Comparative Effectiveness of Pulmonary Embolism Prevention after Hip and Knee Replacement (PEPPER): Balancing Safety and Effectiveness
Background: Nearly 1 million total hip (THR) and knee (TKR) replacements are performed each year in the United States, and comprise the largest single type of operation paid for by Medicare. 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). Sometimes, these blood clots detach from the leg veins and travel to the lungs (pulmonary embolism, PE), where they interfere with the normal pumping of blood from the heart. When a large clot gets stuck in the lung, it can result in death; this happens in 0.1–0.5 percent of patients after hip or knee replacement, which means between 1,000 and 5,000 deaths each year. The use of blood thinners around the time of operation reduces the risk of pulmonary embolism and related death, but also 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 PE and the risk of bleeding associated with their use is not known. Nearly all surgeons and professional organizations agree that use of blood thinners is beneficial in this setting, but some clinical guidelines recommend the use of very strong blood thinners while others favor weaker blood thinners in order to reduce bleeding risk. These events are so uncommon that no clinical trial is large enough to provide an answer as to whether the strongest of blood thinners, or weaker medicines, are the best to use in this setting. Similarly, information that is available from billing records of large healthcare insurance companies, such as Medicare, is unable to provide an answer because this information also has shortcomings that limit its usefulness. Since 2012, no study, including the very detailed AHRQ Comparative Effectiveness Review, has been willing to recommend a specific blood thinner as the best to use after hip and knee replacement because there is so little information about the tradeoff between preventing pulmonary embolism and the risk of bleeding that occurs more frequently with the strongest of blood thinners.
Objectives: Our purpose is to combine information about effectiveness in preventing blood clots in the lungs and legs, which is important to how patients do after total hip and knee replacement, with the opinions of patients about the safety of the most commonly employed blood thinners with respect to the chance of bleeding problems that each drug might cause after the operation. The patient’s preferences for using blood thinners to decrease the risk of blood clots that might result in death will be balanced with patient’s concerns about how bleeding problems related to the blood thinners might reduce the success of the joint replacement by causing pain, stiffness, a need for another operation, or infection that might result in having to remove the joint replacement parts altogether. This work will therefore provide background information to help both patients and their surgeons in deciding which blood thinner would be best to use after hip and knee replacement. We expect that the choice of blood thinner will understandably be different for many patients and their surgeons, depending upon how much of a chance of a poor result after the joint replacement that each patient would be willing to accept in return for lowering the risk of a life-threatening blood clot. Because it is so uncommon for a patient to die from a blood clot in the lung after hip and knee replacement, it takes a very large number of patients to be able to see a real difference in the effects of these drugs on blood clots and bleeding in order to determine which drug is best. In fact, none of the previous studies about this issue have been large enough to see any real differences between drugs with respect to death from blood clots, but there have been differences in bleeding with the stronger blood thinners having as much as three to five times more bleeding problems than aspirin, which is a weak blood thinner that may be equally effective in preventing life-threatening blood clots.
Methods: We propose a study that is large enough to compare real differences in rates of life-threatening blood clots between the three most commonly used blood thinners after hip and knee replacement, while also comparing different rates of bleeding with each drug that can make a repeat operation necessary and may ultimately make the joint replacement function less well. Approximately 25,000 patients undergoing elective THR or TKR will be enrolled at 25 centers over 2.5 years at a rate of 400 patients per site per year. The study will encompass four years, with six months startup for IRB approval, six months follow-up per patient, and six months for final data analysis. Together, the study centers account for 33,000 THR and TKR per year; each center will randomize patients to all three groups representative of current practice; aspirin plus pneumatic compression (least bleeding risk regimen), low-intensity warfarin (most popular North American regimen), and rivaroxaban (greatest effectiveness in preventing blood clots). A patient advisory board (PAB) has been established; each member has undergone THR or TKR and some have experienced PE or reoperation for wound complications. The PAB will attach a relative value to each event, the effort spent in its prevention, and its impact on function, risk of reoperation, and loss of the implant.
Patient Outcomes: Primary effectiveness outcomes will include clinically important PE/DVT resulting in readmission and death from all causes. Safety outcomes will include major bleeding and patient-reported wound and remote bleeding. Patients will attach relative importance to blood clots, bleeding, and death and consider this tradeoff in order to determine the relative risk tolerances for blood clots and bleeding to decide which blood thinner is most appropriate for which patients.