Tranexamic Acid in Hip Fracture Patients: a protocol for a ...bmjopen.bmj.com/content/bmjopen/6/6/e010676.draft-revisions.pdf · For peer review only 5 95 Of the five studies investigating

For peer review only

Tranexamic Acid in Hip Fracture Patients: a protocol for a randomized, placebo controlled trial on the efficacy of

tranexamic acid in reducing blood loss in hip fracture patients

Journal: BMJ Open

Manuscript ID bmjopen-2015-010676

Article Type: Protocol

Date Submitted by the Author: 25-Nov-2015

Complete List of Authors: Gausden, Elizabeth; Hospital for Special Surgery, Orthopaedic Surgery Garner, Matthew; Hospital for Special Surgery, Orthopaedic Surgery Warner, Stephen; Hospital for Special Surgery, Orthopaedic Surgery Nellenstein, Andrew; Hospital for Special Surgery, Orthopaedic Surgery Tedore, Tiffany; Weill Cornell Medical College, Anesthesia Flores, Eva; Weill Cornell Medical College, Internal Medicine Lorich, Dean; Hospital for Special Surgery, Orthopaedic Surgery

<b>Primary Subject Heading</b>:

Surgery

Secondary Subject Heading: Evidence based practice, Haematology (incl blood transfusion)

Keywords: tranexamic acid, hip fracture, blood transfusion

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

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Tranexamic Acid in Hip Fracture patients: a 1

protocol for a randomized, placebo controlled trial 2

on the efficacy of tranexamic acid in reducing 3

blood loss in hip fracture patients 4

5

Elizabeth Gausden, MD; Matthew R. Garner, MD; Stephen J. Warner, MD, PhD; 6 Andrew Nellenstein, BS; Tiffany Tedore, MD; Eva Flores, MD; Dean G. Lorich, MD 7

8

9

10

Abstract 11

Introduction 12

There is a high incidence of blood transfusion following hip fractures in elderly 13

patients. Tranexamic acid (TXA) has proven efficacy in decreasing blood loss in 14

trauma patients as well as patients undergoing elective orthopaedic surgery. In 15

order to prove the efficacy of TXA, a randomized controlled trial will measure the 16

effect in a population of patients undergoing hip fracture surgery. 17

Methods 18

This is a double-blinded, randomized placebo-controlled trial. Patients admitted 19

through the emergency room diagnosed with an intertrochanteric or femoral neck 20

fracture will be eligible for enrollment and randomized to either treatment with 1 21

gram of intravenous TXA or intravenous saline at the time of skin incision. Patients 22

undergoing percutaneous intervention for non or minimally displaced femoral neck 23

fractures will not be eligible for enrollment. Postoperative transfusion rates will be 24

recorded and blood loss will be calculated from serial hematocrits. 25

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Ethics and dissemination 26

This protocol was approved by the Institutional Review Board (IRB) and is 27

registered with clinicaltrials.gov. The findings of the trial will be disseminated 28

through peer-reviewed journals and conference presentations. 29

30

Strengths and limitations of this study 31

• A prospective, randomized, placebo-controlled trial is the optimal study 32

design to address the question of efficacy of tranexamic acid (TXA) use in 33

patients with hip fractures 34

• The outcomes will be reported based on one-year follow-up, which is longer 35

follow-up than any other study examining tranexamic acid use in patients 36

with hip fractures. 37

• Findings will provide objective data from which clinicians can base future 38

guidelines regarding TXA administration 39

• Recruitment is slow as patients and health-care proxies are wary of enrolling 40

in a study in a trauma setting 41

42

Introduction 43

44

Hip fractures in the elderly remains a pressing public health issue in the United 45

States given the aging population. 1 Hip fractures are associated with numerous 46

adverse events and increased mortality up to one year after the event. 2-5 Elderly 47

patients sustaining hip fractures commonly lose more than one liter of blood and up 48

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to 60% will require a blood transfusion. 6 A meta-analysis of 20 studies found a 49

significantly increased risk of post-operative bacterial infection in patients who 50

receive an allogenic blood transfusion in the perioperative period. 7 In addition to 51

the increased risk of infection, patients who require blood transfusion following hip 52

fracture have an increased hospital length of stay. 8 Beyond the risk to the patient 53

from a blood transfusion, an allogenic blood transfusion in the United States was 54

recently estimated to increase costs by $1,731 per admission. 9 55

56

Numerous anti-fibrinolytics have been used to limit bleeding in orthopaedic surgery 57

and prevent the need for blood transfusion. 10-14 One of these anti-fibrinolytics, 58

tranexamic acid (TXA) is a synthetic derivative of the amino acid lysine and acts as a 59

competitive inhibitor in the activation of plasminogen to plasmin and therefore 60

prevents the degradation of fibrin. As a result of the CRASH-2 trial 15,16 that 61

demonstrated reduced mortality in trauma patients administered TXA the World 62

Health Organization (WHO) added it to the essential drugs list. Currently TXA is not 63

routinely used in patients with hip fractures in the United States, despite its 64

common use worldwide and proven efficacy in reducing blood loss. 65

66

Numerous studies have investigated the safety and efficacy of TXA in patients 67

undergoing elective orthopaedic surgery, including total joint replacement and 68

spine surgery. 17-22 The consensus from this literature is overwhelmingly in favor of 69

administration of TXA given the decrease in blood loss, transfusion rates, and cost. 70

23,24 Although several individual studies have found increased risk of 71

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thromboembolic events in groups receiving TXA, 25,26 larger studies and meta-72

analyses have uniformly found no increased risk of thrombosis. 27,28 73

74

Patients who suffer hip fractures frequently have multiple comorbidities making 75

them more susceptible to adverse events from blood loss. 19,20 The most common 76

comorbidities of individuals with hip fractures are congestive heart failure, chronic 77

pulmonary disease and diabetes. 1 Administering TXA to such patients has a 78

potential to offset blood loss, improve patient outcome and lower cost by decreasing 79

the rate of transfusions. 29,30 Five studies, all conducted outside the United States, 80

have reported results of using TXA in hip fracture surgery. 26,31-34 Sadeghi et al 32 81

randomized 67 hip fracture patients to receive either placebo injection or 82

intravenous tranexamic acid at the time of surgery. They found a significantly lower 83

volume of blood loss (652 ± 228 mL vs. 1108 ± 372 mL, P < 0.003) and shorter 84

hospital stays (4.3 ± 1.6 days vs. 5.8 ± 1.5 days, p< 0.05). Vijay et al. 34 also reported 85

significantly reduced transfusion rates in the TXA arm of their clinical trial. In a 86

retrospective cohort study, Lee et al 31 reported similar results, a transfusion rate 87

three times lower in patients who received TXA prior to hemiarthroplasty surgery. 88

In a separate randomized controlled trial that compared intravenous administration 89

of TXA to topical TXA administration as well as placebo in hip fracture patients 90

undergoing hemiarthroplasty, both of the TXA groups experienced less blood loss. 26 91

While this study found a significant reduction in blood loss and transfusion rates in 92

both TXA groups, they found a higher incidence of thromboembolic events in the 93

intravenous TXA group. 94

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Of the five studies investigating the use of TXA in hip fracture patients, four 95

were randomized controlled trials that were underpowered for detecting significant 96

differences in thromboembolic events (Table 1). 26,31-34 Furthermore, patients were 97

only followed perioperatively, and differences in six-month and one-year mortality 98

rates and late-onset complications were not assessed. 99

Use of Tranexamic Acid (TXA) in Patients with Hip Fractures

Country Design Hip fx ( IT or FNF)

TXA Regimen

DVT PPX Sample size

Blood loss (cc)

Transfuse Rate %

Thrombo-embolic Events

Lee 2015 31

UK Cohort Hemi-arthroplasy only

1 g bolus preop

Tinzaparin 84 cases/ 187 controls

- 6* 1

- 19 4

Emara 2014 26

Egypt RCT Hemi-arthroplasty only

10 mg/kg bolus, then 5 mg/kg/h infusion

Clexane 20 cases IV/ 20 cases topical/20 controls

640 5* 5

1100 32 0

Zufferey 2010 33

France RCT Hip fractures

15 mg/kg bolus preop and 3 h later

Fondaparinux x 35 days (mandatory ultrasound)

57 cases/ 53 controls

975 42 0

1178 60 0

Sadeghi and Mehr-Aein 2006 32

Iran RCT Hip fractures

15 mg/kg bolus preop

n/a


960 37 0

1484 57 0

Vijay 2013 34

India RCT Hip fractures

10 mg/kg bolus at surgery

N/a 45 cases/ 45 controls

39* 16 0

91* 40 0

100

In designing this study, we concluded that hip fracture patients are both likely to 101

experience significant blood loss and are susceptible to the adverse effects of blood 102

loss making them an ideal population to target for a randomized controlled trial of 103

the effects of perioperative TXA on blood loss. We hypothesize that administration 104

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of TXA will decrease blood loss in hip fracture patients and lower the rate of 105

allogenic blood transfusion. 106

107

108

109

Objective 110

To investigate the hypothesis that TXA will lower blood loss and transfusion rate in 111

patients with hip fractures. 112

113

Methods and analysis 114

115

Overview of trial design 116

We are conducting a single-center randomized control trial using a parallel two-arm 117

design to investigate whether tranexamic acid use perioperatively will decrease the 118

rate of transfusion in patients with hip fractures (Figure 1). Randomization will be 119

stratified by type of hip fracture, intertrochanteric and femoral neck fractures. The 120

surgical team, anesthesia team, and patients will be blinded to the assignment. Once 121

consent is obtained and a patient is enrolled, a 1:1 randomization system will be 122

employed by our institution’s investigational pharmacy to assign patients to receive 123

TXA or placebo. Patient enrollment will occur over approximately 2 years and 124

enrolled patients will be followed for 1 year postoperatively. Incidence of blood 125

transfusion, total calculated blood loss, transfusion, and acute adverse events 126

(transfusion reaction, cerebrovascular accident, myocardial infarction, pulmonary 127

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embolism, and surgical site infection) will be assessed in the perioperative period. 128

Patients will also be assessed at 2 week, 6 week, 3 month, 6 month and 12 month 129

follow-up for long-term adverse events as well as mortality rate. This trial is 130

registered (NCT01940536) and has received ethics approval from the Weill Cornell 131

Medical College Institutional Review Board (IRB# 1301013463). 132

133

134

Primary research question 135

In patients with hip fractures, does infusion of tranexamic acid at the time of 136

surgery result in lower rate of blood transfusion? 137

138

Secondary research question 139

In patients with hip fractures, does infusion of tranexamic acid at the time of 140

surgery result in: 141

1.) decreased blood loss? 142

2.) Shorter length of hospitalization? 143

3.) Any differences in occurrence of adverse events? 144

145

Hypothesis 146

As a primary outcome, there will be a decreased rate of blood transfusion in patients 147

who receive tranexamic acid intraoperatively and no significant increase in 148

frequency or severity of adverse events in comparison to patients who receive 149

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placebo. This study is powered to address the primary outcome of difference in 150

transfusion rates between the two study arms. 151

152

Setting and participants 153

Adult (over 18 years of age) patients presenting to a single tertiary care center with 154

a hip fracture. All patients with hip fractures at this institution are admitted to the 155

medical orthopaedic trauma service (MOTS). Prior to surgery, patients older than 156

75 years of age, or those with medical comorbidities will be cleared by the general 157

medical service prior to surgery. All potentially eligible patients will be screened 158

and documented as (1) eligible and included, (2) eligible and missed, or (3) 159

excluded. The study coordinator will obtain informed consent for participation in 160

the study using the approved IRB Informed Consent forms. 161

162

All patients will provide written informed consent and will understand that by 163

entering in the study they may receive placebo and not tranexamic acid. 164

Participation in the study is voluntary and their decision to participate will not 165

affect any other aspect of their care in case of refusal. Patients will have the right to 166

withdraw from the study at any point. 167

168

169

170

Inclusion criteria 171

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Patients admitted through the emergency room or transferred into our institution 172

and who meet the following criteria will be included in the study: 173

• Adults over the age of 18 174

• Intertrochanteric or femoral neck hip fracture 175

• Patients treated surgically with cephalomedullary nail or hemiarthroplasty 176

177

Exclusion criteria 178

Patient who meet any one or more of the following criteria will be excluded from the 179

study: 180

• Preoperative use of anticoagulant (Plavix, Warfarin, Lovenox) 181

• Documented allergy to tranexamic acid 182

• History of deep vein thrombosis or pulmonary embolus 183

• Hepatic dysfunction (AST/ALT > 60) 184

• Renal dysfunction (Cr >1.5 of GRR > 30) 185

• Active coronary artery disease (event in the past 12 months), history of 186

cerebrovascular accident (CVA) in the past 12 months, or presence of a drug-187

eluting stent 188

• Color blindness 189

• Leukemia or any active cancer 190

• Coagulopathy (INR> 1.4, PTT > 1.4x normal, Platelets < 100,000) 191

• Non-displaced femoral neck fractures treated percutaneously 192

193

Baseline 194

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Baseline assessment includes sex, birth date, height and weight, mechanism of 195

injury, time from injury to presentation to the emergency room, American Society of 196

Anesthesiologists (ASA) classification, Charlson Comorbidity Index, comorbidities 197

including diabetes, peripheral vascular disease, dementia, hypertension, and history 198

of smoking. The hemoglobin and hematocrit will be recorded at the time of 199

admission and on the morning of surgery, if applicable. 200

201

Blinding 202

After the patient consents and is enrolled in the study, the institution’s 203

investigational pharmacist will perform the randomization and assign the patient to 204

either receive TXA or placebo. Patients will be randomized in blocks of 20. The 205

packaging of the injections will be performed by the investigational pharmacy and 206

will be identical for both TXA and placebo. All clinicians, except for the pharmacist, 207

will remain blinded until the data is analyzed. 208

209

Intervention 210

The patients randomized to the treatment arm will receive 1 gram of intravenous 211

tranexamic acid infused at the time of surgical incision. Those assigned to the 212

placebo group will receive an infusion of saline at the time of surgical incision. 213

Patients with intertrochanteric hip fractures will be treated with a long, 214

intramedullary, cephalomedually implant with a trochanteric start point. Patients 215

with displaced femoral neck fractures will be treated with a cemented or non-216

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cemented hemiarthroplasty or total hip arthroplasty at the discretion of the treating 217

surgeon. 218

219

Blood transfusion criteria will remain consistent with hospital standards (Hb<8 220

g/dL or symptomatic anemia) as determined by an independent, blinded medical 221

team who will follow the patient throughout the hospital stay and number of blood 222

transfusions received will be documented upon patient discharge. Hematocrit and 223

hemoglobin will be recorded in all patients while they are in the hospital, for a 224

minimum of 2 days postoperatively. Further monitoring will be conducted based on 225

need as determined by the independent medical team. Estimated blood volume will 226

be calculated from these values and used to estimate blood loss (Appendix 1). 227

228

All patients will be permitted to weight-bear as tolerated post-operatively and deep 229

vein thrombosis (DVT) prophylaxis will be standardized. All enrolled patients will 230

receive subcutaneous heparin, 5000 units every 8 hours beginning upon admission 231

until 12 hours prior to surgery and restarting 6 hours after surgery. Calf mechanical 232

compression devices will also be utilized during the inpatient stay and will remain 233

on at all times with the exception of physical therapy sessions. Following discharge 234

from the hospital patients will be given aspirin 325 mg twice daily for DVT 235

prophylaxis for a total of 6 weeks. Diagnostic studies to assess for thromboembolic 236

events (i.e. DVT, pulmonary embolism, and stroke) will be ordered only if the 237

patient develops clinical signs or symptoms that justify their use. 238

Primary Outcome 239

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The primary outcome of the study will be the rate of blood transfusion in the 240

postoperative period until time of discharge. Patients will be monitored with serial 241

hemoglobin and hematocrit measurements and their vital signs will be recorded as 242

per the standard of care to determine the need for blood transfusion. 243

Secondary Outcome 244

The secondary study outcomes include the calculated blood loss (calculated based 245

on validated methods as outlined in Appendix 1), frequency of adverse events 246

(including transfusion reaction, myocardial infarction, deep vein thrombosis, 247

pulmonary embolus, cerebrovascular accident, re-operation, re-admission, 248

infection, and death) (Figure 1). 249

250

Sample size consideration 251

The transfusion rate amongst patients with hip fractures is between 19-60%. 26,31-34 252

The average reduction in transfusion rate in the previous 5 studies using TXA was 253

20%. 26,31-34 We plan to include 110 patients in each treatment arm for a total of 254

