RCT: Single IV Dose of TXA Is Safe, Effective for TKA
Along the spectrum of early and late adopters in medicine, most orthopaedic surgeons fall in the middle. They wait for science to prove the efficacy and safety of an innovation, carefully review the published studies regarding that innovation, and adopt it if it will improve their patients’ outcomes.
In the December 4, 2019 issue of JBJS, Jules-Elysee et al. compare tranexamic acid (TXA) administered intravenously (IV) versus topically in a double-blinded, randomized controlled trial (RCT) of patients undergoing primary total knee arthroplasty (TKA). Level-I evidence is rare in the orthopaedic literature, so when a well-performed RCT comes out, we should closely evaluate its findings.
A potent antifibrinolytic, TXA has been shown in multiple studies to decrease blood loss associated with major orthopaedic procedures. However, there are persistent (but not necessarily evidence-based) concerns about its potential to cause thrombogenic complications, and the safest and most effective route of TXA administration remains an open question.
In this study, the IV group received TXA once before tourniquet inflation and again 3 hours later, along with a topical placebo given 5 minutes before tourniquet release. The topical group received an IV placebo at the same time intervals as the IV group, along with TXA delivered topically in the wound prior to tourniquet release. The authors found lower systemic levels of plasmin-anti-plasmin (PAP, a measure of fibrinolysis) in both groups 1 hour after tourniquet release, but PAP levels remained significantly lower in the IV group (indicating higher antifibrinolytic activity) 4 hours after tourniquet release, which was likely related to the second IV dose of TXA.
The authors also found no between-group difference in systemic or wound levels of prothrombin fragment 1.2 (PF1.2, a marker of thrombin generation), indicating there was no increase in thrombogenicity in the IV group. Interestingly, Jules-Elysee also found that the IV group had significantly higher hemoglobin and hematocrit levels 1 and 2 days after surgery, and those patients had a significantly shorter hospital stay.
Finding no major between-group differences in the mechanism of action, coagulation, or fibrinolytic profile, the authors concluded that a single IV dose of TXA may be the most simple protocol for hospitals to adopt if they are still concerned about TXA safety. Perhaps these Level-I findings will help some of the late adopters get over their fears about the safety of IV TXA.
Matthew R. Schmitz, MD
JBJS Deputy Editor for Social Media
What’s New in Hip Replacement 2019
Every month, JBJS publishes a review of the most pertinent and impactful studies published in the orthopaedic literature during the previous year in 13 subspecialties. Click here for a collection of all OrthoBuzz Specialty Update summaries. This month, Mengnai Li, MD, co-author of the September 18, 2019 “What’s New in Hip Replacement,” selected the five most clinically compelling findings from among the more than 100 studies summarized in the article.
THA Dislocation
–Pathology involving the spinopelvic relationship has dominated the recent literature on THA dislocation. For patients presenting with a flatback deformity and stiff spine, who had the highest risk of dislocation, the authors of a recent study suggested the use of a dual-mobility implant construct with targeted 30° of anteversion relative to the functional pelvic plane, based on a standing anteroposterior radiograph.1
Preferred Implant Designs
–A study comparing data from the American Joint Replacement Registry with national registry data from other countries found that cementless stem fixation with the use of ceramic and 36-mm heads was the current US preference, while non-US registries indicated that cemented implants and metal and 32-mm heads were used most commonly.2
Opioid Use
–The ongoing effort in the orthopaedic community to reduce opioid consumption without compromising quality of life for joint-replacement patients may be aided by findings from a recent randomized controlled trial. The study found that prescribing 30 immediate-release oxycodone pills instead of 90 pills was associated with a significant reduction in unused pills and decreased opioid consumption without affecting pain scores and patient-reported outcomes.3
Penicillin Allergy
– A retrospective review of >4,900 patients who underwent THA or TKA found that 16.2% reported a history of penicillin allergy. No patients among those with a stated penicillin allergy who were given cefazolin had an adverse reaction. Also, there was no increased rate of surgical site infections among those with a stated penicillin allergy who received clindamycin or vancomycin, although the authors acknowledged that this part of the study was underpowered due to the low overall rate of infection.4
Use of TXA
–Recent guidelines on the use of tranexamic acid (TXA) state that no specific routes of administration, dosage, dosing regimen, or time of administration have been shown to provide clearly superior blood-sparing properties.5
References
- Luthringer TA, Vigdorchik JM. A preoperative workup of a “hip-spine” total hip arthroplasty patient: a simplified approach to a complex problem. J Arthroplasty.2019 Jan 18. [Epub ahead of print].
