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AAOS Now

Published 10/11/2022
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Kenoma Anighoro, MD, MBA; Alan Reznik, MD, MBA, FAAOS

Tranexamic Acid: A Paradigm Shift in Total Joint Care

Years ago, total joint arthroplasty (TJA) postoperative protocols consisted of two-week hospital stays and multiweek stays in nursing care facilities. In time, discharges occurred a few days after surgery and nursing home stays converted to visiting nurse services. Less than 10 years ago, outpatient discharges for lower-extremity TJA were limited to rare “rock star” patients at cutting-edge centers.

Today, orthopaedic surgeons have moved away from questioning whether outpatient TJAs are possible to debating the definition of what “outpatient” surgery means. This discussion ranges from discharges within a daylight cycle (“same-day”) to stays less than 23 hours (“outpatient” or “observation status”). Most surgeons credit this shift to new perspectives on perioperative care, including improved preoperative optimization, less traumatic surgical approaches, and greater use of multimodal pain management.

Fig. 1 Tranexamic acid (TXA) molecule (A). In solution, it exists in equilibrium as two structure versions (B). At physiological pH (~7), the acid is de-protonated, and the amine is protonated, so it primarily exists in the Zwitterion form (right).
Fig. 2 Lysine molecule
Table 1 The authors’ recommendations for use of tranexamic acid (TXA) in patients undergoing total joint arthroplasty based on patient characteristics or potential complications. VTE, venous thromboembolism

There has also been a dramatic decrease in transfusion rates over the past decade. The adoption of tranexamic acid (TXA) by orthopaedic surgeons has played a key role in ongoing transfusion reduction. It has contributed to the collective paradigm shift in TJA care that has enabled the transition to outpatient surgical management. As TXA use is becoming more uniformly adopted in total joint and other bone-cutting procedures, it is important to reflect on its origins, chemistry, and evolving role in orthopaedic surgery, along with its limitations.

TXA (Fig. 1) is a synthetic analog of lysine (Fig. 2) with anti-fibrinolytic properties. It reversibly binds to plasminogen, preventing conversion to plasmin, thus interfering with plasmin-mediated fibrin clot degradation. As an analog to a natural alpha amino acid, its unique mechanism of action allows reductions in bleeding by minimizing trauma-related clot degradation without increasing pathologic thrombogenesis. When compared with similar compounds such as epsilon-aminocaproic acid, TXA is associated with higher efficacy and lower mortality risk. This is supported by several studies in which venous thromboembolism (VTE) rates after TJA with TXA were not significantly different from rates among controls, even in high-risk patient populations.

Modern outpatient TJA protocols have incorporated preoperative optimization of nutritional, cardiac, and endocrine comorbidities. Postoperative care has been enhanced by multimodal pain control with the use of peripheral nerve blocks and neuraxial anesthesia as well as accelerated physical therapy programs with extended therapy hours. Many of these components have gained national recognition as standard components of TJA care pathways and have become essential in the push to outpatient TJA.

In the past five years, TXA has also been incorporated into standard TJA protocols. The accelerated adoption of all of the above advances spurred the formalization of newer guidelines from AAOS and the American Association of Hip and Knee Surgeons (AAHKS).

History of TXA use
It is important to reflect on the clinical innovation of TXA, as this agent has been in existence for over half a century. It was developed in the 1960s by Japanese scientists and approved by the FDA for safety in the 1980s. TXA was used by cardiac and obstetric surgeons for decades prior to its use in orthopaedic surgery. In short, TXA use in surgery is an old technology.

In the 1990s, TXA was found to substantially decrease blood loss and improve mortality rates in cardiac bypass surgery. Orthopaedic surgeons in Europe and elsewhere began using TXA in orthopaedic and TJA surgery before widespread use was noted in the United States. As multidisciplinary evidence of effectiveness mounted, AAOS eventually formalized clinical practice guidelines endorsing TXA for total knee arthroplasty in September 2015 and for total hip arthroplasty in March 2017. AAHKS formalized its guidelines for TJA in 2018, endorsing it as the new standard of care.

