Article
Reference
A single dose of tranexamic acid reduces blood loss after reverse and anatomic shoulder arthroplasty: a randomized controlled trial
CUNNINGHAM, Gregory, et al.
Abstract
Hematoma formation and the need for blood transfusions are commonly reported complications after shoulder arthroplasty. Tranexamic acid (TXA) has been widely used in hip and knee arthroplasty to decrease perioperative blood loss. The role of TXA is still being established in shoulder arthroplasty.
CUNNINGHAM, Gregory, et al . A single dose of tranexamic acid reduces blood loss after
reverse and anatomic shoulder arthroplasty: a randomized controlled trial. Journal of Shoulder and Elbow Surgery , 2021, vol. 30, no. 7, p. 1553-1560
DOI : 10.1016/j.jse.2020.11.022 PMID : 33421559
Available at:
http://archive-ouverte.unige.ch/unige:155133
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1 / 1
A single dose of tranexamic acid reduces blood loss after reverse and anatomic shoulder
arthroplasty: a randomized controlled trial
Gregory Cunningham, MD
a,b, Jeffery Hughes, MBBS, MS, FRACS
c,
Benoit Borner, MD
a,*, Owen Mattern, MBBS, MS, FRACS
d, Mohy E. Taha, MBBCh, MD
e, Margaret M. Smith, PhD
f, Allan A. Young, MBBS, MSpMed, PhD, FRACS
c,
Benjamin Cass, MBBS, MS, FRACS
caDivision of Orthopaedic and Trauma Surgery, Geneva University Hospitals, Geneva, Switzerland
bShoulder Center, Hirslanden Clinique la Colline, Geneva, Switzerland
cSydney Shoulder Research Institute, Sydney, NSW, Australia
dThe Orthopaedic Group, Melbourne, VIC, Australia
eDivision of Orthopaedics and Trauma Surgery, Basel University Hospital, Basel, Switzerland
fInstitute of Bone and Joint Research, Royal North Shore Hospital, Sydney, NSW, Australia
Background: Hematoma formation and the need for blood transfusions are commonly reported complications after shoulder arthro- plasty. Tranexamic acid (TXA) has been widely used in hip and knee arthroplasty to decrease perioperative blood loss. The role of TXA is still being established in shoulder arthroplasty.
Materials and methods: We conducted a double-blind randomized controlled trial comparing intravenous TXA vs. placebo in 60 pa- tients undergoing primary anatomic or reverse shoulder arthroplasty. Of these patients, 29 received a placebo whereas 31 received a single dose of 2 g of intravenous TXA. Patient demographic characteristics, as well as drain tube output, blood loss, hematoma forma- tion, transfusion requirement, length of hospital stay, and pain score, were recorded. Patients were followed up for 12 weeks to assess for complications.
Results: Patients who received TXA had a lower drain tube output at all time points: 41 mL vs. 133 mL at 6 hours, 75 mL vs. 179 mL at 12 hours, and 94 mL vs. 226 mL at 24 hours (P<.001 for all). They also had a higher postoperative hemoglobin (Hb) level (12.3 g/dL vs. 11.4 g/dL,P¼.009), lower change in Hb level (1.7 g/dL vs. 2.3 g/dL,P¼.011), lower total Hb loss (0.078 g vs. 0.103 g,P¼.042), lower blood volume loss (0.55 L vs. 0.74 L,P¼.021), higher postoperative hematocrit level (36.7% vs. 34.6%,P¼.020), and lower hematocrit change (5.4% vs. 7.6%,P¼.022). There was no significant difference in pain score or length of hospital stay, and no patients required a transfusion.
Conclusion: A single dose of 2 g of intravenous TXA decreases blood loss and drain tube output in primary anatomic and reverse arthroplasty of the shoulder. No differences were detected in the occurrence of complications, need for transfusion, pain score, or length of hospital stay. With the mounting evidence now available, patients undergoing elective primary shoulder arthroplasty should be given intravenous TXA to decrease perioperative blood loss.