220 patients. This study design will achieve 81% power to detect a reduction in 255

blood transfusion from 40% in the placebo control group to 20% in the tranexamic 256

acid group using two-sided Fisher’s exact test with statistical significance set to 257

alpha equal to 0.05. 258

259

260

Data analysis plan 261

Descriptive analyses of the patient population will include reporting means (with 262

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standard deviations) for continuous variables and frequencies (with percentages) 263

for categorical or discrete variables. Following the descriptive analysis, a chi-square 264

analysis will be conducted to evaluate the superiority of tranexamic acid in reducing 265

the rate of transfusion versus the placebo control group. The analysis and reporting 266

of the results of the clinical outcomes will follow the CONSORT guidelines 267

(www.consort-statement.org). We will conduct a multiple logistic regression model 268

to determine if type of fracture (intertrochanteric or femoral neck), comorbidities, 269

Charlson comorbidity index, age, time to surgery, and mechanism of injury are 270

related to transfusion administration. Similarly we will conduct a multiple linear 271

regression model to determine if patient comorbidities, age, time to surgery, and 272

mechanism of injury are related to blood loss. We will also conduct subgroup 273

analyses to determine if the effect of TXA is modified by fracture type 274

(intertrochanteric or femoral neck). 275

Our a priori hypothesis, based on retrospective data, 6 is that patients with 276

intertrochanteric fractures incur more blood loss than femoral neck fractures and 277

will have a higher rate of transfusion. If these subgroup analyses are 278

underpowered, the subgroup data will be used to generate further hypotheses to be 279

tested in the future. All analyses will be performed using Stata 14.0 software (Stata 280

Corporation, College Station, TX, USA). 281

282

Data safety monitoring 283

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The data safety monitoring board (DSMB) has been established to monitor the trial 284

and renew the study biannually. This board is independent of the trial and free of 285

conflicts with any of the investigation team. 286

287

Discussion 288

There is clinical uncertainty and a lack of high-quality evidence regarding the use of 289

TXA in hip fracture patients. Despite its proven efficacy in elective orthopaedic 290

surgery, 20,35 the optimal dosing and timing of TXA administration is still debated. 36 291

Furthermore, the efficacy and side effect profile of TXA in patients with fractures 292

remains unclear. The immediate goal of this trial is to provide high-quality evidence 293

that can be used to develop clinical guidelines for use of TXA in patients with hip 294

fractures. 295

296

Patients undergoing total joint arthroplasty and elective spine surgery represent a 297

different population from patients who sustain hip fractures. A larger percentage of 298

hip fracture patients have significant medical comorbidities, and many have history 299

of cardiac disease. 1 While TXA has demonstrated safety and efficacy in patients 300

without significant cardiac disease undergoing elective surgery, there is still debate 301

if TXA will have the same effect in patients with significant comorbidities. 20,36,37 The 302

data investigating TXA in patients with comorbidities is limited, which has further 303

deterred clinicians from using TXA in patients with hip fractures. However, the 304

potential benefit of decreasing blood loss and decreasing the number of transfusions 305

following hip fracture surgery is overwhelming and will likely result in improved 306

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patient outcomes, shorter length of stay and lower cost. The study investigators 307

believe that the potential benefit of TXA in such patients outweighs the risk of TXA. 308

The majority of literature regarding TXA has confirmed its safety and squelched 309

concerns that its use will result in higher rates of thrombosis. 15,25,28,37,38 310

311

The literature to date regarding TXA and hip fractures (Table 1) is limited. Four out 312

of five studies identified a significant decrease in rate of transfusion in patients who 313

received TXA compared to those that did not. 26,31-34 The largest study, with a total 314

of 219 patients, was a cohort study with no randomization. 31 Furthermore, the 315

studies did not follow patients up to 1 year postoperatively, which is our intention. 316

The extended follow-up period allows for assessment of mortality at 12 months as 317

well as incidence of unanticipated adverse events following discharge from the 318

hospital. 319

320

Tranexamic acid has the potential to decrease transfusion rates by decreasing blood 321

loss in patients with hip fractures. Ultimately, this will decreased hospital length of 322

stay and improve outcomes in the hundreds of thousands of patients with hip 323

fractures every year. If the results prove the efficacy of TXA in hip fracture patients, 324

this study may change the standard of care across the United States for these 325

patients. 326

327

Funding 328

This work is supported by a Dr. Thomas Sculco grant. 329 330

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331

332

333

Appendix 334

Blood Loss Calculation:Patient’s Blood Volume (PBV) = (k1 x Height3

(m)) + (k2 x Weight (kg)) + k3 335

k1 = 0.3669, k2 = 0.03219, and k3 = 0.6041 for men k1 = 0.3561, k2=0.03308, and k3 = 0.1833 for 336 women 337

Multiplying the PBV by the hematocrit (Hct) gives the red blood cell (RBC) volume. As 338

such, a change in the RBC volume can be calculated from a change in the Hct level as 339

follows: 340

Pre-op RBC volume loss = PBV x (Admit Hct – Day of surgery Hct) Operative RBC volume loss = PBV x 341 (Day of surgery Hct – PACU Hct) 342

If a patient requires a pre-op or intraoperative transfusion, the calculation will be adjusted as 343 follows: 344

Pre-op RBC volume loss = [PBV x (Admit Hct – Day of surgery Hct)]+ (No. of Units Transfused x 345 0.285) / (Admit Hct – Day of surgery Hct) / 2)Operative RBC volume loss = [PBV x (Day of surgery 346 Hct – PACU Hct)] +)]+ (No. of Units Transfused x 0.285) / (Day of surgery Hct – Post-op Hct) / 2 347

348

349

350

351

352

Figure Legend 353

354

Figure 1: Study Design (TXA: tranexamic acid; PRBC: packed red blood cells) 355

356

Table 1: Previously reported outcomes of TXA in hip fracture patients. *drain 357 output. Thromboembolic events include only symptomatic thromboembolic events. 358 359

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Contributorship Statement: 360

Elizabeth B. Gausden: This author made substantial contributions to the design of 361 the work, planning of data analysis, drafting and revising of the protocol, final 362 approval of the version to be published and agrees to be accountable for all aspects 363 of the work in ensuring that questions related to the accuracy of the work. 364 Matthew R. Garner: This author made substantial contributions to conception of the 365 study and the design of the work, planning of data analysis, drafting and revising of 366 the protocol, final approval of the version to be published and agrees to be 367 accountable for all aspects of the work in ensuring that questions related to the 368 accuracy of the work. 369 Stephen Warner: This author made substantial contributions to the design of the 370 work, planning of data analysis, drafting and revising of the protocol, final approval 371 of the version to be published and agrees to be accountable for all aspects of the 372 work in ensuring that questions related to the accuracy of the work. 373 Andrew Nellenstein: This author made substantial contributions to the design of the 374 work, planning of data analysis, drafting and revising of the protocol, final approval 375 of the version to be published and agrees to be accountable for all aspects of the 376 work in ensuring that questions related to the accuracy of the work. 377 Tiffany Tedore: This author made substantial contributions to the design of the 378 work, planning of data analysis, drafting and revising of the protocol, final approval 379 of the version to be published and agrees to be accountable for all aspects of the 380 work in ensuring that questions related to the accuracy of the work. 381 Eva Flores: This author made substantial contributions to the design of the work, 382 planning of data analysis, drafting and revising of the protocol, final approval of the 383 version to be published and agrees to be accountable for all aspects of the work in 384 ensuring that questions related to the accuracy of the work. 385 Dean G. Lorich: This author made substantial contributions to the design of the 386 work, planning of data analysis, drafting and revising of the protocol, final approval 387 of the version to be published and agrees to be accountable for all aspects of the 388 work in ensuring that questions related to the accuracy of the work. 389

390

Competing Interests: 391

No, there are no competing interests 392

393

394

395

396

397

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hip fractures in the united states. JAMA. 2009;302(14):1573-1579. 400

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9. Saleh A, Small T, Chandran Pillai AL, Schiltz NK, Klika AK, Barsoum WK. Allogenic 420

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12. Yuan C, Zhang H, He S. Efficacy and safety of using antifibrinolytic agents in spine 429

surgery: A meta-analysis. PLoS One. 2013;8(11):e82063. 430

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blood transfusion in orthopedic surgery? Anesthesiology. 2006;105(5):1034-1046. 432

14. Tse EY, Cheung WY, Ng KF, Luk KD. Reducing perioperative blood loss and 433

allogeneic blood transfusion in patients undergoing major spine surgery. J Bone Joint 434

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16. CRASH-2 collaborators, Roberts I, Shakur H, et al. The importance of early 440

treatment with tranexamic acid in bleeding trauma patients: An exploratory 441

analysis of the CRASH-2 randomised controlled trial. Lancet. 2011;377(9771):1096-442

101, 1101.e1-2. 443

17. Whiting DR, Gillette BP, Duncan C, Smith H, Pagnano MW, Sierra RJ. Preliminary 444

results suggest tranexamic acid is safe and effective in arthroplasty patients with 445

severe comorbidities. Clin Orthop Relat Res. 2014;472(1):66-72. 446

18. Cid J, Lozano M. Tranexamic acid reduces allogeneic red cell transfusions in 447

patients undergoing total knee arthroplasty: Results of a meta-analysis of 448

randomized controlled trials. Transfusion. 2005;45(8):1302-1307. 449

19. Lemay E, Guay J, Cote C, Roy A. Tranexamic acid reduces the need for allogenic 450

red blood cell transfusions in patients undergoing total hip replacement. Can J 451

Anaesth. 2004;51(1):31-37. 452

20. Poeran J, Rasul R, Suzuki S, et al. Tranexamic acid use and postoperative 453

outcomes in patients undergoing total hip or knee arthroplasty in the united states: 454

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acid reduce blood transfusion in complex spine surgery: A prospective randomized 457

study. Spine (Phila Pa 1976). 2015. 458

22. Wind TC, Barfield WR, Moskal JT. The effect of tranexamic acid on transfusion 459

rate in primary total hip arthroplasty. J Arthroplasty. 2014;29(2):387-389. 460

23. Tuttle JR, Ritterman SA, Cassidy DB, Anazonwu WA, Froehlich JA, Rubin LE. Cost 461

benefit analysis of topical tranexamic acid in primary total hip and knee 462

arthroplasty. J Arthroplasty. 2014;29(8):1512-1515. 463

24. Huang F, Wu D, Ma G, Yin Z, Wang Q. The use of tranexamic acid to reduce blood 464

loss and transfusion in major orthopedic surgery: A meta-analysis. J Surg Res. 465

2014;186(1):318-327. 466

25. Nishihara S, Hamada M. Does tranexamic acid alter the risk of thromboembolism 467

after total hip arthroplasty in the absence of routine chemical thromboprophylaxis? 468

Bone Joint J. 2015;97-B(4):458-462. 469

26. Emara WM, Moez KK, Elkhouly AH. Topical versus intravenous tranexamic acid 470

as a blood conservation intervention for reduction of post-operative bleeding in 471

hemiarthroplasty. Anesth Essays Res. 2014;8(1):48-53. 472

27. Duncan CM, Gillette BP, Jacob AK, Sierra RJ, Sanchez-Sotelo J, Smith HM. Venous 473

thromboembolism and mortality associated with tranexamic acid use during total 474

hip and knee arthroplasty. J Arthroplasty. 2015;30(2):272-276. 475

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28. Yang ZG, Chen WP, Wu LD. Effectiveness and safety of tranexamic acid in 476

reducing blood loss in total knee arthroplasty: A meta-analysis. J Bone Joint Surg Am. 477

2012;94(13):1153-1159. 478

29. Foss NB, Kristensen MT, Kehlet H. Anaemia impedes functional mobility after hip 479

fracture surgery. Age Ageing. 2008;37(2):173-178. 480

30. Lawrence VA, Silverstein JH, Cornell JE, Pederson T, Noveck H, Carson JL. Higher 481

hb level is associated with better early functional recovery after hip fracture repair. 482

Transfusion. 2003;43(12):1717-1722. 483

31. Lee C, Freeman R, Edmondson M, Rogers BA. The efficacy of tranexamic acid in 484

hip hemiarthroplasty surgery: An observational cohort study. Injury. 2015. 485

32. Sadeghi M MA. Does a single bolus dose of tranexamic acid reduce blood loss and 486

transfusion requirements during hip fracture surgery? A prospective randomized 487

double blind study in 67 patients. Acta Medica Iranica. 2007;45(6):437-442. 488

33. Zufferey PJ, Miquet M, Quenet S, et al. Tranexamic acid in hip fracture surgery: A 489

randomized controlled trial. Br J Anaesth. 2010;104(1):23-30. 490

34. Vijay BS, Bedi V, Mitra S, Das B. Role of tranexamic acid in reducing 491

postoperative blood loss and transfusion requirement in patients undergoing hip 492

and femoral surgeries. Saudi J Anaesth. 2013;7(1):29-32. 493

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35. Danninger T, Memtsoudis SG. Tranexamic acid and orthopedic surgery-the 494

search for the holy grail of blood conservation. Ann Transl Med. 2015;3(6):77-495

5839.2015.01.25. 496

36. Simmons J, Sikorski RA, Pittet JF. Tranexamic acid: From trauma to routine 497

perioperative use. Curr Opin Anaesthesiol. 2015;28(2):191-200. 498




38. Gillette BP, DeSimone LJ, Trousdale RT, Pagnano MW, Sierra RJ. Low risk of 502

thromboembolic complications with tranexamic acid after primary total hip and 503

knee arthroplasty. Clin Orthop Relat Res. 2013;471(1):150-154. 504

505

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254x243mm (72 x 72 DPI)

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Tranexamic Acid in Hip Fracture patients: a protocol

for a randomized, placebo controlled trial on the

efficacy of tranexamic acid in reducing blood loss in

hip fracture patients

Elizabeth Gausden, MD; Matthew R. Garner, MD; Stephen J. Warner, MD, PhD; Andrew Nellenstein,

BS; Tiffany Tedore, MD; Eva Flores, MD; Dean G. Lorich, MD

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Journal: BMJ Open

Manuscript ID bmjopen-2015-010676.R1


Date Submitted by the Author: 08-Feb-2016

Complete List of Authors: Gausden, Elizabeth; Hospital for Special Surgery, Orthopaedic Surgery Garner, Matthew; Hospital for Special Surgery, Orthopaedic Surgery Warner, Stephen; Hospital for Special Surgery, Orthopaedic Surgery Levack, Ashley; Hospital for Special Surgery, Orthopaedic Surgery Nellestein, Andrew; Weill Cornell Medical College, Anesthesia Tedore, Tiffany; Weill Cornell Medical College, Anesthesia Flores, Eva; Weill Cornell Medical College, Internal Medicine Lorich, Dean; Hospital for Special Surgery, Orthopaedic Surgery


Surgery

Secondary Subject Heading: Evidence based practice, Haematology (incl blood transfusion)





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1

Title: Tranexamic Acid in Hip Fracture patients: a protocol for a randomized, placebo 1 controlled trial on the efficacy of tranexamic acid in reducing blood loss in hip fracture 2

patients 3 4 5

Please send all correspondences and requests for reprints to: 6 7 8 9 10

Elizabeth B. Gausden, MD 11 [email protected] 12

Hospital for Special Surgery 13 535 East 70

th Street 14

New York, NY 10021 15 Tel: 212 606 1057 16 Fax: 212 734 3833 17

18 Matthew R. Garner, MD 19

Hospital for Special Surgery 20 New York, NY USA 21

22 Stephen J. Warner, MD 23


26 Ashley Levack, MD 27


30 Andrew Nellestein, BS, MS 31

New York Presbyterian Hospital 32 New York, NY USA 33

34 Tiffany Tedore, MD 35


38 Eva Flores, MD 39


42 Dean G. Lorich, MD 43


46

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Abstract 47

Introduction 48

There is a high incidence of blood transfusion following hip fractures in elderly 49

patients. Tranexamic acid (TXA) has proven efficacy in decreasing blood loss in 50

general trauma patients as well as patients undergoing elective orthopaedic surgery. 51

