UPMC study may reshape liver transplant standards

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1 UPMC study may reshape liver transplant standards By Andrew Conte and Luis Fabregas TRIBUNE-REVIEW Sunday, December 14, 2008 Dr. Thomas Starzl was working on an organ transplant research project in December 2006 when he saw something unexpected. Sixty-five percent of 121 patients who underwent live-donor liver transplants at the University of Pittsburgh Medical Center experienced a significant complication, he said. At that rate, he said, complications were "higher than reported elsewhere," even though UPMC patients had not died or lost transplanted organs at an unusual rate. "The end results are OK, but the firestorm that you have to go through with that operation to get to where you want to go is much bigger, I think, than people have said," Starzl said. Starzl's findings set off a chain reaction within UPMC and the University of Pittsburgh that stopped his findings from publication and led UPMC to conduct its own independent review. The review's outcome has the potential to help reshape the controversial field of using live donors for liver transplants. Once thought of as a clear alternative to a critical shortage of organs from deceased donors, the surgery is under intense scrutiny by doctors worldwide. UPMC spokesman Paul Wood said it is "simply false" to say that UPMC's complication rates are higher than a national average, and that it's impossible to compare its rates with those at other centers because of the thoroughness of UPMC's review. Centers track and define complication rates differently, making it impossible to compare them, he said. By conducting its review, UPMC is striving to "improve the status quo" and the results will establish a "standardized baseline" for the field, he said. Starzl and Dr. Wallis Marsh, UPMC's interim chief of transplantation, offered similar assessments. When Starzl submitted his findings to the New England Journal of Medicine, the dean of Pitt's School of Medicine, Dr. Arthur Levine, sought to prevent their publication. He and others worried that Starzl, who retired from clinical practice 17 years ago, violated newer federal privacy laws by accessing patient records to conduct his analysis. Federal laws make "no exceptions for retired physicians, even one with the stature of Dr. Starzl," Wood said. Levine said in an this month his actions were appropriate: "As the leader

2 of the university's Health Sciences Schools, it is my ultimate responsibility to ensure our scientific and academic credibility, and I acted in the interest of that responsibility. I have done so in other situations that demanded my personal engagement." Upon learning about Starzl's findings, UPMC immediately directed Marsh to begin an independent program review. Marsh said his findings were "pretty similar." The two doctors are working together and expect to submit their study for publication next year. Both said complications could be intrinsic to the procedure -- in which a portion of a live donor's liver is transplanted -- and not indicative of medical error. Independent scientists outside of UPMC have not validated the findings for publication in a medical journal. The findings, however, are in line with a review conducted at UPMC's transplant hospital in Sicily published last year, Starzl said. They follow results of a national study showing complication rates among recipients of livers from live donors are higher than among those who received livers from deceased ones. The number of live-donor liver transplants appears to be down at UPMC -- to four of them so far this year through September, from 36 in all of 2006 and 19 last year -- according to the United Network for Organ Sharing. Marsh said the decline is unrelated to the review. Nationally, the transplant numbers are on pace to match last year's total of 266 cases. Starzl, 82, said UPMC's review can make UPMC a "flagship of integrity." "This was an active search to identify the true rate of complications, and I think if we put this out there, it's going to embolden other people, or perhaps even force them, to do the same thing," he said. "All we're saying right now is that this rate of complications is higher than reported elsewhere. It may be that complications are being underreported elsewhere." UPMC's Wood said the medical center's response to Starzl's findings was driven by a desire to perform good medicine, and the outcome of the review could set a standard worldwide. "It will provide other transplant centers both with what we hope will become a standard methodology for reporting complications of the live-donor operation, as well as provide them with our results so that complication rates can be compared in a standardized, scrupulous fashion," he said. STARZL'S CONCERNS EMERGE Starzl's interest in complications from live-donor liver transplants surfaced when he was a consultant in a UPMC study about tolerance -- when an organ recipient's immune system accepts a transplanted organ as its own. It has been one of Starzl's primary areas of research since he stopped doing surgeries in 1991.

3 The study, involving 10 patients and led by Dr. Amadeo Marcos, then chief of transplantation, aimed to wean patients from powerful immunosuppressive drugs they often must take for life. The number of complications among recipients jumped out when he reviewed data, Starzl said. He began an analysis that involved all of Marcos' 126 livedonor liver transplant patients in Pittsburgh over a three-year period. Marcos did not return repeated phone calls or respond to questions in a letter the Tribune-Review hand-delivered to his Fox Chapel home. Starzl's findings differed from earlier data Marcos published before he resigned in March for personal reasons. A 2007 textbook, which Marcos and two others edited, reported a study of a subset of 47 UPMC patients on a specialized drug regimen found biliary complications in 30 percent of recipients. Starzl said he doesn't think Marcos misrepresented complications in his cases, but rather focused on his successes. Marcos was a co-author on the 2007 paper that looked at complication rates among live-donor liver transplants at UPMC's Sicily hospital, where he occasionally performed surgeries. That study reported 41.5 percent of patients experienced a bile duct complication within one year. Starzl said the Italy findings were closer to his. Still, when Starzl reviewed cases at UPMC, the outcome was "different than everybody expected," said Randy P. Juhl, Pitt's vice chancellor for research conduct and compliance. Ten days after Starzl submitted his manuscript to the New England Journal of Medicine, Levine sent an to the editor, Dr. Jeffrey M. Drazen, asking him to withhold editorial action on the paper. He cited "substantial problems with this report." Levine wrote in the to Drazen: "Given Dr. Starzl's great stature in the medical and scientific communities, dealing with this manuscript has been a painful exercise." In a subsequent letter to the Journal, dated Oct. 16, Levine expressed more detailed concerns about Starzl's manuscript. Chief among them was what he said was a failure to follow accepted scientific standards such as formulating a testable hypothesis or randomizing patients. "The manuscript is a simple description of the results of one surgeon's patients without hypothesis or context," Levine wrote. "This single surgeon is not a coauthor, did not participate in the analysis, and does not approve of the submission." Levine said UPMC's vice president for information security and privacy, John Houston, concluded the paper might violate federal privacy laws because patients did not authorize use of their medical information. Levine called Starzl's paper premature and incomplete.