- Heckmann N, Ihn H, Stefl M, Etkin CD, Springer BD, Berry DJ, Lieberman JR. Early results from the American Joint Replacement Registry: a comparison with other national registries. J Arthroplasty.2019 Jan 5.
- Hannon CP, Calkins TE, Li J, Culvern C, Darrith B, Nam D, Gerlinger TL, Buvanendran A, Della Valle CJ. The James A. Rand Young Investigator’s Award: large opioid prescriptions are unnecessary after total joint arthroplasty: a randomized controlled trial. J Arthroplasty.2019 Feb 4. [Epub ahead of print].
- Stone AH, Kelmer G, MacDonald JH, Clance MR, King PJ. The impact of patient-reported penicillin allergy on risk for surgical site infection in total joint arthroplasty. J Am Acad Orthop Surg.2019 Feb 27. [Epub ahead of print].
- Fillingham YA, Ramkumar DB, Jevsevar DS, Yates AJ, Bini SA, Clarke HD, Schemitsch E, Johnson RL, Memtsoudis SG, Sayeed SA, Sah AP, Della Valle CJ. Tranexamic acid use in total joint arthroplasty: the clinical practice guidelines endorsed by the American Association of Hip and Knee Surgeons, American Society of Regional Anesthesia and Pain Medicine, American Academy of Orthopaedic Surgeons, Hip Society, and Knee Society. J Arthroplasty.2018 Oct;33(10):3065-9. Epub 2018 Aug 7.
In THA, Less Blood Loss with Multidose Postop Oral TXA
The recent orthopaedic literature, including a 2017 JBJS study, provides substantial evidence that oral and intravenous tranexamic acid (TXA) are equivalent in their effectiveness at reducing blood loss after total hip arthroplasty (THA)—with oral administration being less expensive and more convenient. But what are the optimal doses and timing of oral TXA in the setting of THA?
The findings of a randomized controlled trial by Wang et al. in the March 6, 2019 issue of JBJS go a long way toward answering that question. The authors randomized 200 patients undergoing primary THA to 1 of 4 groups, with all patients receiving an intraoperative topical dose of 1.0 g of TXA and a single dose of 2.0 g of TXA orally at 2 hours postoperatively. In addition,:
- Group A received 1.0 g of oral placebo at 3, 9, and 15 hours postoperatively
- Group B received 1.0 g of oral TXA at 3 hours postoperatively and 1.0 g of placebo at 9 and 15 hours postoperatively
- Group C received 1.0 g of oral TXA at 3 and 9 hours postoperatively and 1.0 g of placebo at 15 hours postoperatively
- Group D received 1.0 g of TXA at 3, 9, and 15 hours postoperatively
The mean total blood loss during hospitalization was significantly less in Groups B, C, and D (792, 631, and 553 mL, respectively) than in Group A (984 mL). Groups C and D had lower mean reductions in hemoglobin than did Groups A and B. No significant between-group differences were observed regarding 90-day thromboembolic complications (there were none) or transfusions (there was only 1, in Group A), but the authors said “this study was likely underpowered for establishing meaningful comparisons concerning [those 2] outcomes.”
Although this study documented significantly lower total blood losses in patients who were managed with multiple doses of oral TXA postoperatively, additional studies are required to determine whether the 3-dose regimen is superior to the 2-dose regimen.