In order to prove the efficacy of TXA, a randomized controlled trial will measure the 52

effect in a population of patients undergoing hip fracture surgery. 53

Methods 54

This is a double-blinded, randomized placebo-controlled trial. Patients admitted 55

through the emergency room diagnosed with an intertrochanteric or femoral neck 56

fracture will be eligible for enrollment and randomized to either treatment with 1 57

gram of intravenous TXA or intravenous saline at the time of skin incision. Patients 58

undergoing percutaneous intervention for non or minimally displaced femoral neck 59

fractures will not be eligible for enrollment. Postoperative transfusion rates will be 60

recorded and blood loss will be calculated from serial hematocrits. 61

Ethics and dissemination 62

This protocol was approved by the Institutional Review Board (IRB) and is 63

registered with clinicaltrials.gov. The findings of the trial will be disseminated 64

through peer-reviewed journals and conference presentations. 65

66

Key Words: tranexamic acid, hip fracture, blood transfusion 67

68

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69

Strengths and limitations of this study 70

• A prospective, randomized, placebo-controlled trial is the optimal study 71

design to address the question of efficacy of tranexamic acid (TXA) use in 72

patients with hip fractures 73

• The outcomes will be reported based on one-year follow-up, which is longer 74

follow-up than any other study examining tranexamic acid use in patients 75

with hip fractures. 76

• Findings will provide objective data from which clinicians can base future 77

guidelines regarding TXA administration 78

• Recruitment is slow as patients and health-care proxies are wary of enrolling 79

in a study in a trauma setting 80

81

Introduction 82

83

Hip fractures in the elderly remains a pressing public health issue in the United 84

States given the aging population.1 Hip fractures are associated with numerous 85

adverse events and increased mortality up to one year after the event.2-5 The 86

hidden blood loss in hip fractures, in addition to intraoperative blood loss, may be as 87

high as 1500 cc. 6,7 The rate of blood transfusion in the perioperative period for hip 88

fracture patients is reported between 20-60%.8-11 Total blood loss, and thus rate of 89

transfusion, is greater for extracapsular hip fractures compared to intracapsular hip 90

fractures. 6 A meta-analysis of 20 studies found a significantly increased risk of post-91

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operative bacterial infection in patients who receive an allogenic blood transfusion 92

in the perioperative period.12 In addition to the increased risk of infection, patients 93

who require blood transfusion following hip fracture have an increased hospital 94

length of stay.13 Beyond the risk to the patient from a blood transfusion, an allogenic 95

blood transfusion in the United States was recently estimated to increase costs by 96

$1,731 per admission.14 97

98

Numerous anti-fibrinolytics have been used to limit bleeding in orthopaedic surgery 99

and prevent the need for blood transfusion.15-19 One of these anti-fibrinolytics, 100

tranexamic acid (TXA) is a synthetic derivative of the amino acid lysine and acts as a 101

competitive inhibitor in the activation of plasminogen to plasmin and therefore 102

prevents the degradation of fibrin. As a result of the CRASH-2 trial20,21 that 103

demonstrated reduced mortality in trauma patients administered TXA the World 104

Health Organization (WHO) added it to the essential drugs list. Currently TXA is not 105

routinely used in patients with hip fractures in the United States, despite its 106

common use worldwide and proven efficacy in reducing blood loss. 107

108

Numerous studies have investigated the safety and efficacy of TXA in patients 109

undergoing elective orthopaedic surgery, including total joint replacement and 110

spine surgery.22-27 The consensus from this literature is overwhelmingly in favor of 111

administration of TXA given the decrease in blood loss, transfusion rates, and 112

cost.28,29 Although several individual studies have found increased risk of 113

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thromboembolic events in groups receiving TXA,9,30 larger studies and meta-114

analyses have uniformly found no increased risk of thrombosis.31,32 115

116

Patients who suffer hip fractures frequently have multiple comorbidities making 117

them more susceptible to adverse events from blood loss. 19,20 The most common 118

comorbidities of individuals with hip fractures are congestive heart failure, chronic 119

pulmonary disease and diabetes.1 Administering TXA to such patients has a 120

potential to offset blood loss, improve patient outcome and lower cost by decreasing 121

the rate of transfusions.33,34 Five studies, all conducted outside the United States, 122

have reported results of using TXA in hip fracture surgery.8-11,35 Sadeghi et al8 123

randomized 67 hip fracture patients to receive either placebo injection or 124

intravenous tranexamic acid at the time of surgery. They found a significantly lower 125

volume of blood loss (652 ± 228 mL vs. 1108 ± 372 mL, P < 0.003) and shorter 126

hospital stays (4.3 ± 1.6 days vs. 5.8 ± 1.5 days, p< 0.05). Vijay et al.35 also reported 127

significantly reduced transfusion rates in the TXA arm of their clinical trial. In a 128

retrospective cohort study, Lee et al11 reported similar results, a transfusion rate 129

three times lower in patients who received TXA prior to hemiarthroplasty surgery. 130

In a separate randomized controlled trial that compared intravenous administration 131

of TXA to topical TXA administration as well as placebo in hip fracture patients 132

undergoing hemiarthroplasty, both of the TXA groups experienced less blood loss.9 133

While this study found a significant reduction in blood loss and transfusion rates in 134

both TXA groups, they found a higher incidence of thromboembolic events in the 135

intravenous TXA group. 136

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Of the five studies investigating the use of TXA in hip fracture patients, four 137

were randomized controlled trials that were underpowered for detecting significant 138

differences in thromboembolic events (Table 1).8-11,35 Furthermore, patients were 139

only followed perioperatively, and differences in six-month and one-year mortality 140

rates and late-onset complications were not assessed. 141



TXA Regimen

DVT PPX Sample size

Blood loss (cc)

Transfuse Rate %


Lee 201511


1 g bolus preop


- 6* 1

- 19 4

Emara 20149




640 5* 5

1100 32 0

Zufferey 201010





975 42 0

1178 60 0

Sadeghi and Mehr-Aein 20068



n/a


960 37 0

1484 57 0

Vijay 201335




39* 16 0

91* 40 0

142

In designing this study, we concluded that hip fracture patients are both likely to 143

experience significant blood loss and are susceptible to the adverse effects of blood 144

loss making them an ideal population to target for a randomized controlled trial of 145

the effects of perioperative TXA on blood loss. We hypothesize that administration 146

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of TXA will decrease blood loss in hip fracture patients and lower the rate of 147

allogenic blood transfusion. 148

149

150

151

Objective 152

To investigate the hypothesis that TXA will lower blood loss and transfusion rate in 153

patients with hip fractures. 154

155

Methods and analysis 156

157

Overview of trial design 158

We are conducting a single-center randomized control trial using a parallel two-arm 159

design to investigate whether tranexamic acid use perioperatively will decrease the 160

rate of transfusion in patients with hip fractures (Figure 1). Randomization will be 161

stratified by type of hip fracture(ie. intertrochanteric versus femoral neck fracture). 162

The surgical team, anesthesia team, and patients will be blinded to the assignment. 163

Once consent is obtained and a patient is enrolled, a 1:1 randomization system will 164

be employed by our institution’s investigational pharmacy to assign patients to 165

receive TXA or placebo. Patient enrollment will occur over approximately 2 years 166

and enrolled patients will be followed for 1 year postoperatively. Incidence of blood 167

transfusion, total calculated blood loss, transfusion, and acute adverse events 168

(transfusion reaction, cerebrovascular accident, myocardial infarction, pulmonary 169

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embolism, and surgical site infection) will be assessed in the perioperative period. 170

Patients will also be assessed at 2 week, 6 week, 3 month, 6 month and 12 month 171

follow-up for long-term adverse events as well as mortality rate. This trial is 172

registered (NCT01940536) and has received ethics approval from the Weill Cornell 173

Medical College Institutional Review Board (IRB# 1301013463). 174

175

176

Primary research question 177

In patients with hip fractures, does a single bolus of tranexamic acid at the time of 178

surgery result in lower rate of blood transfusion? 179

180

Secondary research question 181

In patients with hip fractures, does a single bolus of tranexamic acid at the time of 182

surgery result in: 183

1.) decreased calculated blood loss? 184

2.) Shorter length of hospitalization? 185

3.) Any differences in occurrence of adverse events? 186

187

Hypothesis 188

As a primary outcome, there will be a decreased rate of blood transfusion in patients 189

who receive tranexamic acid intraoperatively and no significant increase in 190

frequency or severity of adverse events in comparison to patients who receive 191

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placebo. This study is powered to address the primary outcome of difference in 192

transfusion rates between the two study arms. 193

194

Setting and participants 195

Adult (over 18 years of age) patients presenting to a single tertiary care center with 196

an acute hip fracture. All patients with hip fractures at this institution are admitted 197

to the medical orthopaedic trauma service (MOTS). Prior to surgery, patients older 198

than 75 years of age, or those with medical comorbidities will be optimized by the 199

general medical service prior to surgery. All potentially eligible patients will be 200

screened and documented as (1) eligible and included, (2) eligible and missed, or 201

(3) excluded. The study coordinator will obtain informed consent for participation 202

in the study using the approved IRB Informed Consent forms. 203

204

All patients will provide written informed consent and will understand that by 205

entering in the study they may receive placebo or tranexamic acid. Participation in 206

the study is voluntary and their decision to participate will not affect any other 207

aspect of their care in case of refusal. Patients will have the right to withdraw from 208

the study at any point. 209

210

211

212

213

214

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Inclusion criteria 215

Patients admitted through the emergency room or transferred into our institution 216

and who meet the following criteria will be included in the study: 217

• Adults over the age of 18 218

• Acute intertrochanteric or femoral neck hip fracture 219

• Patients treated surgically with cephalomedullary nail, hemiarthroplasty, or 220

total hip arthroplasty (THA) 221

Exclusion criteria 222

Patient who meet any one or more of the following criteria will be excluded from the 223

study: 224

• Preoperative use of anticoagulant (clopidogrel, enoxaparin, warfarin, 225

argatroban, rivaroxaban, fondaparinux) 226

• Documented allergy to tranexamic acid 227

• History of deep vein thrombosis or pulmonary embolus 228

• Hepatic dysfunction (AST/ALT > 60) 229

• Renal dysfunction (Cr >1.5 of GRR > 30) 230

• Active coronary artery disease (event in the past 12 months), history of 231

cerebrovascular accident (CVA) in the past 12 months, or presence of a drug-232

eluting stent 233

• Color blindness 234

• Leukemia or any active cancer 235

• Coagulopathy (INR> 1.4, PTT > 1.4x normal, Platelets < 50,000) 236

• Non-displaced femoral neck fractures treated percutaneously 237

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238

Baseline 239

Baseline assessment includes sex, birth date, height and weight, mechanism of 240

injury, time from injury to presentation to the emergency room, American Society of 241

Anesthesiologists (ASA) classification, Charlson Comorbidity Index, comorbidities 242

including diabetes, cardiovascular disease, pulmonary disease, peripheral vascular 243

disease, dementia, hypertension, and history of smoking. The hemoglobin and 244

hematocrit will be recorded at the time of admission and on the morning of surgery. 245

246

Blinding 247

After the patient consents and is enrolled in the study, the patients will be stratified 248

based on type of hip fracture, intracapsular or extracapsular. The institution’s 249

investigational pharmacist will perform the randomization following the 250

stratification by fracture type and assign the patient to either receive TXA or 251

placebo. Patients will be randomized in blocks of 20. The packaging of the 252

injections will be performed by the investigational pharmacy and will be identical 253

for both TXA and placebo. All clinicians, except for the pharmacist, and the patients 254

will remain blinded until the data is analyzed. 255

256

Intervention 257

The patients randomized to the treatment arm will receive 1 gram of intravenous 258

tranexamic acid mixed in 100 cc of saline bolused at the time of surgical incision. 259

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Those assigned to the placebo group will receive an equivalent volume bolus of 260

saline at the time of surgical incision. 261

Patients with intertrochanteric hip fractures will be treated with a long, 262

intramedullary hip screw implant with a trochanteric start point. Patients with 263

displaced femoral neck fractures will be treated with a cemented or non-cemented 264

hemiarthroplasty or total hip arthroplasty at the discretion of the treating surgeon. 265

All surgeries will be supervised by the attending surgeon with the assistance of 266

orthopaedic residents. The surgical technique as well as the anesthetic technique, 267

regional versus general anesthesia, will be recorded and assessed in the final 268

analysis. The time from injury to surgery will also be recorded and included in the 269

analysis. 270

271

Blood transfusion criteria will remain consistent with hospital standards (Hb<8 272

g/dL or symptomatic anemia) as determined by an independent, blinded medical 273

team who will follow the patient throughout the hospital stay and number of blood 274

transfusions received will be documented upon patient discharge. Hematocrit and 275

hemoglobin will be recorded daily in all patients while they are in the hospital. 276

Further monitoring will be conducted based on need as determined by the 277

independent medical team. Estimated blood volume will be calculated from these 278

values and used to estimate blood loss (Appendix 1).36 279

280

All patients will be permitted to weight-bear as tolerated post-operatively and deep 281

vein thrombosis (DVT) prophylaxis will be standardized. All enrolled patients will 282

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receive subcutaneous heparin, 5000 units every 8 hours beginning upon admission 283

until 12 hours prior to surgery and restarting 6 hours after surgery. Calf mechanical 284

compression devices will also be utilized during the inpatient stay and will remain 285

on at all times with the exception of physical therapy sessions. Following discharge 286

from the hospital patients will be given aspirin 325 mg twice daily for DVT 287

prophylaxis for a total of 6 weeks. Diagnostic studies to assess for thromboembolic 288

events (i.e. DVT, pulmonary embolism, and stroke) will be ordered only if the 289

patient develops clinical signs or symptoms that justify their use. 290

Primary Outcome 291

The primary outcome of the study will be the rate of blood transfusion in the 292

postoperative period until time of discharge. Patients will be monitored with serial 293

hemoglobin and hematocrit measurements and their vital signs will be recorded as 294

per the standard of care to determine the need for blood transfusion. Only 295

intraoperative and postoperative blood transfusions will be considered for the primary 296

outcome measure as the drug will be administered at the time of surgical incision. 297

Therefore, we anticipate TXA in this study only modifying the rate of intraoperative or 298

postoperative transfusion, not pre-operative transfusion.. 299

300

Secondary Outcome 301

The secondary study outcomes include the calculated blood loss (calculated based 302

on validated methods as outlined in Appendix 1), frequency of adverse events 303

(including transfusion reaction, myocardial infarction, symptomatic deep vein 304

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thrombosis, pulmonary embolus, cerebrovascular accident, re-operation, re-305

admission, infection, and death) (Figure 1). 306

307

For the study purposes, a transfusion reaction will be defined as any constellation of 308

symptoms during a blood transfusion that necessitate discontinuation of the 309

transfusion. 310

Myocardial infarction will be defined as a cardiologist diagnosis of myocardial 311

infarction in combination with electrocardiogram changes, echocardiogram 312

changes, or creatine kinase MB or troponin changes. A pulmonary embolism must 313

be confirmed by pulmonary angiography, computed tomographic (CT) scan of the 314

chest, echocardiographic visualization or visualization of thrombus at autopsy. A 315

symptomatic deep vein thrombosis must be confirmed by venography, CT scan, 316

magnetic resonance imaging, or pathologic evidence at autopsy. A cerebrovascular 317

accident must be diagnosed by a neurologist and will be defined as an embolic, 318

thrombotic or hemorrhagic vascular accident or stroke with motor, sensory, or 319

cognitive dysfunction that persists for longer than 24 hours.37 320

A surgical site infection (SSI) will be defined as either superficial or deep infections. 321

Superficial SSI involves only skin or subcutaneous tissue while a deep SSI extends 322

deep to the fascial and muscle layers. Reoperation is defined as any return to the 323

operating room for a procedure related to the fractured hip. 324

325

326

Sample size consideration 327

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The transfusion rate amongst patients with hip fractures is between 6-60%.8-11,35 328

Our institutional transfusion rate was calculated based on a random sample of 60 329

patients and was 65% for extracapsular hip fractures and 35% for intracapsular hip 330

fractures, for an overall transfusion rate of 49%. The average reduction in 331

transfusion rate in the previous 5 studies using TXA was 20%.8-11,35 We plan to 332

include a total of 338 patients, 146 intracapsular hip fractures and 192 333

extracapsular hip fractures. This study design will achieve 81% power to detect a 334

reduction in blood transfusion from 65% in the placebo control group to 45% in the 335

tranexamic acid group with statistical significance set to alpha equal to 0.05 for the 336

extracapsular hip fracture group. Similarly the study will achieve 81% power to 337

detect a reduction in blood transfusion from 35% in the placebo control group to 338

15% in the tranexamic acid group with statistical significance set to alpha equal to 339

0.05 for the intracapsular hip fracture group. 340

341

342

Data analysis plan 343

Descriptive analyses of the patient population will include reporting means (with 344

standard deviations) for continuous variables and frequencies (with percentages) 345

for categorical or discrete variables. Following the descriptive analysis, a chi-square 346

analysis will be conducted to evaluate the superiority of tranexamic acid in reducing 347

the rate of transfusion versus the placebo control group. The analysis and reporting 348

of the results of the clinical outcomes will follow the CONSORT guidelines 349

(www.consort-statement.org). We will conduct a multiple logistic regression model 350

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to determine if type of fracture (intertrochanteric or femoral neck), comorbidities, 351