This study was approved by the Human Research Ethics Committee at St Vincent’s Hospital (file no. 16/105) and registered with the Australian New Zealand Clinical Trials Registry (identification no.
ACTRN12616000723482).
*Reprint requests: Benoit Borner, MD, Division of Orthopaedic and Trauma Surgery, Geneva University Hospitals, Rue Gabrielle-Perret-Gentil 4, CH-1205 Geneve, Switzerland.
E-mail address:benoit.borner@hcuge.ch(B. Borner).
www.elsevier.com/locate/ymse
1058-2746/Ó2021 The Authors. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
https://doi.org/10.1016/j.jse.2020.11.022
Level of evidence: Level I; Randomized Controlled Trial; Treatment Study
Ó2021 The Authors. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/
4.0/).
Keywords:Shoulder arthroplasty; total shoulder arthroplasty; reverse shoulder arthroplasty; tranexamic acid; TXA
Shoulder arthroplasty is becoming a more frequently performed procedure, with the rate of shoulder arthroplasty increasing by 11.1% in Australia from 2015 to 2016 and by 115.5% since 2008. This is a steeper increase than that shown by either hip or knee replacement.3 Perioperative management of blood loss and bleeding has also become an increasing area of interest in shoulder arthroplasty. Hema- toma formation is one of the most commonly recorded complications of reverse shoulder arthroplasty (RSA),11,51 whereas the blood transfusion rate following shoulder arthroplasty has a reported range of 3.9%- 43%.2,7,19,20,32,39,40 An analysis has shown an increase in the rate of transfusions after shoulder arthroplasty in recent years,38which may be because of the increased number of revisions.2,51
Allogeneic blood transfusion has been linked to an increase in postoperative bacterial infections,23 respira- tory tract infections, and wound inflammation.12 In shoulder arthroplasty specifically, it has been associated with increased rates of myocardial infarction, respiratory infection, sepsis, venous thromboembolism, and cerebro- vascular accident, as well as an increased rate of peri- prosthetic joint infection, which appears to be dose dependent.10,18 With the periprosthetic infection rate of around 1% remaining unchanged between 2002 and 2011,33 it is important to establish treatments that can affect infection rates, such as improved perioperative blood management.
Tranexamic acid (TXA) has been widely studied and used in lower-limb arthroplasty, as well as spine and trauma surgery, to decrease perioperative blood loss and trans- fusion rates.5,9,24-26,30,37,42,46,50
TXA inhibits fibrinolysis indirectly by competitively blocking lysine-binding sites on plasminogen.44 Its use and safety in shoulder surgery is currently being investigated, but it has been shown to be safe and effective in lower-limb surgery without increasing the thromboembolic rate.5,14,22,31,42
We conducted a prospective, randomized, double-blind trial to test our hypothesis that intravenous TXA would decrease drainage volume and bleeding, improve surgical field visibility, and decrease surgical time and complexity, as well as decrease blood loss, need for transfusion, he- matoma formation, and length of hospital stay and improve postoperative pain, in primary total anatomic shoulder arthroplasty (TSA) or RSA.
Materials and methods
Study design and patient enrollment and randomization
This was a double-blind randomized controlled trial comparing intravenous TXA vs. placebo in 60 patients undergoing primary anatomic shoulder arthroplasty or RSA. Of these patients, 29 received a placebo whereas 31 received a single dose of 2 g of intravenous TXA.
Between April 2016 and September 2018, all consecutive eligible patients undergoing shoulder arthroplasty after failed nonoperative treatment were prospectively enrolled in the trial.
The patients were given a standardized information sheet about the study and completed an informed patient consent form.
Patients were randomized to either the treatment group, in which 2 g of TXA was given intravenously, or the placebo group (saline solution). They were block randomized (n¼6) in a double-blind fashion via a sealed, numbered envelope, which was opened by the anesthetist on the day of the operation. Only the anesthetist and study coordinator were aware of the patient’s allocated group. Each surgeon’s patients were separately randomized (separate pile of envelopes) to avoid potential selection bias.
