Article intéressant du Wall Street Journal concernant l'early goal directed therapy de Rivers dans le sepsis... Hoffman dans les EMA's en parlait dans l'édition de septembre: AUGUST 14, 2008 New Therapy for Sepsis Infections Raises Hope but Many Questions Seven years ago, doctors got some hopeful news about sepsis, a fast-moving bloodstream infection that kills four million people a year world-wide. A study said an aggressive new therapy cut the death rate by a third. Two medical groups endorsed the new therapy, and scores of U.S. hospitals have adopted it. But now some doctors are questioning the rigor of the research behind it, which was done at a single hospital. Adding to the concerns: That hospital held patents on a medical device critical to the therapy. And one of the groups that later endorsed the treatment had financial backing from the maker of the device."One concern I have is that this hypothesis has been accepted almost without debate by so many people," says Mitchell Fink, a professor of critical-care medicine at the University of Pittsburgh Medical Center. The new therapy typically costs about $1,100 more per patient, by the estimate of Derek Angus, chief of critical care at the University of Pittsburgh. The U.S. has about 750,000 cases of sepsis each year.Critics cite a statistical red flag: The study of the new therapy reported death rates for traditional care much higher than a number of other studies have found. Amid these concerns, the National Institutes of Health is beginning a large new study to re-evaluate the findings. All this has angered the doctor who pioneered the aggressive therapy, Emanuel P. Rivers, vice chairman of emergency medicine at Henry Ford Hospital in Detroit. The controversy has taken on an ugly tone rare in medicine. Dr. Rivers has called his critics in Pittsburgh "the Pittsburgh pirates." In an email to a Toronto doctor, Dr. Rivers said some see criticism of his therapy as a "thinly veiled academic lynching." Sepsis is a medical blitzkrieg, a shockingly efficient killing machine that turns the body's immune response against itself. It often occurs in hospitals after surgery but can arise from such mundane things as a skin or urinary-tract infection. In its worst form, it leaves the lungs stiff and fluid-filled, mimicking pneumonia. Heart, kidney and other organ failure can ensue. Conventional care includes giving antibiotics and fluids. But some years ago, Dr. Rivers sought a better approach.Dr. Rivers, 53, grew up in the Detroit area in River Rouge, Mich., and studied at the University of Michigan. He, like other emergency-care doctors, began thinking that rapid diagnosis and aggressive treatment could be critical to stopping the deadly cascade of sepsis. He developed a concept he called "early goal-directed therapy."Sepsis kills in part because tissues don't get enough oxygen from the blood. Dr. Rivers's idea: Continuously monitor the level of oxygen in the blood and take steps to raise it if it gets too low.For monitoring, he used a catheter, inserted in the jugular vein and slid to near the heart. If it showed that blood oxygen was too low, he elevated it with transfusions and often added a drug to make the heart beat harder. Dr. Rivers modified the catheter, which was made by Edwards Lifesciences Corp., and obtained patents for its design and use.In a pivotal study he led, 133 sepsis patients got standard treatment and 130 his new therapy. In the New England Journal of Medicine in 2001, Dr. Rivers and colleagues reported death rates in the standard-treatment group of 46.5% but only 30.5% in those getting the new therapy.One problem critics now cite: Conventional therapy itself has generally produced death rates of 30% or lower, according to data from Australia and the Netherlands. Dr. Rivers's explanation is that his patients were sicker -- hence a higher death rate for those on conventional care.But another number in the study also has raised a question: What was the true number of sepsis patients studied?The medical-journal article analyzed 263. But it also said that 288 patients were "evaluated," of whom 25 "were excluded or did not consent to participate."Dr. Rivers, in an April interview describing how he proceeded, said "all 288 are randomized" -- that is, placed into either the standard-therapy group or the other group -- "and then some are excluded because they're not considered severe septic shock." But once patients are randomly placed in a group, they must be included in a final analysis, according to a fundamental principle of medical research. Twenty-five were not, the medical-journal article makes clear. Further muddying the waters, Dr. Rivers, despite having said all 288 patients were "randomized," stated in a later email that "there were absolutely no patients pulled out before the analysis."The result appears to be a lack of clarity about exactly how this seminal study was done.Hospital statisticians who worked on it had concerns about the data and recalculated the results with all 288 patients, according to people familiar with the events. When they did, these people say, the death-rate gap wasn't statistically significant.Statisticians were especially concerned when they noticed that a relatively high proportion of the other 25 -- those not included in the final analysis -- were either conventional-therapy