Charlson comorbidity index, age, time to surgery, and mechanism of injury are 352

related to transfusion administration. Similarly we will conduct a multiple linear 353

regression model to determine if patient comorbidities, age, time to surgery, and 354

mechanism of injury are related to blood loss. We will also conduct subgroup 355

analyses to determine if the effect of TXA is modified by fracture type 356

(intertrochanteric or femoral neck). 357

Our a priori hypothesis, based on retrospective data,6 is that patients with 358

intertrochanteric fractures incur more blood loss than femoral neck fractures and 359

will have a higher rate of transfusion. If these subgroup analyses are 360

underpowered, the subgroup data will be used to generate further hypotheses to be 361

tested in the future. All analyses will be performed using Stata 14.0 software (Stata 362

Corporation, College Station, TX, USA). 363

364

Data safety monitoring 365

The data safety monitoring board (DSMB) has been established to monitor the trial 366

and renew the study biannually. This board is independent of the trial and free of 367

conflicts with any of the investigation team. 368

369

Discussion 370

There is clinical uncertainty and a lack of high-quality evidence regarding the use of 371

TXA in hip fracture patients. Despite its proven efficacy in elective orthopaedic 372

surgery,25,38 the optimal dosing and timing of TXA administration is still debated.39 373

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Furthermore, the efficacy and side effect profile of TXA in patients with fractures 374

remains unclear. The immediate goal of this trial is to provide high-quality evidence 375

that can be used to develop clinical guidelines for use of TXA in patients with hip 376

fractures. 377

378

Patients undergoing elective total joint arthroplasty and elective spine surgery 379

represent a different population from patients who sustain hip fractures. A larger 380

percentage of hip fracture patients have significant medical comorbidities, and 381

many have history of cardiac disease.1 While TXA has demonstrated safety and 382

efficacy in patients without significant cardiac disease undergoing elective surgery, 383

there is still debate if TXA will have the same effect in patients with significant 384

comorbidities.25,39,40 The data investigating TXA in patients with comorbidities is 385

limited, which has further deterred clinicians from using TXA in patients with hip 386

fractures. However, the potential benefit of decreasing blood loss and decreasing 387

the number of transfusions following hip fracture surgery is overwhelming and will 388

likely result in improved patient outcomes, shorter length of stay and lower cost. 389

The study investigators believe that the potential benefit of TXA in such patients 390

outweighs the risk of TXA. The majority of literature regarding TXA has confirmed 391

its safety and squelched concerns that its use will result in higher rates of 392

thrombosis.20,30,32,40,41 393

394

The literature to date regarding TXA and hip fractures (Table 1) is limited. Four out 395

of five studies identified a significant decrease in rate of transfusion in patients who 396

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received TXA compared to those that did not.8-11,35 The largest study, with a total of 397

219 patients, was a cohort study with no randomization.11 While they found a 398

significant decrease in blood transfusion rate, the study design limits the 399

interpretation of the results secondary to the potential biases of surgeon and patient 400

preference. Several excluded all patients with preoperative anemia, which limits the 401

generalizability of their findings.8,9 None of the randomized trials provided a 402

detailed analysis of total number of patients excluded from the study at each stage. 403

While the early results from these studies are promising, the overall validity cannot 404

be confirmed without this information. Similarly, there has yet to be a large study to 405

perform a complete subanalysis to determine the efficacy of TXA amongst both 406

intracapsular and extracapsular hip fracture patients. Furthermore, the studies did 407

not follow patients up to 1 year postoperatively, which is our intention. The 408

extended follow-up period allows for assessment of mortality at 12 months as well 409

as incidence of unanticipated adverse events following discharge from the hospital. 410

The most novel characteristic of this study in comparison to the other studies is that 411

it is powered to detect a significant difference in blood transfusion rates in both 412

intracapsular and extracapsular hip fractures. As the hidden blood loss experienced 413

by hip fracture patients is distinct between these two patterns of hip fractures,6 it is 414

important to demonstrate efficacy in both groups independently. 415

416

Tranexamic acid has the potential to decrease transfusion rates by decreasing blood 417

loss in patients with hip fractures. Ultimately, this will decreased hospital length of 418

stay and improve outcomes in the hundreds of thousands of patients with hip 419

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fractures every year. If the results prove the efficacy of TXA in hip fracture patients, 420

this study may change the standard of care across the United States for these 421

patients. 422

423

Funding 424

This work is supported by a Dr. Thomas Sculco grant and a Dr. Joseph M. Lane grant. 425 426

Word Count 427

3,690 words 428

429

Data Sharing 430

This article presents the study design; data being collected during the research will 431

become available as the study begins. 432

433

Competing Interest 434

None of the authors has any potential financial conflict of interest related to this 435

manuscript 436

437

Contributorship 438

Elizabeth B. Gausden: This author revised the study from its original form 439

and condensed the application of the tranexamic acid to one dose in the 440

operating room in order to facilitate the flow of the project. This author 441

made substantial contributions to the planning of data analysis, drafting 442

and revising of the protocol, final approval of the version to be published 443

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and agrees to be accountable for all aspects of the work in ensuring that 444

questions related to the accuracy of the work. 445

446

Matthew R. Garner: This author conceived of the study and designed the 447

first draft of the protocol. He was awarded the Thomas P. Sculco 448

Research Grant and the Joseph M. Lane Research Grant for his proposal of 449

the project. He made substantial contributions to the drafting and 450

revising of the protocol, final approval of the version to be published and 451

agrees to be accountable for all aspects of the work in ensuring that 452


454

455

Stephen Warner: This author made substantial contributions to the 456

design of the work, planning of data analysis, drafting and revising of the 457

protocol, final approval of the version to be published and agrees to be 458

accountable for all aspects of the work in ensuring that questions related 459

to the accuracy of the work. 460

461

Ashley Levack: This author made substantial contributions to the study 462

design, modifications of the study to conform to guidelines and for 463

logistics. She will also be involved in patient recruitment, data collection 464

and analysis. This author made substantial contributions to the design of 465

the work, planning of data analysis, drafting and revising of the protocol, 466

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final approval of the version to be published and agrees to be accountable 467

for all aspects of the work in ensuring that questions related to the 468

accuracy of the work. 469

470

Andrew Nellestein: This is a research assistant who facilitated IRB 471

submissions and amendments. He is also coordinating the enrollment of 472

patients in the study and working with the orthopaedic trauma team 473

during the process of drug administration. This author made substantial 474

contributions to the design of the work, planning of data analysis, drafting 475

and revising of the protocol, final approval of the version to be published 476

and agrees to be accountable for all aspects of the work in ensuring that 477


479

Tiffany Tedore: Dr. Tedore is the main anesthesiologist who will be 480

orchestrating the anesthesiologists who administer the drug prior to skin 481

incision. This author made substantial contributions to the design of the 482

work, planning of data analysis, drafting and revising of the protocol, final 483

approval of the version to be published and agrees to be accountable for 484

all aspects of the work in ensuring that questions related to the accuracy 485

of the work. 486

487

Eva Flores: Dr, Flores is the head of the Medical Orthopaedic Trauma 488

Service (MOTS) who organizes the medical attendings who manage the 489

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patients following surgery. This author made substantial contributions to 490

the design of the work, planning of data analysis, drafting and revising of 491

the protocol, final approval of the version to be published and agrees to 492

be accountable for all aspects of the work in ensuring that questions 493

related to the accuracy of the work. 494

495

Dean G. Lorich: Dr. Lorich is the chief of the orthopaedic trauma service 496

at NYP. This author made substantial contributions to the design of the 497

work, planning of data analysis, drafting and revising of the protocol, final 498

approval of the version to be published and agrees to be accountable for 499

all aspects of the work in ensuring that questions related to the accuracy 500

of the work. 501

502

503

504

505 506 507

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461. 614

38. Danninger T, Memtsoudis SG. Tranexamic acid and orthopedic surgery-the 615

search for the holy grail of blood conservation. Ann Transl Med. 2015;3(6):77-616

5839.2015.01.25. 617

39. Simmons J, Sikorski RA, Pittet JF. Tranexamic acid: From trauma to routine 618

perioperative use. Curr Opin Anaesthesiol. 2015;28(2):191-200. 619




41. Gillette BP, DeSimone LJ, Trousdale RT, Pagnano MW, Sierra RJ. Low risk of 623

thromboembolic complications with tranexamic acid after primary total hip and 624

knee arthroplasty. Clin Orthop Relat Res. 2013;471(1):150-154. 625

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626

627

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Figure Legend 628

629

Figure 1: Study Design (TXA: tranexamic acid; PRBC: packed red blood cells) 630

631

Table 1: Previously reported outcomes of TXA in hip fracture patients. *drain 632 output. Thromboembolic events include only symptomatic thromboembolic events. 633 634

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Figure 1: Study Design (TXA: tranexamic acid; PRBC: packed red blood cells)

254x243mm (72 x 72 DPI)

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Appendix


(m)) + (k2 x Weight (kg)) + k3

k1 = 0.3669, k2 = 0.03219, and k3 = 0.6041 for men k1 = 0.3561, k2=0.03308, and k3 = 0.1833 for

women

Multiplying the PBV by the hematocrit (Hct) gives the red blood cell (RBC) volume. As

such, a change in the RBC volume can be calculated from a change in the Hct level as

follows:

Pre-op RBC volume loss = PBV x (Admit Hct – Day of surgery Hct)

Operative RBC volume loss = PBV x (Day of surgery Hct – PACU Hct)

Post-operative RBC volume loss= PBX x (PACU Hct – Hct POD#x)If a patient requires a pre-op or

intraoperative transfusion, the calculation will be adjusted as follows:

Pre-op RBC volume loss = [PBV x (Admit Hct – Day of surgery Hct)]+ (No. of Units Transfused x

0.285) / (Admit Hct – Day of surgery Hct) / 2)

Operative RBC volume loss = [PBV x (Day of surgery Hct – PACU Hct)] +)]+ (No. of Units Transfused x

0.285) / (Day of surgery Hct – Post-op Hct) / 2

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Spirit Checklist 1.) Title

Tranexamic Acid in Hip Fracture patients: a protocol for a randomized, placebo controlled trial on the efficacy of tranexamic acid in reducing blood loss in hip fracture patients

2.) Trial Registration

a.) Registry set

“The Effect of Tranexamic Acid on Transfusion Rates in Intertrochanteric Hip Fractures” Registered August 2014 clinicaltrials.gov: NCT01940536 13083

b.) Data set

Data Category Information

Primary registry and trial identifying number

Clinicaltrials.gov NCT01940536

Date of registration in primary registry

August 2014

Secondary identifying numbers

13083

Source of monetary support

Thomas Sculco Grant Joseph Lane Grant

Primary sponsor Thomas P. Sculco Research Grant

Secondary sponsor Joseph M. Lane Research Grant

Contact for public queries

Elizabeth Gausden, MD; [email protected]

Contact for scientific queries


Public Title Tranexamic Acid in Hip Fracture patients

Scientific title Tranexamic Acid in Hip Fracture patients: a protocol for a

randomized, placebo controlled trial on the efficacy of

tranexamic acid in reducing blood loss in hip fracture

patients

Countries of recruitment

United States

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Health condition(s) studied

Blood loss after hip fracture and hip fracture surgery

Intervention Use of intravenous tranexamic acid at the time of hip fracture surgery versus placebo (intravenous 0.9% saline)

Key inclusion and exclusion criteria

Inclusion

• Adults over the age of 18

• Intertrochanteric or femoral neck hip fracture

• Patients treated surgically with cephalomedullary nail or hemiarthroplasty

Exclusion

• Preoperative use of anticoagulant (Plavix, Warfarin, Lovenox)

• Documented allergy to tranexamic acid

• History of deep vein thrombosis or pulmonary embolus

• Hepatic dysfunction (AST/ALT > 60)

• Renal dysfunction (Cr >1.5 of GRR > 30)

• Active coronary artery disease (event in the past 12 months), history of cerebrovascular accident (CVA) in the past 12 months, or presence of a drug-eluting stent

• Color blindness

• Leukemia or any active cancer

• Coagulopathy (INR> 1.4, PTT > 1.4x normal, Platelets < 100,000)

• Non-displaced femoral neck fractures treated percutaneously

Study type Interventional Allocation: randomized Intervention model: parallel assignment Masking: Double blinded Primary purpose: preventing blood loss in hip fractures Phase III

Date of first enrollment

Pending

Target sample size 338

Primary outcome (s)

Transfusion of packed red blood cells (PRBC) following hip fracture surgery

Secondary outcome(s)

Calculated blood loss following surgery Adverse events (including transfusion reaction, myocardial infarction, deep vein thrombosis, pulmonary embolus, cerebrovascular accident, re-operation, re-admission, infection, and death)

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3.) Protocol version

The protocol has been modified from the original version listed on clinicaltrials.gov. The 2 changes reflect the inclusion of intracapsular hip fractures to be treated with arthroplasty as well as a revised power analysis and target study size.

4.) Funding

The funding for this study is coming from two grants, one from Dr. Joseph Lane and one from Dr. Thomas Sculco.

5.) Roles and Responsibilities

a.) Contributorship

Elizabeth B. Gausden: This author revised the study from its original form and condensed the application of the tranexamic acid to one dose in the operating room in order to facilitate the flow of the project. This author made substantial contributions to the planning of data analysis, drafting and revising of the protocol, final approval of the version to be published and agrees to be accountable for all aspects of the work in ensuring that questions related to the accuracy of the work. Matthew R. Garner: This author conceived of the study and designed the first draft of the protocol. He was awarded the Thomas P. Sculco Research Grant and the Joseph M. Lane Research Grant for his proposal of the project. He made substantial contributions to the drafting and revising of the protocol, final approval of the version to be published and agrees to be accountable for all aspects of the work in ensuring that questions related to the accuracy of the work. Ashley Levack: This author made substantial contributions to the study design, modifications of the study to conform to guidelines and for logistics. She will also be involved in patient recruitment, data collection and analysis. This author made substantial contributions to the design of the work, planning of data analysis, drafting and revising of the protocol, final approval of the version to be published and agrees to be accountable for all aspects of the work in ensuring that questions related to the accuracy of the work. Stephen Warner: This author made substantial contributions to the design of the work, planning of data analysis, drafting and revising of the protocol, final approval of the version to be published and agrees to be accountable for all aspects of the work in ensuring that questions related to the accuracy of the work.

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Andrew Nellestein: This is a research assistant who facilitated IRB submissions and amendments. He is also coordinating the enrollment of patients in the study and working with the orthopaedic trauma team during the process of drug administration. This author made substantial contributions to the design of the work, planning of data analysis, drafting and revising of the protocol, final approval of the version to be published and agrees to be accountable for all aspects of the work in ensuring that questions related to the accuracy of the work. Tiffany Tedore: Dr. Tedore is the main anesthesiologist who will be orchestrating the anesthesiologists who administer the drug prior to skin incision. This author made substantial contributions to the design of the work, planning of data analysis, drafting and revising of the protocol, final approval of the version to be published and agrees to be accountable for all aspects of the work in ensuring that questions related to the accuracy of the work. Eva Flores: Dr, Flores is the head of the Medical Orthopaedic Trauma Service (MOTS) who organizes the medical attendings who manage the patients following surgery. This author made substantial contributions to the design of the work, planning of data analysis, drafting and revising of the protocol, final approval of the version to be published and agrees to be accountable for all aspects of the work in ensuring that questions related to the accuracy of the work. Dean G. Lorich: Dr. Lorich is the chief of the orthopaedic trauma service at NYP. This author made substantial contributions to the design of the work, planning of data analysis, drafting and revising of the protocol, final approval of the version to be published and agrees to be accountable for all aspects of the work in ensuring that questions related to the accuracy of the work.

b.) Sponsor contact information

“Trial sponsor: Dr. Thomas P. Sculco Research Grant

Sponsor’s reference:

Contact name: Karla Felix

Address: 535 E. 70th St.

Telephone: 212 774 2717

Email: [email protected]

“Trial sponsor: Dr. Joseph M. Lane Research Grant

Sponsor’s reference:

Contact name: Karla Felix

Address: 535 E. 70th St.