Confirmed: TXA Works Well in Adolescent Scoliosis Surgery
The evidence favoring tranexamic acid (TXA) for reducing surgical blood loss is ample and growing, but until now robust data were sparse regarding its efficacy in the setting of adolescent idiopathic scoliosis surgery. In the December 5, 2018 issue of The Journal of Bone & Joint Surgery, Goobie et al. report on a randomized, blinded, placebo-controlled trial showing that, in that population, TXA reduced perioperative blood loss by 27%, compared with blood loss in a placebo group.
Even with recent advances in scoliosis surgical technique, blood transfusions are common. And, because transfusions are associated with significant morbidity and mortality, limiting operative blood loss and reducing the need for transfusion have become focal points for orthopaedic surgeons.
In this Level-I trial, >100 patients between the ages of 10 and 18 years undergoing elective posterior instrumented spinal fusion were randomized to receive either TXA (infusion of a 50-mg/kg loading dose and a 10-mg/kg/h maintenance dose) or normal saline (delivered in the same way and dose) during surgery. The TXA group demonstrated an overall 27% reduction in cumulative blood loss and a 2-fold reduction in the percentage of patients with clinically relevant blood loss (defined as >20 mL/kg).
The cumulative effect of reduced blood loss was enhanced over time, with the positive effect of TXA being most evident in procedures lasting >4 hours. None of the patients in the TXA group required a transfusion or developed side effects such as thromboembolism or seizures.
In an interesting sidenote, the authors asked the participating orthopaedic surgeons, who were blinded to the randomization, to guess which group each patient had been assigned to by evaluating the relative ooziness of the surgical field. The surgeons guessed correctly 72% of the time.
Overall, these findings prompted the authors to conclude that “the use of TXA as part of a multimodal blood management strategy, as was employed in this study, should be considered the standard of care for patients undergoing surgery for adolescent idiopathic scoliosis.”
Tranexamic Acid: Effective—and Safe—in THA
Prior research has established that total hip arthroplasty (THA), in and of itself, is associated with a small increased risk of venous thromboembolism (VTE). Hence the concern that routinely administering the antifibrinolytic drug tranexamic acid (TXA) perioperatively, as is commonly done nowadays to reduce blood loss during surgery, might further increase the risk of THA-related thromboembolic events. But the findings from a large population-based cohort study by Dastrup et al. in the October 17, 2018 JBJS, should allay many of those concerns.
The authors evaluated >45,000 Danish patients who had a THA between 2006 and 2013. Approximately 85% of those patients received intravenous TXA perioperatively, while the rest did not. Dastrup et al. evaluated adverse cardiovascular events (VTE, deep venous thrombosis, pulmonary embolism, myocardial infarction, and ischemic stroke) among those patients over 30 postoperative days, and they found no increased risk in any of those outcomes among the patients who received TXA relative to those who did not. These optimistic findings were essentially the same when the authors analyzed the data using a multivariable model and with propensity-score matching.
Dastrup et al. conclude that TXA in the setting of THA is safe with respect to VTE, and David Ayers, MD, commenting on the study, concurs. However, Dr. Ayers cautions that the study did not have the statistical strength to evaluate the potential cardiovascular risks of TXA in THA patients who have undergone previous cardiac procedures, such as stent placement. He therefore suggests that “further safety evaluation should be directed toward [such] patients at higher risk for complications after receiving TXA.”
What’s New in Hip Replacement 2018
Every month, JBJS publishes a Specialty Update—a review of the most pertinent and impactful studies published in the orthopaedic literature during the previous year in 13 subspecialties. Click here for a collection of all OrthoBuzz Specialty Update summaries.
This month, Mengnai Li, MD, co-author of the September 19, 2018 Specialty Update on Hip Replacement, selected the five most clinically compelling findings from among the more than 100 studies covered in the Specialty Update.
The Benefits of HXLPE
–A double-blinded study that randomized patients to receive either a conventional polyethylene liner or one made from highly cross-linked polyethylene (HXLPE) found that, after a minimum of 10 years, the HXLPE group had significantly lower wear rates, lower prevalence of osteolysis, and lower revision rates than the conventional-liner group.