The inclusion criteria were any patient undergoing primary anatomic or reverse shoulder replacement who consented to participate in the study. The exclusion criteria were allergy to TXA, history of seizure, revision arthroplasty, refusal to undergo potential blood transfusion, and any known coagulopathy or pre- operative use of anticoagulant agents.
Surgical treatment and postoperative protocol
Shoulder replacements were performed by 3 high-volume senior shoulder-specialized surgeons (B.C., A.A.Y., and J.H.), who routinely perform shoulder replacements with patients in the semi–beach-chair position via a standard deltopectoral approach.
The procedure was performed with the patient under general anesthesia with an interscalene block. The patient was adminis- tered either TXA or placebo (saline solution) before skin incision.
At the end of the procedure, each patient underwent placement of a drain tube deep to the deltoid, exiting laterally to the distal part of the incision, which was then removed at 24 hours post- operatively. All patients received thromboprophylaxis with sequential calf compressors, graduated compression stockings, and low-molecular-weight heparin. The postoperative protocols regarding the use of a sling and the permitted range of motion followed each surgeon’s preference. All patients underwent stan- dard follow-up appointments at 2, 6, and 12 weeks.
1554 G. Cunningham et al.
Outcome measurement
Patient demographic characteristics including age, sex, hand dominance, relevant comorbidities, body mass index (BMI), and American Society of Anesthesiologists classification were recor- ded. Preoperative hemoglobin (Hb) and hematocrit levels were also recorded. Operative time was recorded, as were subjective parameters rated by the surgeon, including intraoperative surgical field visibility (poor, fair, good, or excellent) and procedure complexity (less than usual, as usual, or more than usual).
Postoperatively, in all patients, drain tube output was recorded at 6, 12, and 24 hours, in addition to the need for a blood transfusion, hematoma formation, recovery room duration, overall hospital duration, and visual analog scale pain score at 24 hours. Blood loss was also calculated using the Hb balance method.15Any adverse events were noted and reported until the 12-week mark. The threshold for blood transfusion was a postoperative Hb level<7.0 g/dL or a postoperative Hb level< 9.0 g/dL with symptoms (fa- tigue, breathlessness, chest pain, tachycardia, and fatigue).
Statistical analysis
All statistical analyses were performed using the Stata 15 program (StataCorp, College Station, TX, USA). A sample size power calculation was performed with drain output as the primary vari- able anda set at .05. From previous studies on arthroplasty in other joints, we estimated that the drainage output would reduce by 40% when TXA treatment was given. By use of the standard deviation for drainage reported in the literature (30%), a group number of 20 would be required to give a power of 99%. For blood loss as a variable, a reduction of 25% with a 25% standard deviation would require a group number of 27 to give 95% power.
A group number of 30 (60 total) was thus selected to ensure enough power to detect expected differences in these 2 variables.
Differences between treatment groups were determined using the Studentttest (normally distributed continuous data) and thec2 test of proportions or Mann-Whitney U test (non-normally distributed or ordinal data) as indicated inTables I-III. Subgroup analysis was carried out between the different prosthesis types (reverse vs. anatomic) using the same tests. The effect of de- mographic and treatment variables on surgery outcomes (oper- ating time, procedural complexity, field visibility, postoperative pain, and length of hospital stay) was measured using mixed- model regression, correcting for the site of operation (Supplementary Appendix S1).P <.05 was considered statisti- cally significant.
Results
Of the 100 patients screened to be enrolled in the trial, 26 were excluded and 11 chose not to participate (Fig. 1).
There were 63 patients who qualified and were randomized.
Thirty-one patients were randomized to placebo, of whom 2 were excluded (1 because of incorrect randomization and 1 because the drain tube dislodged and was removed early).
Thirty-two patients were allocated to receive TXA, of whom 1 was excluded because the procedure was cancelled owing to concerns regarding infection. No loss to follow-up occurred, leaving 29 patients in the placebo group and 31 patients in the intervention group at 6 weeks. There were 19 RSAs and 12 TSAs in the TXA group and 22 RSAs and 7 TSAs in the control group. There was no significant dif- ference in procedure types between the 2 groups (P¼.11).