Telephone: 212 774 2717

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Email: [email protected]

c.) Sponsor and funder:

This funder has no role in the design of the study and will not have any role during its execution, analyses, interpretation of the data, or decision to submit results. d.) Committees

As this is a single institution study, there is no steering committee other than the authors listed above. 6.) Background and rationale

a.) Background and rationale:

Hip fractures in the elderly remains a pressing public health issue in the United States given the aging population. 1 Hip fractures are associated with numerous adverse events and increased mortality up to one year after the event. 2-5 Elderly patients sustaining hip fractures commonly lose more than one liter of blood and up to 60% will require a blood transfusion. 6 A meta-analysis of 20 studies found a significantly increased risk of post-operative bacterial infection in patients who receive an allogenic blood transfusion in the perioperative period. 7 In addition to the increased risk of infection, patients who require blood transfusion following hip fracture have an increased hospital length of stay. 8 Beyond the risk to the patient from a blood transfusion, an allogenic blood transfusion in the United States was recently estimated to increase costs by $1,731 per admission. 9 Numerous anti-fibrinolytics have been used to limit bleeding in orthopaedic surgery and prevent the need for blood transfusion. 10-14 One of these anti-fibrinolytics, tranexamic acid (TXA) is a synthetic derivative of the amino acid lysine and acts as a competitive inhibitor in the activation of plasminogen to plasmin and therefore prevents the degradation of fibrin. As a result of the CRASH-2 trial15,16 that demonstrated reduced mortality in trauma patients administered TXA the World Health Organization (WHO) added it to the essential drugs list. Currently TXA is not routinely used in patients with hip fractures in the United States, despite its common use worldwide and proven efficacy in reducing blood loss. Numerous studies have investigated the safety and efficacy of TXA in patients undergoing elective orthopaedic surgery, including total joint replacement and spine surgery. 17-22 The consensus from this literature is overwhelmingly in favor of administration of TXA given the decrease in blood loss, transfusion rates, and cost. 23,24 Although few individual studies have found increased risk of thromboembolic events in groups

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receiving TXA, 25,26 larger studies and meta-analyses have uniformly found no increased risk of thrombosis.27,28 Patients who suffer hip fractures frequently have multiple comorbidities making them more susceptible to adverse events from blood loss. 19,20 The most common comorbidities of individuals with hip fractures are congestive heart failure, chronic pulmonary disease and diabetes. 1 Administering TXA to such patients has a potential to offset blood loss, improve patient outcome and lower cost by decreasing the rate of transfusions. 29,30 Five studies, all conducted outside the United States, have reported results of using TXA in hip fracture surgery. 26,31-33 Sadeghi et al34 randomized 67 hip fracture patients to receive either placebo injection or intravenous tranexamic acid at the time of surgery. They found a significantly lower volume of blood loss (652 ± 228 mL vs. 1108 ± 372 mL, P < 0.003) and shorter hospital stays (4.3 ± 1.6 days vs. 5.8 ± 1.5 days, p< 0.05). Vijay et al. 33 also reported significantly reduced transfusion rates in the TXA arm of their clinical trial. In a retrospective cohort study, Lee et al31 reported similar results, a transfusion rate three times lower in patients who received TXA prior to hemiarthroplasty surgery. In a separate randomized controlled trial that compared intravenous administration of TXA to topical TXA administration as well as placebo in hip fracture patients undergoing hemiarthroplasty, both of the TXA groups experienced less blood loss. 26 While this study found a significant reduction in blood loss and transfusion rates in both TXA groups, they found a higher incidence of thromboembolic events in the intravenous TXA group. Of the five studies investigating the use of TXA in hip fracture patients, four were randomized controlled trials that were underpowered for detecting significant differences in thromboembolic events (Table 1). Furthermore, patients were only followed perioperatively, and differences in six-month and one-year mortality rates and late-onset complications were not assessed.

In designing this study, we concluded that hip fracture patients are both likely to experience significant blood loss and are susceptible to the adverse effects of blood loss making them an ideal population to target for a randomized controlled trial of the effects of perioperative TXA on blood loss.

b.) Choice of comparators

The choice of intravenous saline as a control in this study is to replicate the standard of care at this time in the United States, which is no drug intervention for preventing blood loss in hip fracture surgery.

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7.) Objective

Hypothesis: We hypothesize that administration of TXA will decrease blood loss in hip fracture patients and lower the rate of allogenic blood transfusion.

Objective

To investigate the hypothesis that TXA will lower blood loss and transfusion rate in patients with hip fractures.

8.) Trial Design

This trial is designed as a stratified randomized, placebo-controlled, surgeon and patient blinded single-institution trial with four parallel groups and a primary endpoint of blood transfusion in the immediate postoperative hospitalization following hip fracture surgery. Randomization will be performed as block randomization with 1:1 allocation for both the intracapsular and the extracapsular hip fracture groups. 9.) Study Setting

Adult (over 18 years of age) patients presenting to a single urban tertiary care

center in with a hip fracture. All patients with hip fractures at this institution are admitted to the medical orthopaedic trauma service (MOTS) after presenting through the emergency room. 10.) Eligibility criteria

Inclusion criteria

Patients admitted through the emergency room or transferred into our institution and who meet the following criteria will be included in the study:


• Intertrochanteric or femoral neck hip fracture

• Patients treated surgically with cephalomedullary nail or hemiarthroplasty

Exclusion criteria

Patient who meet any one or more of the following criteria will be excluded from the study:

• Preoperative use of anticoagulant (clopidogrel, enoxaparin, warfarin, argatroban, rivaroxaban, fondaparinux)




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• Active coronary artery disease (event in the past 12 months), history of cerebrovascular accident (CVA) in the past 12 months, or presence of a drug-eluting stent

• Color blindness


• Coagulopathy (INR> 1.4, PTT > 1.4x normal, Platelets < 100,000)

• Non-displaced femoral neck fractures treated percutaneously 11.) Interventions

a.) Interventions

The patients randomized to the treatment arm will receive 1 gram of intravenous tranexamic acid infused at the time of surgical incision. Those assigned to the placebo group will receive an infusion of saline at the time of surgical incision. Patients with intertrochanteric hip fractures will be treated with a long, intramedullary hip screw implant with a trochanteric start point. Patients with displaced femoral neck fractures will be treated with a cemented or non-cemented hemiarthroplasty or total hip arthroplasty at the discretion of the treating surgeon. Blood transfusion criteria will remain consistent with hospital standards (Hb<8 g/dL or symptomatic anemia) as determined by an independent, blinded medical team who will follow the patient throughout the hospital stay and number of blood transfusions received will be documented upon patient discharge. Hematocrit and hemoglobin will be recorded in all patients while they are in the hospital, for a minimum of 2 days postoperatively. Further monitoring will be conducted based on need as determined by the independent medical team. Estimated blood volume will be calculated from these values and used to estimate blood loss (Appendix 1 All patients will be permitted to weight-bear as tolerated post-operatively and deep vein thrombosis (DVT) prophylaxis will be standardized. All enrolled patients will receive subcutaneous heparin, 5000 units every 8 hours beginning upon admission until 12 hours prior to surgery and restarting 6 hours after surgery. Calf mechanical compression devices will also be utilized during the inpatient stay and will remain on at all times with the exception of physical therapy sessions. Following discharge from the hospital patients will be given aspirin 325 mg twice daily for DVT prophylaxis for a total of 6 weeks. Diagnostic studies to assess for thromboembolic events (i.e. DVT, pulmonary embolism, and stroke) will be ordered only if the patient develops clinical signs or symptoms that justify their use.

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b.) Modifications

As the administration of TXA or placebo will occur at one time point in the operating room at the time of skin incision, there will be no criteria for modifying or discontinuing the treatment allocation following surgery. If a patient becomes unstable, experiences a sudden change in vital signs, drop in blood pressure or increase in heart rate, during the admission of the drug, the drug will be discontinued at that time. The patient will still be analyzed on an intention-to-treat basis. c.) Adherence

We do not anticipate adherence as an issue since the administration of the intervention will be performed by the anesthesiologist at the time of skin incision. d.) Concomitant care

No concomitant interventions will be permitted during the trial.

12.) Outcomes

Primary Outcome

The primary outcome of the study will be the rate of blood transfusion in the postoperative period until time of discharge. Patients will be monitored with serial hemoglobin and hematocrit measurements and their vital signs will be recorded as per the standard of care to determine the need for blood transfusion. Secondary Outcome

The secondary study outcomes include the calculated blood loss (calculated based on validated methods as outlined in Appendix 1), frequency of adverse events (including transfusion reaction, myocardial infarction, deep vein thrombosis, pulmonary embolus, cerebrovascular accident, re-operation, re-admission, infection, and death).

13.) Participation timeline

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Figure 1: Study Design (TXA: tranexamic acid; PRBC: packed red blood cells) 14.) Sample size consideration

The transfusion rate amongst patients with hip fractures is between 6-60%.8-11,35

Our institutional transfusion rate was calculated based on a random sample of 60

patients and was 65% for extracapsular hip fractures and 35% for intracapsular hip

fractures, and an overall transfusion rate of 49%. The average reduction in

transfusion rate in the previous 5 studies using TXA was 20%.8-11,35 We plan to

include a total of 338 patients, 146 intracapsular hip fractures and 192

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extracapsular hip fractures. This study design will achieve 81% power to detect a

reduction in blood transfusion from 65% in the placebo control group to 45% in the

tranexamic acid group with statistical significance set to alpha equal to 0.05 for the

extracapsular hip fracture group. Similarly the study will achieve 81% power to

detect a reduction in blood transfusion from 35% in the placebo control group to

15% in the tranexamic acid group with statistical significance set to alpha equal to

0.05 for the intracapsular hip fracture group.

15.) Recruitment

Adult (over 18 years of age) patients presenting to a single tertiary care center with a hip fracture. All patients with hip fractures at this institution are admitted to the medical orthopaedic trauma service (MOTS). Prior to surgery, patients older than 75 years of age, or those with medical comorbidities will be optimized by the general medical service prior to surgery. All potentially eligible patients will be screened and documented as (1) eligible and included, (2) eligible and missed, or (3) excluded. The study coordinator will obtain informed consent for participation in the study using the approved IRB Informed Consent forms. All patients will provide written informed consent and will understand that by entering in the study they may receive placebo and not tranexamic acid. Participation in the study is voluntary and their decision to participate will not affect any other aspect of their care in case of refusal. Patients will have the right to withdraw from the study at any point. 16.) Allocation

a.)Sequence generation

After the patient consents and is enrolled in the study, the institution’s investigational pharmacist will assign the patient to either receive TXA or placebo via computer generated randomization. Patients will be randomized in blocks of b.)Concealment

The packaging of the injections will be performed by the investigational pharmacy and will be identical for both TXA and placebo. All clinicians, except for the pharmacist, will remain blinded until the data is analyzed.

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c.)Implementation

After the patient consents and is enrolled in the study, the institution’s investigational pharmacist will perform the randomization and assign the patient to either receive TXA or placebo. Patients will be randomized in blocks of 20. The packaging of the injections will be performed by the investigational pharmacy and will be identical for both TXA and placebo. All clinicians, except for the pharmacist, will remain blinded until the data is analyzed. 17.) Blinding

a.) Masking

The patient, the surgeon, the anesthesiologist and the hospitalist will all be blinded to the assignment of intervention. Therefore, the decision to transfuse a patient will be made independent of the intervention. b.)Emergency unblinding

Unblinding of intervention assignment will only be allowed in exceptional circumstances if knowlegde of treatment is crucial to further management of the patient. An example of this is if a patient becomes unstable during drug administration in the operating room. The allocation will not be disclosed to the surgeon or the patient or other study personnel who are not directly treating the patient at that time. All code breaks will be reported and documented. 18.) Methods

a.) Data collection methods

Baseline assessment includes sex, birth date, height and weight, mechanism of injury, time from injury to presentation to the emergency room, American Society of Anesthesiologists (ASA) classification, Charlson Comorbidity Index, comorbidities including diabetes, peripheral vascular disease, dementia, hypertension, and history of smoking. The hemoglobin and hematocrit will be recorded at the time of admission and on the morning of surgery, if applicable. Blood transfusion criteria will remain consistent with hospital standards (Hb<8 g/dL or symptomatic anemia) as determined by an independent, blinded medical team who will follow the patient throughout the hospital stay and number of blood transfusions received will be documented upon patient discharge. Hematocrit and hemoglobin will be recorded in all patients while they are in the hospital, for a minimum of 2 days postoperatively. Further monitoring will be conducted based on need as determined by the independent medical team. Estimated blood volume will be calculated from these values and used to estimate blood loss. After discharge, patients will undergo routine follow-up at 2wk, 6wk, 3mo, 6mo and 1 yr after surgery. Each will be questioned regarding possible adverse events that may have occurred since their previous visit. Further, electronic inpatient records

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will be reviewed at the 1 year follow-up appointment to determine if any undocumented adverse events may have occurred and patients will also be called at that time if they fail to attend their 1 year follow-up appointment. 19.) Data Management

All data will be entered electronically into a Microsoft Excel database that will be password protected on an institutional computer. Any identifying health information will be removed or, if needed, coded when data is summarized in a spreadsheet format for statistical analysis purposes. 20.) Statistical Analysis

a.) Outcomes

Descriptive analyses of the patient population will include reporting means (with standard deviations) for continuous variables and frequencies (with percentages) for categorical or discrete variables. Following the descriptive analysis, a chi-square analysis will be conducted to evaluate the superiority of tranexamic acid in reducing the rate of transfusion versus the placebo control group. The analysis and reporting of the results of the clinical outcomes will follow the CONSORT guidelines (www.consort-statement.org). We will conduct a multiple logistic regression model to determine if type of fracture (intertrochanteric or femoral neck), comorbidities, Charlson comorbidity index, age, time to surgery, and mechanism of injury are related to transfusion administration. Similarly we will conduct a multiple linear regression model to determine if patient comorbidities, age, time to surgery, and mechanism of injury are related to blood loss. We will also conduct subgroup analyses to determine if the effect of TXA is modified by fracture type (intertrochanteric or femoral neck). All analyses will be performed using Stata 14.0 software (Stata Corporation, College Station, TX, USA). b.)Additional analyses Our a priori hypothesis, based on retrospective data, 6 is that patients with intertrochanteric fractures incur more blood loss than femoral neck fractures and will have a higher rate of transfusion. If these subgroup analyses are underpowered, the subgroup data will be used to generate further hypotheses to be tested in the future.

c.)Analysis population and missing data

Not applicable- as there will largely be no compliance breakdowns given that the intervention is a one-time administration of a drug during a surgical procedure. Should a patient consent and be enrolled in the trial and decide to unenroll prior to drug administration they will not be taken into account for the analysis.

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In the event of missing data, ie missing hemoglobin levels postoperatively, we do not plan on using an imputing method but rather analyzing only the data collected given that these missing data points will likely be randomly arranged throughout the study. 21.) Methods: Monitoring

a.)Formal Committee

The data safety monitoring board (DSMB) has been established to monitor the trial and renew the study biannually. This board is independent of the trial and free of conflicts with any of the investigation team. b.)Interim analysis

Data will be analyzed every six months throughout the study by the study investigators.

22.) Harms

The secondary outcomes of this study including adverse outcomes and events. These events will be monitored for after the subject has provided consent and has been enrolled in the study. If a subject experiences an adverse event after the informed consent document is signed (entry) but the subject has not yet received the intervention in the operating room, the event will be reported as not related to study drug. Adverse events during hospitalization will be recorded and patients will be asked about adverse events during their follow-up appointments. Adverse events will be reported to the DSMB as well.

23.) Auditing

The data safety monitoring board (DSMB) has been established to monitor the trial and renew the study biannually. This board is independent of the trial and free of conflicts with any of the investigation team.

24.) Research ethics approval

The protocol and site specific consent forms have been approved by our institutional review board (IRB) with respect to scientific content and compliance with applicable research and human subjects regulations.

25.) Protocol amendments

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See attached.

26.) Consent or assent

a.) Consent

Informed consent will be obtained by research associated personnel at the time of patient presentation. Written consent will be obtained from the patient when possible, or from the health care proxy if the patient is unable to consent for themselves.

Each patient will be provided the written informed consent form to read and will have the opportunity to ask any questions related to the research protocol/methods to the researcher obtaining consent.

b.)Ancillary studies

not applicable

27.) Confidentiality

Data is only recorded electronicallyand will be kept in the Principal Investigator’s locked office on a password-protected computer. Only research personnel will have access to electronic files kept in the PIs locked office, and only research personnel will know the password needed to access research files. Patients will be numbered sequentially on the data collection sheet. Numbers will be associated with names and medical records, which will be stored in a separate file by the research coordinator.

28.) Declaration of interests

None of the authors of the study or study personnel have any financial relationships

related to the nature of the study.

29.) Access to data

n/a – single institution study

30.) Ancillary and post-trial care

n/a- this is a privately funded study with no study-specific insurance policy.

31.) Dissemination policy

a.) trial results

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The results from the trial will be reviewed by the authors and following editing from each member a manuscript will be prepared for publication in a peer reviewed journal. b.)authorship

The authors currently listed will be included as authors on the final manuscript submitted for publication according to their maintained involvement. New authors will be required by meet guidelines for authorship as stated previously. c.)Reproducible research

n/a

32.) Informed consent material

see attached

33.) Biological specimens

n/a

References

1. Brauer CA, Coca-Perraillon M, Cutler DM, Rosen AB. Incidence and mortality of hip

fractures in the united states. JAMA. 2009;302(14):1573-1579.

