Embolism Risk Study: The PEPPER Trial
MUSC leads massive nation-wide study to balance risks of pulmonary embolisms and excessive bleeding after hip and knee replacement
The Comparative Effectiveness of Pulmonary Embolism Prevention After Hip & Knee Replacement (The PEPPER Trial)
More than one million total hip and knee replacements are performed each year in the United States. Because disturbing the bone marrow cavity turns on the blood clotting system in humans, these operations are often complicated by formation of blood clots in the veins of the leg (deep vein thrombosis). These clots sometimes detach from the leg veins and travel to the lungs (pulmonary embolism, PE) where they interfere with the normal pumping of the blood from the heart. When a large clot gets stuck in the lung, it can result in death. The use of blood thinners around the time of operation reduces the risk of PEs, but increases the risk of bleeding from the raw bony surfaces that are created when the joint replacement is done.
The ideal balance between use of blood thinners to prevent PEs and the risk of bleeding associated with their use is unknown.
The purpose of the study “Comparative Effectiveness of Pulmonary Embolism Prevention after Hip and Knee Replacement (PEPPER),” which is funded through a Patient-Centered Outcomes Research Institute (PCORI) award, is to combine information about effectiveness in preventing blood clots in the lungs and legs with information about the safety of the most commonly employed blood thinners. The relative concern of patients about avoiding blood clots compared with bleeding is a novel and important part of the study. This work will provide background information to help both patients and their surgeons in deciding which blood thinner would be best to use around the time of hip and knee replacement.
In order to generate enough data, 25,000 patients undergoing elective total hip or knee replacements will be enrolled at 25 centers across the country over a period of three and a half years. The study will encompass five years, with a six-month startup, a six-month follow-up per patient, and six months for final data analysis. The principal investigator is Vincent Pellegrini, M.D., John A. Siegling Professor and Chair of the Department of Orthopaedics and Physical Medicine at the Medical University of South Carolina.
For Pellegrini, this has been a three-decade quest. As chief resident at the University of Rochester (NY) Medical Center in the 1980s, he befriended a hip replacement patient who – at the time – typically stayed three weeks in the hospital following surgery. One day that patient failed to show for his follow-up appointment. Sad to say, he had died in the ED with a pulmonary embolism. Since then, Pellegrini has pursued several grants and trials to study the role of anticoagulants in preventing such events. Many of them were small and not definitive. Some were promising, but succumbed to the vagaries of funding and politics. Until now.
After unsuccessfully applying to NIH and AHRQ, PCORI – an instrument of the federal government created under the Affordable Care Act – was impressed with the need and particularly the design of the study and has awarded nearly $14.5 million for it.
The scale of this study is huge . . . and necessarily so. With the small fraction of patients who throw an embolism, no way could a small study of just hundreds of patients ever expect to inform surgeons as to the relative merits of the three most commonly prescribed anticoagulants – plain aspirin, warfarin (Coumadin), and rivaroxaban (Xarelto).
Patients are educated about the nature of the trial. MUSC has developed a video for participating sites to inform potential participants of the benefits of contributing to the study. Their surgeon has the last say in whether they will participate or must be treated with a different, specific medicine. And their primary care physician is being made aware of their patient’s involvement.
Twenty-two of the 25 institutions participating have agreed to rely on a central MUSC IRB. Only two have chosen not to. The third is the University of Western Ontario, which under Canadian law must operate separately.
This is a first. Beginning in January 2018, the National Institutes of Health will mandate that multi-site studies have a singular central Institutional Review Board or IRB. This is one of the first times that such a large group of institutions have voluntarily agreed to operate under one central IRB. Most institutions will naturally be reluctant to share control with others. However, since Pellegrini wrote the grant and the protocols and MUSC picks up a lot of the administration of the grant, he serves as the principal investigator and has established that MUSC serve as the central IRB.
Does one automatically take universal precautions to prevent a PE and choose the most aggressive route? Or accept that excessive bleeding has its own risks for infection, additional surgery or even fatal infections. While on the surface, preventing death from a PE seems an obvious option over excessive bleeding, consider the math. Only one or two people in 1,000 are expected to die from a PE. Yet 30 to 50 patients in 1,000 administered the most potent anticoagulant to prevent PEs will have excessive bleeding, which can lead to a need for additional surgery or serious infections that require removal of the new joint replacement.
Typically, a small percentage of patients sign up for clinical trials, citing natural skepticism over being a guinea pig. In this case, more than 70 percent of eligible patients have agreed to participate. Participating sites need 1,000 patients over the three-year period. While a bit behind the original schedule due to the time to recruit 25 sites (as of this publishing date) and contract with them for use of a central IRB, some 3,000 patients are now enrolled and recruiting is back on track.
This study is not a winner-takes-all study; it is attempting to define “comparative effectiveness.” “No less effective” is a lower bar than “better than.” The scale of the study will help determine if – should they all be effective – is one of the meds more appropriate for certain populations? These subgroups might be defined by factors including obesity, ethnicity, smoking, genetics, comorbidities, dialysis patients or other markers. Indeed, it is likely that no one drug will be a runaway winner over the others. In the end, the information collected about these medicines will assist patients and their physicians and surgeons to best decide which blood thinner is best for each individual having hip or knee replacement.
Conclusions will be determined and presented only upon the analysis of 25,000 cases. That is expected in 2020.