Patient demographic characteristics were similar in both groups (Table I). Patients who received TXA were found to have a higher postoperative Hb level of 12.3 g/dL compared
Table I Patient demographics in both group
Non-TXA group (n¼29) TXA group (n¼31) Pvalue
n Mean (SD) or % n Mean (SD) or %
Age at surgery, yr 29 73 (9) 31 72 (8) .60*
Sex
Female 23 79.3 20 64.5
Male 6 20.7 11 35.5 .20y
Body mass index 29 31 (7.8) 31 30 (7.0) .51*
Blood volume, Lz 29 4.6 (0.7) 31 4.7 (1.0) .73*
Side of surgery
Left 12 41.4 13 41.9
Right 17 58.6 18 58.1 .97y
Preoperative CS 25 25 (11) 29 30 (12) .11*
ASA class
1 1 3.4 1 3.2
2 14 48.3 21 67.7
3 14 48.3 9 29.1 .30y
TXA, tranexamic acid;SD, standard deviation;CS,Constant score;ASA, American Society of Anesthesiologists.
* Studentttest.
y c2Proportions test.
z Calculated by Gross equation (Gao et al).15
with 11.4 g/dL in the control group (P¼.009) and a lower change in Hb level from preoperatively to postoperatively of 1.7 g/dL compared with 2.3 g/dL (P¼.011). By use of the Hb balance method, patients who received TXA had lower total Hb loss of 0.078 g compared with 0.103 g in the control group (P¼.042) and lower blood volume loss of 0.55 L compared with 0.74 L (P¼.021). The postoperative hematocrit level was higher in the TXA group, at 36.7%
compared with 34.6% in the control group (P¼.020), and the hematocrit change from preoperatively was lower, at 5.4% compared with 7.6% (P¼.022).
Drain tube output was significantly lower at all time points in patients who received TXA, with the 6-hour measure being 41 mL compared with 133 mL in the control group (P < .001), the 12-hour measure being 75 mL compared with 179 mL (P <.001), and the 24-hour mea- sure being 94 mL compared with 226 mL (P <.001). We observed 1 hematoma in the placebo group, clinically
defined as a painful colored swelling of the operative site and/or arm, and none in the TXA group; this was not sig- nificant. No patient in either the placebo group or TXA group received a blood transfusion, and we found no sig- nificant difference in operative field visibility, operative complexity, operative time, time in recovery, hospital admission stay, or pain score at 24 hours (Table II).
When analyzing the outcomes by procedure, we found no statistically significant differences between anatomic and reverse total shoulder replacements (Table III). We also found that surgery time, procedural complexity, field visi- bility, postoperative pain, time in recovery, and length of hospital admission were not affected by age (P.35 for all except length of time in the postanesthesia care unit, withP
¼ .01), sex (P .092 for all), BMI (P .52 for all), operated side (P .13 for all), or American Society of Anesthesiologists class (P .13 for all) (Supplementary Appendix S1).