2. Richmond J, Aharonoff GB, Zuckerman JD, Koval KJ. Mortality risk after hip

fracture. J Orthop Trauma. 2003;17(1):53-56.

3. Heyes GJ, Tucker A, Marley D, Foster A. Predictors for 1-year mortality following

hip fracture: A retrospective review of 465 consecutive patients. Eur J Trauma

Emerg Surg. 2015.

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4. Shah MR, Aharonoff GB, Wolinsky P, Zuckerman JD, Koval KJ. Outcome after hip

fracture in individuals ninety years of age and older. J Orthop Trauma.

2001;15(1):34-39.

5. Sathiyakumar V, Greenberg SE, Molina CS, Thakore RV, Obremskey WT, Sethi MK.

Hip fractures are risky business: An analysis of the NSQIP data. Injury.

2015;46(4):703-708.

6. Foss NB, Kehlet H. Hidden blood loss after surgery for hip fracture. J Bone Joint

Surg Br. 2006;88(8):1053-1059.

7. Hill GE, Frawley WH, Griffith KE, Forestner JE, Minei JP. Allogeneic blood

transfusion increases the risk of postoperative bacterial infection: A meta-analysis. J

Trauma. 2003;54(5):908-914.

8. Shokoohi A, Stanworth S, Mistry D, Lamb S, Staves J, Murphy MF. The risks of red

cell transfusion for hip fracture surgery in the elderly. Vox Sang. 2012;103(3):223-

230.

9. Saleh A, Small T, Chandran Pillai AL, Schiltz NK, Klika AK, Barsoum WK. Allogenic

blood transfusion following total hip arthroplasty: Results from the nationwide

inpatient sample, 2000 to 2009. J Bone Joint Surg Am. 2014;96(18):e155.

10. Kagoma YK, Crowther MA, Douketis J, Bhandari M, Eikelboom J, Lim W. Use of

antifibrinolytic therapy to reduce transfusion in patients undergoing orthopedic

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surgery: A systematic review of randomized trials. Thromb Res. 2009;123(5):687-

696.

11. Eubanks JD. Antifibrinolytics in major orthopaedic surgery. J Am Acad Orthop

Surg. 2010;18(3):132-138.

12. Yuan C, Zhang H, He S. Efficacy and safety of using antifibrinolytic agents in spine

surgery: A meta-analysis. PLoS One. 2013;8(11):e82063.

13. Zufferey P, Merquiol F, Laporte S, et al. Do antifibrinolytics reduce allogeneic

blood transfusion in orthopedic surgery? Anesthesiology. 2006;105(5):1034-1046.

14. Tse EY, Cheung WY, Ng KF, Luk KD. Reducing perioperative blood loss and

allogeneic blood transfusion in patients undergoing major spine surgery. J Bone Joint

Surg Am. 2011;93(13):1268-1277.

15. CRASH-2 trial collaborators, Shakur H, Roberts I, et al. Effects of tranexamic acid

on death, vascular occlusive events, and blood transfusion in trauma patients with

significant haemorrhage (CRASH-2): A randomised, placebo-controlled trial. Lancet.

2010;376(9734):23-32.

16. CRASH-2 collaborators, Roberts I, Shakur H, et al. The importance of early

treatment with tranexamic acid in bleeding trauma patients: An exploratory

analysis of the CRASH-2 randomised controlled trial. Lancet. 2011;377(9771):1096-

101, 1101.e1-2.

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17. Whiting DR, Gillette BP, Duncan C, Smith H, Pagnano MW, Sierra RJ. Preliminary

results suggest tranexamic acid is safe and effective in arthroplasty patients with

severe comorbidities. Clin Orthop Relat Res. 2014;472(1):66-72.

18. Cid J, Lozano M. Tranexamic acid reduces allogeneic red cell transfusions in

patients undergoing total knee arthroplasty: Results of a meta-analysis of

randomized controlled trials. Transfusion. 2005;45(8):1302-1307.

19. Lemay E, Guay J, Cote C, Roy A. Tranexamic acid reduces the need for allogenic

red blood cell transfusions in patients undergoing total hip replacement. Can J

Anaesth. 2004;51(1):31-37.

20. Poeran J, Rasul R, Suzuki S, et al. Tranexamic acid use and postoperative

outcomes in patients undergoing total hip or knee arthroplasty in the united states:

Retrospective analysis of effectiveness and safety. BMJ. 2014;349:g4829.

21. Raksakietisak M, Sathitkarnmanee B, Srisaen P, et al. Two doses of tranexamic

acid reduce blood transfusion in complex spine surgery: A prospective randomized

study. Spine (Phila Pa 1976). 2015.

22. Wind TC, Barfield WR, Moskal JT. The effect of tranexamic acid on transfusion

rate in primary total hip arthroplasty. J Arthroplasty. 2014;29(2):387-389.

23. Tuttle JR, Ritterman SA, Cassidy DB, Anazonwu WA, Froehlich JA, Rubin LE. Cost

benefit analysis of topical tranexamic acid in primary total hip and knee

arthroplasty. J Arthroplasty. 2014;29(8):1512-1515.

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24. Huang F, Wu D, Ma G, Yin Z, Wang Q. The use of tranexamic acid to reduce blood

loss and transfusion in major orthopedic surgery: A meta-analysis. J Surg Res.

2014;186(1):318-327.

25. Nishihara S, Hamada M. Does tranexamic acid alter the risk of thromboembolism

after total hip arthroplasty in the absence of routine chemical thromboprophylaxis?

Bone Joint J. 2015;97-B(4):458-462.

26. Emara WM, Moez KK, Elkhouly AH. Topical versus intravenous tranexamic acid

as a blood conservation intervention for reduction of post-operative bleeding in

hemiarthroplasty. Anesth Essays Res. 2014;8(1):48-53.

27. Duncan CM, Gillette BP, Jacob AK, Sierra RJ, Sanchez-Sotelo J, Smith HM. Venous

thromboembolism and mortality associated with tranexamic acid use during total

hip and knee arthroplasty. J Arthroplasty. 2015;30(2):272-276.

28. Yang ZG, Chen WP, Wu LD. Effectiveness and safety of tranexamic acid in

reducing blood loss in total knee arthroplasty: A meta-analysis. J Bone Joint Surg Am.

2012;94(13):1153-1159.

29. Foss NB, Kristensen MT, Kehlet H. Anaemia impedes functional mobility after hip

fracture surgery. Age Ageing. 2008;37(2):173-178.

30. Lawrence VA, Silverstein JH, Cornell JE, Pederson T, Noveck H, Carson JL. Higher

hb level is associated with better early functional recovery after hip fracture repair.

Transfusion. 2003;43(12):1717-1722.

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31. Lee C, Freeman R, Edmondson M, Rogers BA. The efficacy of tranexamic acid in

hip hemiarthroplasty surgery: An observational cohort study. Injury.

2015;46(10):1978-1982.

32. Zufferey PJ, Miquet M, Quenet S, et al. Tranexamic acid in hip fracture surgery: A

randomized controlled trial. Br J Anaesth. 2010;104(1):23-30.

33. Vijay BS, Bedi V, Mitra S, Das B. Role of tranexamic acid in reducing

postoperative blood loss and transfusion requirement in patients undergoing hip

and femoral surgeries. Saudi J Anaesth. 2013;7(1):29-32.

34. Sadeghi M MA. Does a single bolus dose of tranexamic acid reduce blood loss and

transfusion requirements during hip fracture surgery? A prospective randomized

double blind study in 67 patients. Acta Medica Iranica. 2007;45(6):437-442.

Appendix



k1 = 0.3669, k2 = 0.03219, and k3 = 0.6041 for men k1 = 0.3561, k2=0.03308, and k3 = 0.1833 for women



follows:

Pre-op RBC volume loss = PBV x (Admit Hct – Day of surgery Hct) Operative RBC volume loss = PBV x (Day of surgery Hct – PACU Hct)

If a patient requires a pre-op or intraoperative transfusion, the calculation will be adjusted as follows:

Pre-op RBC volume loss = [PBV x (Admit Hct – Day of surgery Hct)]+ (No. of Units Transfused x

0.285) / (Admit Hct – Day of surgery Hct) / 2)Operative RBC volume loss = [PBV x (Day of surgery

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Hct – PACU Hct)] +)]+ (No. of Units Transfused x 0.285) / (Day of surgery Hct – Post-op Hct) / 2

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Journal: BMJ Open

Manuscript ID bmjopen-2015-010676.R2


Date Submitted by the Author: 29-Mar-2016

Complete List of Authors: Gausden, Elizabeth; Hospital for Special Surgery, Orthopaedic Surgery Garner, Matthew; Hospital for Special Surgery, Orthopaedic Surgery Warner, Stephen; Hospital for Special Surgery, Orthopaedic Surgery Levack, Ashley; Hospital for Special Surgery, Orthopaedic Surgery Nellestein, Andrew; Weill Cornell Medical College, Anesthesia Tedore, Tiffany; Weill Cornell Medical College, Anesthesia Flores, Eva; Weill Cornell Medical College, Internal Medicine Lorich, Dean; Hospital for Special Surgery, Orthopaedic Surgery


Surgery

Secondary Subject Heading: Evidence based practice, Haematology (incl blood transfusion), Surgery





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Tranexamic Acid in Hip Fracture patients: a protocol for a randomized, placebo controlled trial on the efficacy of tranexamic acid in reducing

blood loss in hip fracture patients

Elizabeth Bishop Gausden, MD*1 [email protected]

Phone: (646) 350-9897 Fax: 212.606.1477

Matthew R. Garner, MD2 [email protected]

Stephen J. Warner, MD, PhD1

[email protected]

Ashley Levack, MD, MAS1 [email protected]

Andrew Nellestein, BS, MS3 [email protected]

Tiffany Tedore, MD4

[email protected]

Eva Flores, MD5 [email protected]

Dean G. Lorich, MD3

[email protected]

1 Hospital for Special Surgery Department of Orthopaedics

535 E. 70th Street New York, NY 10021

2 Harborview Medical Center Department of Orthopaedics

325 9th Ave. Seattle, WA 98104

3 New York Presbyterian Hospital

Department of Orthopaedic Trauma 525 E. 68th St

New York, NY 10065

4 New York Presbyterian Hospital Department of Anesthesiology

525 E. 68th St New York, NY 10065

5 New York Presbyterian Hospital Department of Internal Medicine

525 E. 68th St New York, NY 10065

*corresponding author word count: 3,415 Keywords: tranexamic acid, hip fracture, blood transfusion

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Abstract

Introduction

There is a high incidence of blood transfusion following hip fractures in elderly

patients. Tranexamic acid (TXA) has proven efficacy in decreasing blood loss in

general trauma patients as well as patients undergoing elective orthopaedic surgery.

A randomized controlled trial will measure the effect of TXA in a population of

patients undergoing hip fracture surgery.

Methods

This is a double-blinded, randomized placebo-controlled trial. Patients admitted

through the emergency room that are diagnosed with an intertrochanteric or

femoral neck fracture will be eligible for enrollment and randomized to either

treatment with 1 gram of intravenous TXA or intravenous saline at the time of skin

incision. Patients undergoing percutaneous intervention for non-displaced or

minimally displaced femoral neck fractures will not be eligible for enrollment.

Postoperative transfusion rates will be recorded and blood loss will be calculated

from serial hematocrits.

Ethics and dissemination

This protocol was approved by the Institutional Review Board (IRB) and is

registered with clinicaltrials.gov. The findings of the trial will be disseminated

through peer-reviewed journals and conference presentations.

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Strengths and limitations of this study

• A prospective, randomized, placebo-controlled trial is the optimal study

design to address the question of efficacy of tranexamic acid (TXA) use in

patients with hip fractures

• The outcomes will be reported based on one-year follow-up, which is longer

follow-up than any other study examining tranexamic acid use in patients

with hip fractures.

• Findings will provide objective data from which clinicians can base future

guidelines regarding TXA administration.

• Recruitment is slow as patients and health-care proxies are wary of enrolling

in a study in a trauma setting.

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Introduction

Hip fractures in the elderly remain a pressing public health issue in the United

States given the aging population.1 Hip fractures are associated with numerous

adverse events and increased mortality up to one year after the event.2-5 Hidden

blood loss in hip fractures, in addition to intraoperative blood loss, may be as high

as 1,500 cc. 6,7 The rate of blood transfusion in the perioperative period for hip

fracture patients is reported between 20-60%.8-11 Total blood loss, and thus rate of

transfusion, is greater for extracapsular hip fractures compared to intracapsular hip

fractures.6 A meta-analysis of 20 studies found a significantly increased risk of post-

operative bacterial infection in patients who receive an allogenic blood transfusion

in the perioperative period.12 In addition to the increased risk of infection, patients

who require blood transfusion following hip fracture have an increased hospital

length of stay.13 Furthermore, an allogenic blood transfusion in the United States

was recently estimated to increase costs by $1,731 per admission.14

Numerous anti-fibrinolytics have been used to limit bleeding in orthopaedic surgery

and prevent the need for blood transfusion.15-19 One of these anti-fibrinolytics,

tranexamic acid (TXA), is a synthetic derivative of the amino acid lysine and acts as a

competitive inhibitor in the activation of plasminogen to plasmin, therefore

preventing the degradation of fibrin. As a result of the CRASH-2 trial,20,21 which

demonstrated reduced mortality in trauma patients who received TXA, the World

Health Organization (WHO) added TXA to the essential drugs list. Currently TXA is

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not routinely used in patients with hip fractures in the United States, despite its

common use worldwide and proven efficacy in reducing blood loss in other

populations.

Numerous studies have investigated the safety and efficacy of TXA in patients

undergoing elective orthopaedic surgery, including total joint replacement and

spine surgery.22-27 The consensus from this literature is overwhelmingly in favor of

administration of TXA given the decrease in blood loss, transfusion rates, and

cost.28,29 Although several individual studies have found increased risk of

thromboembolic events in groups receiving TXA,9,30 larger studies and meta-

analyses have uniformly found no increased risk of thrombosis.31,32

Patients who suffer hip fractures frequently have multiple comorbidities making

them more susceptible to adverse events from blood loss. 19,20 The most common

comorbidities of individuals with hip fractures are congestive heart failure, chronic

pulmonary disease and diabetes.1 Administering TXA to such patients has a

potential to offset blood loss, improve patient outcomes and lower cost of care by

decreasing the rate of transfusions.33,34 Five studies, all conducted outside the

United States, have previously reported results of using TXA in hip fracture

surgery.8-11,35 Sadeghi et al8 randomized 67 hip fracture patients to receive either

placebo injection or intravenous tranexamic acid at the time of surgery. They found

a significantly lower volume of blood loss (652 ± 228 mL vs. 1108 ± 372 mL, P <

0.003) and shorter hospital stays (4.3 ± 1.6 days vs. 5.8 ± 1.5 days, p< 0.05). Vijay et

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al.35 also reported significantly reduced transfusion rates in the TXA arm of their

clinical trial. In a retrospective cohort study, Lee et al11 similarly reported a

transfusion rate three times lower in patients who received TXA prior to

hemiarthroplasty. In a separate randomized controlled trial that compared

intravenous administration of TXA to topical TXA administration as well as placebo

in hip fracture patients undergoing hemiarthroplasty, both of the TXA groups

experienced less blood loss.9

In designing this study, we concluded that hip fracture patients are both likely to

experience significant blood loss and are susceptible to the adverse effects of blood

loss making them an ideal population to target for a randomized controlled trial of

the effects of perioperative TXA on blood loss. We hypothesize that administration

of TXA will decrease blood loss in hip fracture patients and lower the rate of

allogenic blood transfusion.

Objective

To investigate the hypothesis that TXA will lower blood loss and transfusion rate in

patients with hip fractures.

Methods and analysis

Overview of trial design

We are conducting a single-center randomized controlled trial using a parallel two-

arm design to investigate whether peri-operative tranexamic acid use will decrease

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the rate of transfusion in patients with hip fractures (Figure 1). Randomization will

be stratified by type of hip fracture (ie. intertrochanteric versus femoral neck

fracture). The surgical team, anesthesia team, and patients will be blinded to the

assignment. Once consent is obtained and a patient is enrolled, a 1:1 randomization

system will be employed by our institution’s investigational pharmacy to assign

patients to receive TXA or placebo. Patient enrollment will occur over

approximately 2 years and enrolled patients will be followed for 1 year

postoperatively. Incidence of blood transfusion, total calculated blood loss, and

acute adverse events (transfusion reaction, cerebrovascular accident, myocardial

infarction, pulmonary embolism, symptomatic deep vein thrombosis, surgical site

infection, and death) will be assessed in the perioperative period. Patients will also

be assessed at 2 weeks, 6 weeks, 3 months, 6 months and 12 months post-

operatively to capture long-term adverse events as well as determine mortality rate.