Outcomes for Hip Fracture vs OA
–A propensity score-matched cohort analysis of NSQIP data found that total hip arthroplasty (THA) undertaken to treat hip fractures among Medicare beneficiaries was significantly associated with an increased risk of CMS-reportable complications, non-homebound discharge, and readmission, relative to THA undertaken to treat osteoarthritis.1
Infection Risk Factors
–A multicenter retrospective study found that a threshold of 7.7% for hemoglobin A1c was more predictive of periprosthetic joint infection than the commonly used 7%, and the authors suggest that 7.7% should be considered the goal in preoperative patient optimization.2
THA in Patients with RA
–Recently published guidelines from the American College of Rheumatology and AAHKS regarding antirheumatic medication use in patients with rheumatic diseases who are undergoing THA suggest the following:
- Continuing nonbiologic disease-modifying antirheumatic drugs (DMARDs)
- Continuing the same daily dose of corticosteroids
- Withholding biologic agents prior to surgery
- Planning surgery for the end of the biologic dosing cycle.
All recommendations are conditional due to the low or moderate-quality evidence on which they were based.3
Blood Management
–A double-blinded, randomized trial found that oral tranexamic acid (TXA) provided equivalent reductions in blood loss in the setting of primary THA, at greatly reduced cost, compared with intravenous TXA.
References
- Qin CD, Helfrich MM, Fitz DW, Hardt KD, Beal MD, Manning DW. The Lawrence D. Dorr Surgical Techniques & Technologies Award: differences in postoperative outcomes between total hip arthroplasty for fracture vs osteoarthritis. J Arthroplasty. 2017 Sep;32(9S):S3-7. Epub 2017 Feb 6.
- Tarabichi M, Shohat N, Kheir MM, Adelani M, Brigati D, Kearns SM, Patel P, Clohisy JC, Higuera CA, Levine BR, Schwarzkopf R, Parvizi J, Jiranek WA. Determining the threshold for HbA1c as a predictor for adverse outcomes after total joint arthroplasty: a multicenter, retrospective study. J Arthroplasty. 2017 Sep;32(9S): S263-7: 267.e1. Epub 2017 May 11.
- Goodman SM, Springer B, Guyatt G, Abdel MP, Dasa V, George M, Gewurz- Singer O, Giles JT, Johnson B, Lee S, Mandl LA, Mont MA, Sculco P, Sporer S, Stryker L, Turgunbaev M, Brause B, Chen AF, Gililland J, Goodman M, Hurley-Rosenblatt A, Kirou K, Losina E, MacKenzie R, Michaud K, Mikuls T, Russell L, Sah A, Miller AS, Singh JA, Yates A. 2017 American College of Rheumatology/American Association of Hip and Knee Surgeons guideline for the perioperative management of antirheumatic medication in patients with rheumatic diseases undergoing elective total hip or total knee arthroplasty. J Arthroplasty. 2017 Sep;32(9):2628-38. Epub 2017 Jun 16.
Using Tranexamic Acid: Not If, But How
Most surgeons agree that tranexamic acid (TXA) is effective at reducing blood loss associated with a variety of surgical procedures, including total joint arthroplasty. The question is no longer whether it works but, more specifically, how is TXA most safely and effectively used. That was the main question Abdel et al. set out to answer in their study in the June 20, 2018 edition of The Journal. The authors completed a two-center randomized trial that compared blood loss, drain output, and transfusion rates among 320 total knee arthroplasty (TKA) patients who received intravenous (IV) TXA and 320 TKA patients who received topical TXA.
Statistically, the results of the study are clear: Patients who received intravenous TXA had significantly less blood loss (271 mL vs 324 mL; p=0.005) than those who received topical TXA. Furthermore, after authors controlled for several patient characteristics, they found that those who received topical TXA were 2.2 times more likely to receive a transfusion than those who received intravenous TXA. Still, both modalities resulted in very low transfusion and complication rates of <2% each.
Although IV TXA seems to be more effective at decreasing blood loss than topical TXA in the setting of TKA, Abdel et al. question whether the 53 mL difference is “clinically important,” considering the very low transfusion rates in both groups. What might be more clinically meaningful is the fact that the topical TXA group experienced a 5-minute delay during the procedure so the TXA could stay in contact with the tissues prior to suction and wound closure. Such a delay (which could account for about 5% of total surgical time) could put some patients at risk for other complications and is questionable without an appreciable benefit.