Table II Results of the measured outcomes in both groups
Non-TXA group (n¼29) TXA group (n¼31) Pvalue n Mean SD or range % n Mean SD or range %
Hb level, g/dL
Preoperative 29 13.8 1.1 31 14.0 1.3 .57*
Postoperative 29 11.4 1.1 31 12.3 1.3 .009*
Change from preoperatively to postoperatively 29 2.3 1.0 31 1.7 1.0 .011*
Hb total loss, gy 29 0.103 0.044 31 0.078 0.049 .042*
Blood volume loss, Ly 29 0.74 0.29 31 0.55 0.34 .021*
Hct change, %
Preoperative 29 42.2 4.5 31 42.1 3.6 .94*
Postoperative 29 34.6 3.3 31 36.7 3.5 .020*
Change from preoperatively to postoperatively 29 7.6 4.4 31 5.4 2.7 .022*
6-h drain output, mL 29 133 58 31 41 40 <.001*
12-h drain output, mL 29 179 70 31 75 49 <.001*
24-h drain output, mL 29 226 87 31 94 72 <.001*
Field visibility
Poor 1 3.4 0 0.0
Fair 16 55.2 12 41.9
Good 10 34.5 11 35.5
Excellent 2 6.9 6 22.6 .25z
Procedure complexity
Less than usual 3 10.3 7 22.6
As usual 18 62.1 18 58.1
More than usual 8 27.6 6 19.3 .40z
Hematoma 1 0
Transfusion 0 0
Operation time, min 29 89 24 31 81 16 .13*
Time in PACU, min 29 86 34 31 83 31 .70*
Hospital stay, d 29 4.8 1.0 31 5.1 1.8 .53*
VAS pain score 29 4 0-8 31 4 0-7 .74x
TXA, tranexamic acid;SD, standard deviation;Hb,hemoglobin;Hct,hematocrit;PACU, postanesthesia care unit;VAS, visual analog scale.
* Studentttest.
y Using method 2 from Gao et al15(2015).
z c2Proportions test.
x Mann-WhitneyUtest.
1556 G. Cunningham et al.
Discussion
The results of this study show that a single dose of 2 g of intravenous TXA provided a simple and effective dosing regimen to decrease blood loss and drain tube output.
Although we did not find any difference in pain scores, this may have been because of the timing of obtaining these scores as the nerve block may have still been having some effect. We also did not observe any transfusions in either group, and we found only 1 hematoma in the placebo group. No adverse events were recorded, which is consis- tent with the recently published meta-analyses of TXA use in shoulder arthroplasty that found no adverse events across all studies.4,21,28,43,49 This finding is also consistent with results from hip and knee arthroplasty.14,16,25,36,50
TXA use in shoulder arthroplasty has received signifi- cant recent interest. Gillespie et al,17 in a prospective ran- domized trial, demonstrated a decrease in drain tube output and a drop in the Hb level in patients given topical TXA intraoperatively compared with normal saline solution.
Intravenous TXA administration has shown similar re- sults.48 Vara et al45 reported in their prospective random- ized trial that patients given 2 doses of intravenous TXA of 10 mg/kg (1 dose given 60 minutes before surgery and 1 dose given at wound closure) had significantly less blood loss, total Hb loss, and drain tube output compared with patients given a placebo. A transfusion was required post- operatively in 14.3% of the patients in the placebo group and 5.7% in the TXA group.
Pauzenberger et al34 found similar results, with lower blood loss and lower drain tube output using 2 doses of TXA (1 g given within 30 minutes of skin incision and 1 g given at wound closure). They also found lower hematoma rates and improved pain scores. No transfusions were per- formed in either the TXA group or placebo group.
In a further randomized trial, Cvetanovich et al6reported that a single dose of 1 g of TXA produced lower blood loss but no difference in drain output. Single-dose TXA administration was also found to be successful for decreasing blood loss and drain output in nonrandomized Table III Results of the measured outcomes according to procedure type
Non-TXA group (n¼29) TXA group (n¼31) Pvalue
n Mean SD or range % n Mean SD or range %
Procedure
Reverse 24 83 20 65
Anatomic 5 17 11 35 .11*
Operation time, min
Reverse 24 88 26 20 77 14 .081y
Anatomic 5 92 15 11 88 18 .72y
Procedure complexity Reverse
Less than usual 2 8.3 6 30
As usual 15 62.5 10 50
More than usual 7 29.2 4 20 .18*
Anatomic
Less than usual 1 20 1 9.1
As usual 3 60 8 72.7
More than usual 1 20 2 18.2 .81*
VAS pain score
Reverse 24 4 0-8 20 4 0-7 .80z
Anatomic 5 24 0-5 11 4 1-6 .95z
Time in PACU, min
Reverse 24 86 30 20 88 36 .83y
Anatomic 5 89 55 11 74 18 .42y
Hospital stay, d
Reverse 24 5.0 1.1 20 5.0 1.6 .92y
Anatomic 5 4.4 0.5 11 5.3 2.1 .37y
TXA, tranexamic acid;SD, standard deviation;VAS, visual analog scale;PACU, postanesthesia care unit.