This trial is registered (NCT01940536) and has received ethical approval from the

Weill Cornell Medical College Institutional Review Board (IRB# 1301013463).

Primary research question

In patients with hip fractures, does a single bolus of tranexamic acid at the time of

surgery result in a lower rate of blood transfusion?

Secondary research question

In patients with hip fractures, does a single bolus of tranexamic acid at the time of

surgery result in:

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1.) decreased calculated blood loss?

2.) shorter length of hospitalization?

3.) differences in occurrence of adverse events?

Hypothesis

As a primary outcome, there will be a decreased rate of blood transfusion in patients

who receive tranexamic acid intraoperatively and no significant increase in

frequency or severity of adverse events in comparison to patients who receive

placebo. This study is powered to address the primary outcome of difference in

transfusion rates between the two study arms for both intracapsular and

extracapsular hip fractures.

Setting and participants

Adult patients (over 18 years of age) presenting to a single tertiary care center with

an acute hip fracture will be screened for eligibility. All patients with hip fractures

at this institution are admitted to the medical orthopaedic trauma service (MOTS).

Prior to surgery, patients older than 75 years of age, or those with medical

comorbidities will be optimized by the general medical service prior to surgery. All

potentially eligible patients will be screened and documented as (1) eligible and

included, (2) eligible and missed, or (3) excluded. The study coordinator will obtain

informed consent for participation in the study using the approved IRB Informed

Consent forms.

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All patients will provide written informed consent and will understand that by

entering in the study they may receive either placebo or tranexamic acid.

Participation in the study is voluntary and their decision to participate will not

affect any other aspect of their care in case of refusal. Patients will have the right to

withdraw from the study at any point.

Inclusion criteria

Patients admitted through the emergency department or transferred to our

institution who meet the following criteria will be included in the study:


• Acute intertrochanteric or femoral neck hip fracture

• Patients treated surgically with cephalomedullary nail, hemiarthroplasty, or

total hip arthroplasty (THA)

Exclusion criteria

Patient who meet any one or more of the following criteria will be excluded from the

study:

• Use of any anticoagulant at the time of admission (for example, vitamin K

antagonists, anti-thrombin agents, antiplatelet agents, or factor IIa & Xa

inhibitors)





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• Active coronary artery disease (event in the past 12 months)

• History of cerebrovascular accident (CVA) in the past 12 months

• Presence of a drug-eluting stent

• Color blindness


• Coagulopathy based on admission laboratory values (INR> 1.4, PTT > 1.4x

normal, Platelets < 50,000)

• Non-displaced femoral neck fractures treated percutaneously

Baseline

Baseline assessment includes sex; birth date; height and weight; mechanism of

injury; time from injury to presentation to our institution; American Society of

Anesthesiologists (ASA) classification; Charlson Comorbidity Index; and

comorbidities including diabetes, cardiovascular disease, pulmonary disease,

peripheral vascular disease, dementia, hypertension, and history of smoking. The

hemoglobin and hematocrit will be recorded at the time of admission and on the

morning of surgery.

Blinding

After consent and enrollment in the study, patients will be stratified based on type

of hip fracture (intracapsular or extracapsular). Following stratification by fracture

type, the institution’s investigational pharmacist will perform the randomization

and assign the patient to either receive TXA or placebo. Patients will be

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randomized in blocks of 20. The packaging of the injections will be performed by

the investigational pharmacy and will be identical for both TXA and placebo. All

patients and clinicians, with the exception of the pharmacist, will remain blinded

until the data is analyzed.

Intervention

The patients randomized to the treatment arm will receive 1 gram of intravenous

tranexamic acid mixed in 100 cc of saline, bolused at the time of surgical incision.

Those assigned to the placebo group will receive an equivalent volume bolus of

saline at the time of surgical incision.

Patients with intertrochanteric hip fractures will be treated with a long

intramedullary hip screw implant with a trochanteric start point. Patients with

displaced femoral neck fractures will be treated with a cemented or non-cemented

hemiarthroplasty or total hip arthroplasty at the discretion of the treating surgeon.

All surgeries will be supervised by the attending surgeon with the assistance of

orthopaedic residents. The surgical technique as well as the anesthetic technique

(regional versus general anesthesia) will be recorded and assessed in the final

analysis. The time from injury to surgery will also be recorded and included in the

analysis.

Blood transfusion criteria will remain consistent with hospital standards (Hb<8

g/dL or symptomatic anemia) as determined by an independent, blinded medical

team who will follow the patient throughout the hospital stay. Number of blood

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transfusions received will be documented upon patient discharge. Hematocrit and

hemoglobin will be recorded daily for all patients while they remain in the hospital.

Further monitoring will be conducted based on need as determined by the

independent medical team. Estimated blood volume will be calculated using

baseline height, weight and gender and the laboaratory values will be used to

calculate estimated blood loss post-operatively (Appendix 1).36

All patients will be permitted to weight-bear as tolerated post-operatively and deep

vein thrombosis (DVT) prophylaxis will be standardized. All enrolled patients will

receive subcutaneous heparin, 5000 units every 8 hours beginning upon admission

until 12 hours prior to surgery and restarting 6 hours after surgery. Calf mechanical

compression devices will also be utilized during the inpatient stay and will remain

on at all times with the exception of physical therapy sessions. Following discharge

from the hospital patients will be given aspirin 325 mg twice daily for DVT

prophylaxis for a total of 6 weeks. Diagnostic studies to assess for thromboembolic

events (i.e. DVT, pulmonary embolism, and stroke) will be ordered only if the

patient develops clinical signs or symptoms that justify their use.

Primary Outcome

The primary outcome of the study will be the rate of blood transfusion from the

time of surgery until discharge. Patients will be monitored with serial hemoglobin

and hematocrit measurements and their vital signs will be recorded as per the

standard of care to determine the need for blood transfusion. Only intraoperative and

postoperative blood transfusions will be considered for the primary outcome measure as

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the drug will be administered at the time of surgical incision. Therefore, we anticipate that

TXA administration in this study will only modify the rate of intraoperative or postoperative

transfusion, and have no effect on the rate of pre-operative transfusion in this population.

Secondary Outcome

The secondary study outcomes include the calculated blood loss (calculated based

on validated methods as outlined in Appendix 1), frequency of adverse events

(including transfusion reaction, myocardial infarction, symptomatic deep vein

thrombosis, pulmonary embolus, cerebrovascular accident, re-operation, re-

admission, infection, and death) (Figure 1).

For the study purposes, a transfusion reaction will be defined as any constellation of

symptoms during a blood transfusion that necessitate discontinuation of the

transfusion.

Myocardial infarction will be defined as a cardiologist diagnosis of myocardial

infarction based on a combination of electrocardiogram changes, echocardiogram

changes, or creatine kinase MB or troponin changes. A pulmonary embolism must

be confirmed by pulmonary angiography, computed tomographic (CT) scan of the

chest, echocardiographic visualization or visualization of thrombus at autopsy. A

symptomatic deep vein thrombosis must be confirmed by venography, CT scan,

magnetic resonance imaging, or pathologic evidence at autopsy. A cerebrovascular

accident must be diagnosed by a neurologist and will be defined as an embolic,

thrombotic or hemorrhagic vascular accident or stroke with motor, sensory, or

cognitive dysfunction that persists for longer than 24 hours.37

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A surgical site infection (SSI) will be defined as either superficial or deep infection.

Superficial SSI involves only skin or subcutaneous tissue while a deep SSI extends

deep to the fascial and muscle layers. Reoperation is defined as any return to the

operating room for a procedure related to the fractured hip.

Sample size consideration

The transfusion rate amongst patients with hip fractures is between 6-60%.8-11,35



fractures, for an overall transfusion rate of 49%. The average reduction in


include a total of 338 patients (146 intracapsular hip fractures and 192

extracapsular hip fractures). This study design will achieve 81% power to detect a







Data analysis plan

Descriptive analyses of the patient population will include reporting means (with

standard deviations) for continuous variables and frequencies (with percentages)

for categorical or discrete variables. A chi-square analysis will be conducted to

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evaluate the superiority of tranexamic acid in reducing the rate of transfusion in the

TXA group versus the placebo control group. The analysis and reporting of the

results of the clinical outcomes will follow the CONSORT guidelines (www.consort-

statement.org). We will conduct a multiple logistic regression model to determine if

type of fracture (intertrochanteric or femoral neck), comorbidities, Charlson

comorbidity index, age, time to surgery, and mechanism of injury are related to

transfusion administration. Similarly we will conduct a multiple linear regression

model to determine which variables are related to blood loss. We will also conduct

subgroup analyses to determine if the effect of TXA is modified by fracture type

(intertrochanteric or femoral neck).

Our a priori hypothesis, based on retrospective data,6 is that patients with

intertrochanteric fractures incur more blood loss than femoral neck fractures and

will have a higher rate of transfusion. If these subgroup analyses are

underpowered, the subgroup data will be used to generate further hypotheses to be

tested in the future. All analyses will be performed using Stata 14.0 software (Stata

Corporation, College Station, TX, USA).

Data safety monitoring

The data safety monitoring board (DSMB) has been established to monitor the trial

safety and renew the study biannually. This board is independent of the trial and

free of conflicts with any of the investigation team.

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Discussion

There is clinical uncertainty and a lack of high-quality evidence regarding the use of

TXA in hip fracture patients. Despite its proven efficacy in elective orthopaedic

surgery,25,38 the optimal dosing and timing of TXA administration is still debated.39

Furthermore, the efficacy and side effect profile of TXA in patients with fractures

remains unclear. The immediate goal of this trial is to provide high-quality evidence

that can be used to develop clinical guidelines for use of TXA in patients with hip

fractures.

Patients undergoing elective total joint arthroplasty and elective spine surgery

represent a different population from patients who sustain hip fractures. A larger

percentage of hip fracture patients have significant medical comorbidities, and

many have history of cardiac disease.1 While TXA has demonstrated safety and

efficacy in patients without significant cardiac disease undergoing elective surgery,

there is still debate if TXA will have the same effect in patients with significant

comorbidities.25,39,40 The data investigating TXA in patients with comorbidities is

limited, which has further deterred clinicians from using TXA in patients with hip

fractures. However, the potential benefit of decreasing blood loss and decreasing

the number of transfusions following hip fracture surgery is overwhelming and will

likely result in improved patient outcomes, shorter length of stay and lower cost.

The study investigators believe that the potential benefit of TXA in such patients

outweighs the risk of TXA. The majority of literature regarding TXA has confirmed

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its safety and squelched concerns that its use will result in higher rates of

thrombosis.20,30,32,40,41

Of the five studies investigating the use of TXA in hip fracture patients, four were

randomized controlled trials that were underpowered for detecting significant

differences in thromboembolic events (Table 1).8-11,35 Furthermore, patients were

only followed perioperatively, and differences in six-month and one-year mortality

rates and late-onset complications were not assessed.



TXA Regimen

DVT PPX Sample size

Blood loss (cc)

Transfuse Rate %


Lee 201511


1 g bolus preop


- 6* 1

- 19 4

Emara 20149




640 5* 5

1100 32 0

Zufferey 201010





975 42 0

1178 60 0

Sadeghi and Mehr-Aein 20068



n/a


960 37 0

1484 57 0

Vijay 201335




39* 16 0

91* 40 0

Four out of five studies identified a significant decrease in rate of transfusion in

patients who received TXA compared to those that did not.8-11,35 The largest study,

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with a total of 219 patients, was a cohort study with no randomization.11 While they

found a significant decrease in blood transfusion rate, the study design limits the

interpretation of the results secondary to the potential biases of surgeon and patient

preference. Several studies excluded all patients with preoperative anemia, which

limits the generalizability of their findings.8,9 None of the randomized trials

provided a detailed analysis of total number of patients excluded from the study at

each stage. While the early results from these studies are promising, the overall

validity cannot be confirmed without this information. Similarly, there has yet to be

a large study to perform a complete subgroup analysis to determine the efficacy of

TXA amongst both intracapsular and extracapsular hip fracture patients.

Furthermore, the studies did not follow patients up to 1 year postoperatively, which

is our intention. The extended follow-up period allows for assessment of mortality

at 12 months as well as incidence of unanticipated adverse events following

discharge from the hospital. The most novel characteristic of this study in

comparison to the other studies is that it is powered to detect a significant

difference in blood transfusion rates in both intracapsular and extracapsular hip

fractures. As the hidden blood loss experienced by hip fracture patients is distinct

between these two patterns of hip fractures,6 it is important to demonstrate efficacy

in both groups independently.

Tranexamic acid has the potential to decrease transfusion rates by decreasing blood

loss in patients with hip fractures. Ultimately, this will decreased hospital length of

stay and improve outcomes in the hundreds of thousands of patients with hip

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fractures every year. If the results prove the efficacy of TXA in hip fracture patients,

this study may change the standard of care across the United States for these

patients.

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Funding

This work is supported by a Dr. Thomas Sculco grant and a Dr. Joseph M. Lane grant.

Contributor Statement

Elizabeth B. Gausden: This author revised the study from its original form and condensed the application of the tranexamic acid to one dose in the operating room in order to facilitate the flow of the project. This author made substantial contributions to the planning of data analysis, drafting and revising of the protocol, final approval of the version to be published and agrees to be accountable for all aspects of the work in ensuring that questions related to the accuracy of the work. Matthew R. Garner: This author conceived of the study and designed the first draft of the protocol. He was awarded the Thomas P. Sculco Research Grant and the Joseph M. Lane Research Grant for his proposal of the project. He made substantial contributions to the drafting and revising of the protocol, final approval of the version to be published and agrees to be accountable for all aspects of the work in ensuring that questions related to the accuracy of the work. Ashley Levack: This author made substantial contributions to the study design, modifications of the study to conform to guidelines and for logistics. She will also be involved in patient recruitment, data collection and analysis. This author made substantial contributions to the design of the work, planning of data analysis, drafting and revising of the protocol, final approval of the version to be published and agrees to be accountable for all aspects of the work in ensuring that questions related to the accuracy of the work. Stephen Warner: This author made substantial contributions to the design of the work, planning of data analysis, drafting and revising of the protocol, final approval of the version to be published and agrees to be accountable for all aspects of the work in ensuring that questions related to the accuracy of the work. Andrew Nellestein: This is a research assistant who facilitated IRB submissions and amendments. He is also coordinating the enrollment of patients in the study and working with the orthopaedic trauma team during the process of drug administration. This author made substantial contributions to the design of the work, planning of data analysis, drafting and revising of the protocol, final approval of the version to be published and agrees to be accountable for all aspects of the work in ensuring that questions related to the accuracy of the work.

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Tiffany Tedore: Dr. Tedore is the main anesthesiologist who will be orchestrating the anesthesiologists who administer the drug prior to skin incision. This author made substantial contributions to the design of the work, planning of data analysis, drafting and revising of the protocol, final approval of the version to be published and agrees to be accountable for all aspects of the work in ensuring that questions related to the accuracy of the work. Eva Flores: Dr, Flores is the head of the Medical Orthopaedic Trauma Service (MOTS) who organizes the medical attendings who manage the patients following surgery. This author made substantial contributions to the design of the work, planning of data analysis, drafting and revising of the protocol, final approval of the version to be published and agrees to be accountable for all aspects of the work in ensuring that questions related to the accuracy of the work. Dean G. Lorich: Dr. Lorich is the chief of the orthopaedic trauma service at NYP. This author made substantial contributions to the design of the work, planning of data analysis, drafting and revising of the protocol, final approval of the version to be published and agrees to be accountable for all aspects of the work in ensuring that questions related to the accuracy of the work.

Competing Interest None of the authors have any disclosures pertaining to this research.

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Figure Legend


Table 1: Previously reported outcomes of TXA in hip fracture patients. *drain output. Thromboembolic events include only symptomatic thromboembolic events.

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fracture. Injury. 2011;42(2):133-135.

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9. Emara WM, Moez KK, Elkhouly AH. Topical versus intravenous tranexamic acid as

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36. George DA, Sarraf KM, Nwaboku H. Single perioperative dose of tranexamic acid

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38. Danninger T, Memtsoudis SG. Tranexamic acid and orthopedic surgery-the

search for the holy grail of blood conservation. Ann Transl Med. 2015;3(6):77-

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knee arthroplasty. Clin Orthop Relat Res. 2013;471(1):150-154.