So, will every knee-replacement surgeon now use IV TXA instead of topical TXA? Of course not. Although the authors emphasize that there does not appear to be an increased risk of blood-clot-related complications when using IV TXA, some surgeons will still shy away from using that route of administration in certain patients. Also, some surgeons may question this study’s generalizability because of the number of perioperative variables described in the methods.
Still, I commend the authors on performing such a large, well-designed study. It is easy to pick apart data from the viewpoint of external validity, but these results are statistically steadfast. While we probably do not need more studies looking at the efficacy of TXA in total joint arthroplasty, further studies looking at the optimal manner in which the medication can be administered are welcomed.
Chad A. Krueger, MD
JBJS Deputy Editor for Social Media
What’s New in Adult Reconstructive Knee Surgery
Every month, JBJS publishes a Specialty Update—a review of the most pertinent and impactful studies published in the orthopaedic literature during the previous year in 13 subspecialties. Click here for a collection of all OrthoBuzz Specialty Update summaries.
This month, Gwo-Chin Lee, MD, author of the January 18, 2017 Specialty Update on Adult Reconstructive Knee Surgery, selected the five most clinically compelling findings from among the more than 100 studies summarized in the Specialty Update.
Nonoperative Knee OA Treatment
—Weight loss is one popular nonoperative recommendation for treating symptoms of knee osteoarthritis (OA). An analysis of data from the Osteoarthritis Initiative found that delayed progression of cartilage degeneration, as revealed on MRI and clinical symptoms, positively correlated with BMI reductions >10% over 48 months.1
Total Knee Arthroplasty
—In total knee arthroplasty (TKA), the drive toward producing normal anatomy has led to explorations of alternative alignment paradigms. A prospective randomized study found that small deviations from the traditional mechanical axis (known as kinematic alignment) can be well tolerated and do not lead to decreased survivorship or poorer functional outcomes at short-term follow up.2
—Controversy exists about the optimal method to achieve stemmed implant fixation in revision TKA. A randomized controlled trial of TKA patients with mild to moderate tibial bone loss found no difference in tibial implant micromotion between cemented and hybrid press-fit stem designs, based on radiostereometric analysis.
Blood Management in TKA
—Minimizing blood loss and transfusions is crucial to minimizing complications after TKA. A randomized, double-blind, placebo-controlled trial found that intra-articular and intravenous administration of tranexamic acid (TXA) was more effective than intravenous TXA alone, without an increased risk of venous thromboembolism (VTE). However, the optimal regimen for TXA remains undefined.
VTE/PE Prophylaxis
—VTE prophylaxis is essential for all patients undergoing TKA. A risk-stratification study of pulmonary embolism (PE) after elective total joint arthroplasty reported that the incidence of PE within 30 days after either hip or knee replacement was 0.5%. Risk factors associated with PE were age of > 70 years, female sex, and higher BMI. The presence of anemia was protective against PE. The authors developed an easy-to-use scoring system to determine risk for VTE to help guide chemical prophylaxis.3
References
- Gersing AS, Solka M, Joseph GB, Schwaiger BJ, Heilmeier U, Feuerriegel G, Nevitt MC, McCulloch CE,Link TM. Progression of cartilage degeneration and clinical symptoms in obese and overweight individuals is dependent on the amount of weight loss: 48-month data from the Osteoarthritis Initiative. Osteoarthritis Cartilage. 2016 Jul;24(7):1126-34. Epub 2016 Jan 30.
- Calliess T, Bauer K, Stukenborg-Colsman C, Windhagen H, Budde S, Ettinger M. PSI kinematic versus non-PSI mechanical alignment in total knee arthroplasty: a prospective, randomized study. Knee Surg Sports Traumatol Arthrosc. 2016 Apr 27. [Epub ahead of print]
- Bohl DD, Maltenfort MG, Huang R, Parvizi J, Lieberman JR, Della Valle CJ. Development and validation of a risk stratification system for pulmonary embolism after elective primary total joint arthroplasty. J Arthroplasty. 2016 Sep;31(9)(Suppl):187-91. Epub 2016 Mar 17.