* c2Proportions test.
y Studentttest.
z Mann-WhitneyUtest.
trials, with Kim et al27using 500 mg in their South Korean population, Friedman et al13 using 20 mg/kg, and Abil- dgaard et al1using 1 g.
The ideal TXA dosing regimen is yet to be established in arthroplasty surgery, with considerable variation in all published data for both lower-limb arthroplasty and shoulder arthroplasty. Fixed dosing and weight-dependent dosing have been used, as have single dosing and multiple dosing, with no clear consensus as to the most effective regimen.4,5,14,24,28,31,41,43There is also considerable debate in lower-limb arthroplasty about intravenous vs. intra- articular TXA dosing, with a recent meta-analysis by Gianakos et al16showing that intra-articular dosing either on its own or combined with intravenous dosing led to less blood loss and drain tube output. Recent studies have seemed to show similar results in shoulder arthroplasty.48 According to another meta-analysis concerning lower- limb arthroplasty, combined administration of TXA is associated with significantly reduced total blood loss, postoperative Hb decline, drainage volume, and transfusion requirements in comparison with a single application.35
The role and safety of TXA in patients at high risk of thromboembolic events are still to be established. Three large database studies on hip and knee arthroplasty patients showed no increased risk of thromboembolic events in those with risk factors; however, not all patients were given TXA, with some excluded because of their risk
factors.8,36,47Our study further adds to the published data about the safety of the use of TXA in shoulder arthroplasty.
This study presents several strengths and limitations.
First, it was a multiple-surgeon randomized controlled trial, including mixed types of procedures (RSA and TSA), with no loss to follow-up. Second, it analyzed additional pa- rameters to blood loss, such as hospital stay length, as well as subjective parameters, including procedure complexity and surgical field visibility.
Although no patient was lost to follow-up, a first limita- tion to this study was the rather limited number of patients.
This is partly related to the strict exclusion criteria, such as the use of preoperative anticoagulants or anti-aggregation agents, which would have negated the results. Greater numbers of patients would be required to detect significant differences in some of the secondary variables. On the basis of the results presented in this study, a post hoc analysis reveals that to achieve a significant difference in operating time and length of hospital stay with 80% power, the study would have required 104 patients per group and 372 patients per group, respectively. With the number of patients included, it was not possible to carry out in-depth cost- effectiveness analysis. Furthermore, the average patient BMI was 30.3 with an average weight of 82.5 kg. The dose of 2 g may not be applicable for all population groups. However, a recent meta-analysis showed no difference when using a weight-adjusted dose vs. a fixed dose.29Two grams appeared Figure 1 CONSORT (Consolidated Standards of Reporting Trials) flowchart of patient selection and randomization.TXA, tranexamic acid;TSA, total shoulder arthroplasty;RSA, reverse shoulder arthroplasty.
1558 G. Cunningham et al.
to be as safe as 1 g, which has been used in previous studies.1,17 Moreover, a fixed dose is easier to administer than a weight-corrected dose, limiting the risk of error.
Conclusion
A single dose of 2g of intravenous TXA decreases blood loss and drain tube output in primary arthroplasty of the shoulder, with no significant difference between anatomic and reverse arthroplasty. There was no differ- ence in the occurrence of complications, need for transfusion, pain score, or length of hospital stay. With the mounting evidence now available, patients under- going elective primary shoulder arthroplasty should be given TXA to decrease perioperative blood loss.
Disclaimer
The authors, their immediate families, and any research foundations with which they are affiliated have not received any financial payments or other benefits from any commercial entity related to the subject of this article.
Supplementary data
Supplementary data to this article can be found online at https://doi.org/10.1016/j.jse.2020.11.022.
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