The Comparative Effectiveness of Pulmonary Embolism Prevention after HiP and 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, DVT). 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 has become standard practice to reduce the risk of PE, 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 reliable comparisons between the groups, 25,000 patients undergoing elective total hip or knee replacements will be enrolled at 25 centers across North America. The study will encompass six 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, MD, 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. And now this has become the marquis clinical trial for the joint replacement surgeons at MUSC. 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. He died in the ED with a pulmonary embolism only a few days before his scheduled follow-up visit. 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. This makes PEPPER the largest clinical trial, both in terms of federal funding dollars and enrolled patients, ever performed in orthopaedics. The scale of this study is huge . . . and necessarily so. With the small fraction of patients who develop 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. In fact, an advisory board of patients who have had hip or knee replacement has worked with the MUSC team to develop 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-five of the 28 institutions participating have agreed to rely on a central MUSC IRB. Only two in the United States 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 mandated 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 death. 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, nearly 70 percent of eligible patients have agreed to participate. Participating sites expect to enroll 1,000 patients each over the four-year period. While a bit behind the original schedule due to the time to recruit 25 sites and contract with them for use of a central IRB, more than 6,500 patients are now enrolled and recruiting is on track.
This study is not a winner-takes-all study; it is attempting to define “comparative effectiveness.” “No less effective” is a more pragmatic bar than “better than.” The scale of the study will help determine if – should they all be effective – one of the meds is 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 by 2022.