjoying normal growth and development.
Lipids Online
A new website called Lipids Online has been developed to ensure that physicians have access to the latest information about cardiovascular disease, its prevention and its management, according to the site’s originator Christie Ballantyne, MD, associate chief and clinical director of the section of atherosclerosis at Baylor College of Medicine.
The site, located at http://www.lipidsonline.org, contains a continuously updated Slide Library with hundreds of high-resolution graphics that are accompanied by talking points and references, a Virtual Meeting forum, and an abstract library with commentaries on key abstracts by top cardiovascular researchers and clinicians.
Site visitors can download the slides and supporting tools to a PowerPoint program, which will allow them to develop their own programs dealing with lipid reduction, said Michael Fordis, MD, director of Baylor’s Center for Collaborative and Interactive Technologies, which designed the site.
A group of distinguished lipid researchers and heart specialists serve on the advisory panel and review board for the site, said Dr Ballantyne. The site was developed with an unrestricted grant from Merck US Human Health.
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