4 Juhl last month said Starzl did not violate the privacy law, known as Health Insurance Portability and Accountability Act. The New England Journal of Medicine never published Starzl's paper. Drazen referred questions to a spokeswoman, who said the publication process is confidential. Three medical experts familiar with the editorial process of medical journals said it is uncommon for a school's top officials to ask for a manuscript to be withdrawn. "I never heard of anything like this," said Dr. Alan R. Leff, a professor at the University of Chicago Medical Center, who is editor of the journal Proceedings of the American Thoracic Society. "It's strange that the dean would ask for a paper to be withdrawn." By the time the paper was withdrawn, tensions between Starzl and UPMC had escalated, and Starzl said UPMC curtailed his access to patient records because he was retired from clinical practice. Starzl said he received a letter telling him he could not enter UPMC premises -- including the Starzl Transplantation Institute at UPMC Montefiore in Oakland -- unless he needed personal medical care. Starzl was allowed in his office along Fifth Avenue. "When Dr. Starzl failed to return patient records, the actions then pursued by UPMC were completely appropriate," Wood said. Leaders at Pitt, UPMC's academic sister, intervened. Juhl, a former School of Pharmacy dean who rose to a senior post overseeing the committee that approves and monitors research, asked UPMC for a "cooling off period." Juhl said medical administrators solved the conflict in a "genuine, academically proper way." He said Levine acted in good faith by wanting to ensure that Starzl's work met academic and scientific standards. "If somebody believes the data was not complete, then the dean has an obligation to look into it," Juhl said. Levine wrote in an that he is pleased with the resolution. Juhl brokered a compromise that allowed Starzl to collaborate with Marsh, who trained under Starzl in the 1980s. Marsh was appointed interim chief of transplantation upon Marcos' resignation. COLLABORATION For their collaboration to be effective, Starzl and Marsh had to determine what medical events to count as complications. In organ transplantation, as in other areas of medicine, minor problems after surgery correct themselves without treatment.

5 They enlisted the help of Dr. Pierre-Alain Clavien, a Swiss surgeon who devised a widely used scale to categorize surgical complications from minor infections to death. Marsh and Starzl threw out five cases, choosing to examine 121 surgeries that used a standard technique. They analyzed the cases using the most recent version of the Clavien scale, published in 2004, which is more detailed in reporting life-threatening complications. Starzl said they identified 79 cases -- or 65 percent -- that were considered Clavien III or higher, meaning the patients required, at least, medical intervention such as a second surgery. About 41 percent of patients had biliary leaks or blockages, which can correct themselves but can be life-threatening or require surgery to repair. Fifteen percent of patients experienced vascular complications; 9 percent experienced other issues. Marsh declined to talk in detail about the findings, saying he and Starzl had asked a statistician to reanalyze the data. He said he suspects the study will show that 40 percent to 50 percent of recipients experienced a bile duct complication. Their study would follow a national study in October by a federally funded group, the Adult-to-Adult Living Donor Liver Transplantation Cohort Study, which reported a 42 percent rate of all types and degrees of bile duct leakage and blockage among recipients. It used a 1994 version of the Clavien scale. "The newer scale would probably not change the overall message of the paper, even though it classifies complications using a five-point scale and uses slightly different criteria for each category," Dr. Chris E. Freise, a transplant surgeon at the University of California San Francisco and first author of the A2ALL paper, wrote in an . "Comparing complication rates from reports with different classification schemes is difficult to do, so (I'm) not certain how (the) Marsh and Starzl report could be compared directly to (the) A2ALL report, without some further careful review of data." Marsh said the findings will help UPMC focus on improving the operation. He said he is working on a technique to reduce bile duct complications. "Now, it may be that there's no way to further improve it," he said. "Just by the mechanisms of this operation, when you cut a liver in half, you're going to somewhat interrupt the blood supply to the bile duct; that's just the way the operations is. Can we make it better than that? I don't know." Marsh said he wants to better inform patients about complications they might face after receiving a liver from a live donor. He wants to tell prospective patients in a written consent form the exact percentage of complications they can encounter. Other transplant centers can learn from the UPMC experience, by examining their programs and studying complications, Starzl said. Wood, the UPMC spokesman, agreed: "The way that patient care is improved

6 is to thoroughly study those patients who have less than optimal outcomes. They teach us how to improve the care that is provided." Starzl said what really is needed is a better picture of risks and benefits for donors and recipients -- and whether it is appropriate to promote the live-donor operation. "That was and still is a key question," Starzl said. "The full profile of that operation has not been painted." Images and text copyright 2010 by Trib Total Media, Inc. Reproduction or reuse prohibited without written consent.