What’s New in Adult Reconstructive Knee Surgery: Level I and II Studies
Every month, JBJS publishes a Specialty Update—a review of the most pertinent and impactful studies published in the orthopaedic literature during the previous year in 13 subspecialties. Here is a summary of selected findings from randomized studies cited in the January 21, 2015 Specialty Update on adult reconstructive knee surgery:
Minimizing Blood Loss
–A randomized study of 101 patients undergoing total knee arthroplasty (TKA) found that those receiving topical tranexamic acid (TXA) intra-articularly at the end of surgery had less blood loss and better postoperative hemoglobin levels than those who received a placebo.
–A randomized study of 50 TKA patients and 50 people undergoing total hip arthroplasty found that those receiving TXA had a significantly smaller decline in postoperative hemoglobin levels and needed 39% fewer units of transfused blood than a group that received normal saline solution.
Patellar Management
–A randomized study of 126 patients who underwent denervation or not after TKA with unresurfaced patellae found that the denervation group had better pain scores at three months and higher satisfaction and better range of motion at two years.
–Two randomized studies evaluated the impact of patellar eversion versus lateral retraction/subluxation for joint exposure. One study (n=117) found no between-group differences in quadriceps strength at one year, and the other (n=66) found no between-group differences in pain scores or flexion at three months and one year.
Implant Design
Most of the implant-design studies summarized in this Specialty Update can be summed up as “no difference.” Specifically,
–Three randomized studies attempting to evaluate high-flexion TKA designs (n=74, n=278, and n=122) caused the authors of the update to suggest that “the intention of providing greater clinical flexion through high-flex arthroplasty designs does not translate to a meaningful difference in patient outcomes.”
–A randomized study of 124 patients found no differences in maximal post-TKA flexion or functional scores between a group that received a bicruciate-substituting implant and one that received a standard posterior-stabilized design.
–A randomized trial of 34 patients who received prostheses with either highly cross-linked polyethylene or conventional polyethylene found no differences in wear-particle number, size, or morphology after one year.
–A 4- to 6.5-year follow-up study of 56 patients who received either mobile or fixed bearings during TKA found that the mobile-bearing group had greater mean range of motion, but there were no between-group differences in satisfaction or functional scores.
Instrumentation and Technique
–A randomized study of 47 patients whose surgeons used either customized cutting blocks or traditional instruments found no differences in clinical outcomes or mean component alignment. Moreover, surgeons abandoned customized blocks in 32% of the cases because of malalignment.
–A randomized study of 129 patients whose surgical approach was either medial parapatellar or subvastus, all of whom were managed with minimally invasive techniques, found no differences in pain, narcotic consumption, functional outcomes, and Knee Society Scores at postoperative times ranging from three days to three months.
Postoperative Care and Pain Management
–A trial among 249 post-TKA patients who received either one-to-one physical therapy (PT), group-based PT, or a monitored home program found no difference in outcomes at 10 weeks and one year.
–A randomized study of 160 post-TKA patients investigating the effect of continuous passive motion (CPM) machines led the study authors to conclude that CPM is neither beneficial nor cost-effective.
–A small randomized study of pain-management protocols found that a “multimodal” approach that included peri-articular injection led to less pain, less narcotic use, and higher satisfaction for up to six weeks after surgery than a patient-controlled analgesia approach.
–A three-way randomized pain-management study of 100 patients led study authors to recommend against posterior capsule injections and to conclude that “a sciatic nerve block [for TKA] has a minimal effect on pain control.”
–A three-way randomized study of 120 TKA patients found that those receiving preoperative dexamethasone and ondansetron had less nausea, shorter hospital stays, and used less narcotic medication than those who received ondansetron alone. “Dexamethasone should be part of a comprehensive total joint arthroplasty protocol,” the study authors concluded.
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