patients who survived or patients on aggressive therapy who died, say the people familiar with the events.In 2005, a medical resident at Henry Ford doing follow-up research complained to senior hospital officials about the data in Dr. Rivers's study. The hospital convened a panel of inquiry, which concluded the issues had been satisfactorily resolved, hospital officials say.The panel did a "thorough investigation" and "unanimously supported the conclusions," the hospital said, adding that Dr. Rivers is "an outstanding clinical investigator whom we support."The hospital declined to make the panel's report available. The medical resident who complained, Michael Donnino, declined to discuss the issue of the other 25 patients not included in the final analysis.Dr. Rivers said that "randomization was valid," that "all patients enrolled in the [early goal-directed therapy] study were appropriately selected, randomized and examined statistically," and that "there are no scientific integrity issues in the study."He pointed to other studies he said corroborate his own. One, from China, does show a significant reduction in deaths with early goal-directed therapy, although it also has a high death rate with standard treatment that doesn't jibe with a number of other studies. Patent IssuesApart from these matters, some doctors who contend that hospitals may be adopting the new therapy prematurely point to financial and patent issues.At the time the study at Henry Ford Hospital was published, in late 2001, the hospital was the owner of patents on the catheter used in the new treatment. Dr. Rivers had transferred the rights to the institution.The New England Journal of Medicine didn't mention the patents when publishing the study. According to its editor, its policy at the time was to ask only whether an investigator had financial ties to companies involved, and Dr. Rivers said, correctly, that he had none. Since the publication, catheter maker Edwards Lifesciences has made various payments to Dr. Rivers and his hospital. Such arrangements aren't unusual in medicine, but their existence can raise doubts about findings.Dr. Rivers and the hospital over the years have received at least $404,000 from Edwards, the Irvine, Calif., company says.For instance, Edwards paid $150,000 between 2001 and 2003 to Henry Ford Hospital for what Edwards terms "nonexclusive patent rights [and] ongoing research" into blood oxygen and the mechanism of shock. Dr. Rivers, in an interview, described this as "money I've gotten from the catheter...all for research."In addition, Edwards said, it has paid Dr. Rivers $158,000 to make speeches about his research, $20,000 to reimburse him for patent legal fees, $36,000 in reimbursed expenses and $40,000 in consulting fees.Edwards Lifesciences said medical evidence has "demonstrated that early goal-directed therapy yields significant reductions in sepsis-related mortality, lower organ failure rates and/or reduced health-care costs, particularly due to reduced stays." In recent articles he has written, Dr. Rivers has disclosed receiving support from Edwards. In 2002, critical-care doctors from several specialties joined together to recommend treatments, calling themselves the Surviving Sepsis Campaign. Leading it were R. Phillip Dellinger of Cooper University Hospital in Camden, N.J., and Mitchell M. Levy of Brown University Medical School. Both, plus four others in the group, received consulting fees, honoraria or research-grant support from catheter maker Edwards.Edwards helped pay for overseas meetings of the group in 2002 and 2004, which cost $861,000 in all. Surviving Sepsis endorsed Dr. Rivers's protocol as well as a drug made by another funder of the conferences, Eli Lilly & Co. Edwards said such support is "routinely given to advance science and treatments for the benefit of patients." 'Vulnerable to Manipulation'Three National Institutes of Health scientists criticized the Surviving Sepsis Campaign. They wrote in a medical journal that groups that draw up sets of recommended treatments are "vulnerable to manipulation for inappropriate -- and possibly harmful -- ends" by makers of drugs and medical devices.Drs. Levy and Dellinger asked a second group, the Institute for Healthcare Improvement, to endorse their sepsis recommendations. It did so. The IHI stands by its recommendations, though it "was unaware that there were potential conflicts of interest," said a member, Sean Townsend, a medical professor at Brown.Drs. Levy and Dellinger noted that the Surviving Sepsis Campaign disclosed the possible conflicts. Dr. Dellinger said that, while his group endorsed early goal-directed therapy, it didn't specifically recommend use of the Edwards catheter. Dr. Levy added that "a lot of the experts are turned to by industry for consulting."A large NIH-funded study to re-evaluate Dr. Rivers's early goal-directed therapy is under way at the University of Pittsburgh Medical Center. In contrast to the one-hospital study that launched the therapy, this one will include up to two dozen hospitals. Another multicenter study of the therapy is planned in Australia.Dr. Rivers in Detroit has a simple reply to skeptics about his therapy: It "continues to save lives and hospital costs every day around the world." _________________________________________________________________