Prior to widespread use of TXA, historic transfusion rates in TJA ranged from 5 percent to 30 percent for elective lower-extremity procedures, compared with around 0 percent to 5 percent with current routine TXA use. The highest-risk patients, such as those with preoperative anemia or those who require revision surgery, often still need transfusions. However, the more typical lower-risk patients often do not. The resultant reduced rates of transfusion nearly obviated the need for longer-term inpatient monitoring beyond 24 hours in routine cases. Therefore, the widespread adoption of TXA in lower-extremity TJA was well-timed for the transition to outpatient surgery.

Contraindications to TXA use
There are few situations where TXA use is contraindicated. Generally accepted contraindications include use in patients who are within six months of coronary stenting, have a concurrent diagnosis of a coagulopathic disorder or concomitant subarachnoid hemorrhage (i.e., elevated stroke risk), or are allergic to TXA. Caution is also advised for patients with low renal clearance, as the medication is cleared renally. There does not appear to be an increased risk of stroke unless a patient has a concomitant subarachnoid hemorrhage.

For patients with a personal history of VTE, there is no substantiated risk of increased VTE with TXA administration. Some surgeons prefer to use topical TXA in such patients. However, this choice does not seem to affect the risk of VTE, as the use of either IV or topical TXA has an insignificant impact on VTE rates.

The most notable side effect with TXA is an increased risk of perioperative seizure, as high doses of TXA can lead to GABAergic receptor inhibition through competitive antagonism. Patients who have a postoperative seizure may also be at higher risk of developing stroke. Fortunately, this is an exceedingly rare phenomenon in TJA care.

Seizure is a known dose-related adverse reaction to TXA and is more common at high doses. For example, some historic cardiac protocols called for 30 mg/kg loading doses of TXA followed by 10 mg/kg per hour during cardiac bypass procedures, far beyond typical doses used in orthopaedic surgery applications. Low-dose protocols, defined as a 10 mg/kg loading dose followed by 10 mg/kg per hour or limiting to 2 g per day, result in seizure rates that are no different from controls, even in the presence of seizure history. Most orthopaedic protocols use low doses. As such, postoperative seizures are rare in TJA care despite widespread TXA use. To avoid medical complications of TXA, optimal and limited dosing is important, as more is not always better. Table 1 summarizes the current recommendations and contraindications for TXA.

Widespread use
TXA has also been used to great effect outside of lower-extremity TJA. It is also effective in reducing blood loss in primary and revision shoulder arthroplasty, though it is not yet substantiated whether it significantly impacts transfusion rates. In spine surgery, TXA use substantially decreases blood loss and transfusion rates, particularly in adult-deformity surgery or long lumber fusion cases.

In orthopaedic trauma, TXA has been incorporated into many geriatric hip-fracture protocols. As a result, there have been significant reductions in blood loss and transfusion rates, without impacts on VTE rates or mortality. In high-energy pelvic and acetabular fractures, TXA use has been found to yield significant reductions in total blood loss, though it is not yet established whether transfusion rates are reduced.

Factors contributing to the outpatient surgery transition
Previously, the substantial perioperative variability conferred by a nearly one-in-five transfusion rate in TJA underpinned the historical dependence on hospitals for perioperative TJA care. When that need diminished, traditional hospital dependence, blood bank access, and long-term vitals monitoring became optional.

The transition to outpatient settings was also accelerated by the logistical challenges imposed by the COVID-19 pandemic. With hospital resources stretched, many surgeons were forced to guarantee same-day discharge to preserve inpatient access for respiratory patients. Many practices resorted to ambulatory surgery centers to conserve hospital resources.

Openness to interdisciplinary knowledge transfer paved the way for the widespread use of TXA today, and countless patients have benefited from this medical advance. In a way, TXA has disproved the adage, “Old dogs can’t learn new tricks.” It also serves as a great example of what orthopaedic surgeons can glean from our peers in other surgical specialties to continually advance musculoskeletal care.

Kenoma Anighoro, MD, MBA, is an orthopaedic surgeon practicing at Connecticut Orthopaedics, based in Hamden, Conn. He recently completed his fellowship in Austin, Texas, where he served as the Joseph M. Abell Adult Reconstruction Fellow at the Dell Medical School.

Alan M. Reznik, MD, MBA, FAAOS, who specializes in sports medicine and arthroscopic surgery, is chief medical officer of Connecticut Orthopaedics, associate professor of surgery at Quinnipiac University Netter School of Medicine, and assistant professor of orthopaedics at Yale University School of Medicine. He is a former member of the AAOS Now Editorial Board.

References

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