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254x243mm (300 x 300 DPI)

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Appendix

Blood Loss Calculation:Patient’s Blood Volume (PBV) = (k1 x Height3 (m)) + (k2 x Weight (kg)) + k3




follows:

Pre-‐op RBC volume loss = PBV x (Admit Hct – Day of surgery Hct)

Operative RBC volume loss = PBV x (Day of surgery Hct – PACU Hct)

Post-‐operative RBC volume loss= PBX x (PACU Hct – Hct POD#x)If a patient requires a pre-‐op or intraoperative transfusion, the calculation will be adjusted as follows:

Pre-‐op RBC volume loss = [PBV x (Admit Hct – Day of surgery Hct)]+ (No. of Units Transfused x 0.285) / (Admit Hct – Day of surgery Hct) / 2)

Operative RBC volume loss = [PBV x (Day of surgery Hct – PACU Hct)] +)]+ (No. of Units Transfused x 0.285) / (Day of surgery Hct – Post-‐op Hct) / 2

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Spirit Checklist 1.) Title

Tranexamic Acid in Hip Fracture patients: a protocol for a randomized, placebo controlled trial on the efficacy of tranexamic acid in reducing blood loss in hip fracture patients

2.) Trial Registration

a.) Registry set “The Effect of Tranexamic Acid on Transfusion Rates in Intertrochanteric Hip Fractures” Registered August 2014 clinicaltrials.gov: NCT01940536 13083

b.) Data set

Data Category Information Primary registry and trial identifying number

Clinicaltrials.gov NCT01940536

Date of registration in primary registry

August 2014

Secondary identifying numbers

13083

Source of monetary support

Thomas Sculco Grant Joseph Lane Grant

Primary sponsor Thomas P. Sculco Research Grant Secondary sponsor Joseph M. Lane Research Grant Contact for public queries


Contact for scientific queries


Public Title Tranexamic Acid in Hip Fracture patients Scientific title Tranexamic Acid in Hip Fracture patients: a protocol for a

randomized, placebo controlled trial on the efficacy of tranexamic acid in reducing blood loss in hip fracture patients

Countries of recruitment

United States

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mailto:[email protected]

mailto:[email protected]



2

Health condition(s) studied

Blood loss after hip fracture and hip fracture surgery

Intervention Use of intravenous tranexamic acid at the time of hip fracture surgery versus placebo (intravenous 0.9% saline)

Key inclusion and exclusion criteria

Inclusion Adults over the age of 18 Intertrochanteric or femoral neck hip fracture Patients treated surgically with cephalomedullary

nail or hemiarthroplasty Exclusion

Preoperative use of anticoagulant (Plavix, Warfarin, Lovenox)

Documented allergy to tranexamic acid History of deep vein thrombosis or pulmonary

embolus Hepatic dysfunction (AST/ALT > 60) Renal dysfunction (Cr >1.5 of GRR > 30) Active coronary artery disease (event in the past 12

months), history of cerebrovascular accident (CVA) in the past 12 months, or presence of a drug-eluting stent

Color blindness Leukemia or any active cancer Coagulopathy (INR> 1.4, PTT > 1.4x normal,

Platelets < 100,000) Non-displaced femoral neck fractures treated

percutaneously

Study type Interventional Allocation: randomized Intervention model: parallel assignment Masking: Double blinded Primary purpose: preventing blood loss in hip fractures Phase III

Date of first enrollment

Pending

Target sample size 338 Primary outcome (s)

Transfusion of packed red blood cells (PRBC) following hip fracture surgery

Secondary outcome(s)

Calculated blood loss following surgery Adverse events (including transfusion reaction, myocardial infarction, deep vein thrombosis, pulmonary embolus, cerebrovascular accident, re-operation, re-admission, infection, and death)

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3.) Protocol version

The protocol has been modified from the original version listed on clinicaltrials.gov. The 2 changes reflect the inclusion of intracapsular hip fractures to be treated with arthroplasty as well as a revised power analysis and target study size.

4.) Funding The funding for this study is coming from two grants, one from Dr. Joseph Lane and one from Dr. Thomas Sculco.

5.) Roles and Responsibilities a.) Contributorship

Elizabeth B. Gausden: This author revised the study from its original form and condensed the application of the tranexamic acid to one dose in the operating room in order to facilitate the flow of the project. This author made substantial contributions to the planning of data analysis, drafting and revising of the protocol, final approval of the version to be published and agrees to be accountable for all aspects of the work in ensuring that questions related to the accuracy of the work. Matthew R. Garner: This author conceived of the study and designed the first draft of the protocol. He was awarded the Thomas P. Sculco Research Grant and the Joseph M. Lane Research Grant for his proposal of the project. He made substantial contributions to the drafting and revising of the protocol, final approval of the version to be published and agrees to be accountable for all aspects of the work in ensuring that questions related to the accuracy of the work. Ashley Levack: This author made substantial contributions to the study design, modifications of the study to conform to guidelines and for logistics. She will also be involved in patient recruitment, data collection and analysis. This author made substantial contributions to the design of the work, planning of data analysis, drafting and revising of the protocol, final approval of the version to be published and agrees to be accountable for all aspects of the work in ensuring that questions related to the accuracy of the work. Stephen Warner: This author made substantial contributions to the design of the work, planning of data analysis, drafting and revising of the protocol, final approval of the version to be published and agrees to be accountable for all aspects of the work in ensuring that questions related to the accuracy of the work.

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Andrew Nellestein: This is a research assistant who facilitated IRB submissions and amendments. He is also coordinating the enrollment of patients in the study and working with the orthopaedic trauma team during the process of drug administration. This author made substantial contributions to the design of the work, planning of data analysis, drafting and revising of the protocol, final approval of the version to be published and agrees to be accountable for all aspects of the work in ensuring that questions related to the accuracy of the work. Tiffany Tedore: Dr. Tedore is the main anesthesiologist who will be orchestrating the anesthesiologists who administer the drug prior to skin incision. This author made substantial contributions to the design of the work, planning of data analysis, drafting and revising of the protocol, final approval of the version to be published and agrees to be accountable for all aspects of the work in ensuring that questions related to the accuracy of the work. Eva Flores: Dr, Flores is the head of the Medical Orthopaedic Trauma Service (MOTS) who organizes the medical attendings who manage the patients following surgery. This author made substantial contributions to the design of the work, planning of data analysis, drafting and revising of the protocol, final approval of the version to be published and agrees to be accountable for all aspects of the work in ensuring that questions related to the accuracy of the work. Dean G. Lorich: Dr. Lorich is the chief of the orthopaedic trauma service at NYP. This author made substantial contributions to the design of the work, planning of data analysis, drafting and revising of the protocol, final approval of the version to be published and agrees to be accountable for all aspects of the work in ensuring that questions related to the accuracy of the work.

b.) Sponsor contact information “Trial sponsor: Dr. Thomas P. Sculco Research Grant Sponsor’s reference: Contact name: Karla Felix Address: 535 E. 70th St. Telephone: 212 774 2717 Email: [email protected] “Trial sponsor: Dr. Joseph M. Lane Research Grant Sponsor’s reference: Contact name: Karla Felix Address: 535 E. 70th St. Telephone: 212 774 2717

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Email: [email protected] c.) Sponsor and funder: This funder has no role in the design of the study and will not have any role during its execution, analyses, interpretation of the data, or decision to submit results. d.) Committees As this is a single institution study, there is no steering committee other than the authors listed above. 6.) Background and rationale (page 3-6)

a.) Background and rationale: Hip fractures in the elderly remains a pressing public health issue in the United States given the aging population. 1 Hip fractures are associated with numerous adverse events and increased mortality up to one year after the event. 2-5 Elderly patients sustaining hip fractures commonly lose more than one liter of blood and up to 60% will require a blood transfusion. 6 A meta-analysis of 20 studies found a significantly increased risk of post-operative bacterial infection in patients who receive an allogenic blood transfusion in the perioperative period. 7 In addition to the increased risk of infection, patients who require blood transfusion following hip fracture have an increased hospital length of stay. 8 Beyond the risk to the patient from a blood transfusion, an allogenic blood transfusion in the United States was recently estimated to increase costs by $1,731 per admission. 9 Numerous anti-fibrinolytics have been used to limit bleeding in orthopaedic surgery and prevent the need for blood transfusion. 10-14 One of these anti-fibrinolytics, tranexamic acid (TXA) is a synthetic derivative of the amino acid lysine and acts as a competitive inhibitor in the activation of plasminogen to plasmin and therefore prevents the degradation of fibrin. As a result of the CRASH-2 trial15,16 that demonstrated reduced mortality in trauma patients administered TXA the World Health Organization (WHO) added it to the essential drugs list. Currently TXA is not routinely used in patients with hip fractures in the United States, despite its common use worldwide and proven efficacy in reducing blood loss. Numerous studies have investigated the safety and efficacy of TXA in patients undergoing elective orthopaedic surgery, including total joint replacement and spine surgery. 17-22 The consensus from this literature is overwhelmingly in favor of administration of TXA given the decrease in blood loss, transfusion rates, and cost. 23,24 Although few individual studies have found increased risk of thromboembolic events in groups

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receiving TXA, 25,26 larger studies and meta-analyses have uniformly found no increased risk of thrombosis.27,28 Patients who suffer hip fractures frequently have multiple comorbidities making them more susceptible to adverse events from blood loss. 19,20 The most common comorbidities of individuals with hip fractures are congestive heart failure, chronic pulmonary disease and diabetes. 1 Administering TXA to such patients has a potential to offset blood loss, improve patient outcome and lower cost by decreasing the rate of transfusions. 29,30 Five studies, all conducted outside the United States, have reported results of using TXA in hip fracture surgery. 26,31-33 Sadeghi et al34 randomized 67 hip fracture patients to receive either placebo injection or intravenous tranexamic acid at the time of surgery. They found a significantly lower volume of blood loss (652 ± 228 mL vs. 1108 ± 372 mL, P < 0.003) and shorter hospital stays (4.3 ± 1.6 days vs. 5.8 ± 1.5 days, p< 0.05). Vijay et al. 33 also reported significantly reduced transfusion rates in the TXA arm of their clinical trial. In a retrospective cohort study, Lee et al31 reported similar results, a transfusion rate three times lower in patients who received TXA prior to hemiarthroplasty surgery. In a separate randomized controlled trial that compared intravenous administration of TXA to topical TXA administration as well as placebo in hip fracture patients undergoing hemiarthroplasty, both of the TXA groups experienced less blood loss. 26 While this study found a significant reduction in blood loss and transfusion rates in both TXA groups, they found a higher incidence of thromboembolic events in the intravenous TXA group. Of the five studies investigating the use of TXA in hip fracture patients, four were randomized controlled trials that were underpowered for detecting significant differences in thromboembolic events (Table 1). Furthermore, patients were only followed perioperatively, and differences in six-month and one-year mortality rates and late-onset complications were not assessed.

In designing this study, we concluded that hip fracture patients are both likely to experience significant blood loss and are susceptible to the adverse effects of blood loss making them an ideal population to target for a randomized controlled trial of the effects of perioperative TXA on blood loss.

b.) Choice of comparators The choice of intravenous saline as a control in this study is to replicate the standard of care at this time in the United States, which is no drug intervention for preventing blood loss in hip fracture surgery.

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7.) Objective (line 158-160)

Hypothesis: We hypothesize that administration of TXA will decrease blood loss in hip fracture patients and lower the rate of allogenic blood transfusion.

Objective To investigate the hypothesis that TXA will lower blood loss and transfusion rate in patients with hip fractures.

8.) Trial Design (line 164-181) This trial is designed as a stratified randomized, placebo-controlled, surgeon and patient blinded single-institution trial with four parallel groups and a primary endpoint of blood transfusion in the immediate postoperative hospitalization following hip fracture surgery. Randomization will be performed as block randomization with 1:1 allocation for both the intracapsular and the extracapsular hip fracture groups. 9.) Study Setting (line 204-205) Adult (over 18 years of age) patients presenting to a single urban tertiary care center in with a hip fracture. All patients with hip fractures at this institution are admitted to the medical orthopaedic trauma service (MOTS) after presenting through the emergency room. 10.) Eligibility criteria (line 222-246)

Inclusion criteria Patients admitted through the emergency room or transferred into our institution and who meet the following criteria will be included in the study:

Adults over the age of 18 Intertrochanteric or femoral neck hip fracture Patients treated surgically with cephalomedullary nail or hemiarthroplasty

Exclusion criteria Patient who meet any one or more of the following criteria will be excluded from the study:

Preoperative use of anticoagulant (clopidogrel, enoxaparin, warfarin, argatroban, rivaroxaban, fondaparinux)

Documented allergy to tranexamic acid History of deep vein thrombosis or pulmonary embolus Hepatic dysfunction (AST/ALT > 60)

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Renal dysfunction (Cr >1.5 of GRR > 30) Active coronary artery disease (event in the past 12 months), history of

cerebrovascular accident (CVA) in the past 12 months, or presence of a drug-eluting stent

Color blindness Leukemia or any active cancer Coagulopathy (INR> 1.4, PTT > 1.4x normal, Platelets < 100,000) Non-displaced femoral neck fractures treated percutaneously

11.) Interventions (line 267-301)

a.) Interventions The patients randomized to the treatment arm will receive 1 gram of intravenous tranexamic acid infused at the time of surgical incision. Those assigned to the placebo group will receive an infusion of saline at the time of surgical incision. Patients with intertrochanteric hip fractures will be treated with a long, intramedullary hip screw implant with a trochanteric start point. Patients with displaced femoral neck fractures will be treated with a cemented or non-cemented hemiarthroplasty or total hip arthroplasty at the discretion of the treating surgeon. Blood transfusion criteria will remain consistent with hospital standards (Hb<8 g/dL or symptomatic anemia) as determined by an independent, blinded medical team who will follow the patient throughout the hospital stay and number of blood transfusions received will be documented upon patient discharge. Hematocrit and hemoglobin will be recorded in all patients while they are in the hospital, for a minimum of 2 days postoperatively. Further monitoring will be conducted based on need as determined by the independent medical team. Estimated blood volume will be calculated from these values and used to estimate blood loss (Appendix 1 All patients will be permitted to weight-bear as tolerated post-operatively and deep vein thrombosis (DVT) prophylaxis will be standardized. All enrolled patients will receive subcutaneous heparin, 5000 units every 8 hours beginning upon admission until 12 hours prior to surgery and restarting 6 hours after surgery. Calf mechanical compression devices will also be utilized during the inpatient stay and will remain on at all times with the exception of physical therapy sessions. Following discharge from the hospital patients will be given aspirin 325 mg twice daily for DVT prophylaxis for a total of 6 weeks. Diagnostic studies to assess for thromboembolic events (i.e. DVT, pulmonary embolism, and stroke) will be ordered only if the patient develops clinical signs or symptoms that justify their use.

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b.) Modifications As the administration of TXA or placebo will occur at one time point in the operating room at the time of skin incision, there will be no criteria for modifying or discontinuing the treatment allocation following surgery. If a patient becomes unstable, experiences a sudden change in vital signs, drop in blood pressure or increase in heart rate, during the admission of the drug, the drug will be discontinued at that time. The patient will still be analyzed on an intention-to-treat basis. c.) Adherence We do not anticipate adherence as an issue since the administration of the intervention will be performed by the anesthesiologist at the time of skin incision. d.) Concomitant care No concomitant interventions will be permitted during the trial.

12.) Outcomes (line 241-275) Primary Outcome The primary outcome of the study will be the rate of blood transfusion in the postoperative period until time of discharge. Patients will be monitored with serial hemoglobin and hematocrit measurements and their vital signs will be recorded as per the standard of care to determine the need for blood transfusion. Secondary Outcome The secondary study outcomes include the calculated blood loss (calculated based on validated methods as outlined in Appendix 1), frequency of adverse events (including transfusion reaction, myocardial infarction, deep vein thrombosis, pulmonary embolus, cerebrovascular accident, re-operation, re-admission, infection, and death).

13.) Participation timeline (Figure 1)

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Figure 1: Study Design (TXA: tranexamic acid; PRBC: packed red blood cells) 14.) Sample size consideration (line 335-348) The transfusion rate amongst patients with hip fractures is between 6-60%.8-11,35



fractures, and an overall transfusion rate of 49%. The average reduction in


include a total of 338 patients, 146 intracapsular hip fractures and 192

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extracapsular hip fractures. This study design will achieve 81% power to detect a







15.) Recruitment (line 203-218) Adult (over 18 years of age) patients presenting to a single tertiary care center with a hip fracture. All patients with hip fractures at this institution are admitted to the medical orthopaedic trauma service (MOTS). Prior to surgery, patients older than 75 years of age, or those with medical comorbidities will be optimized by the general medical service prior to surgery. All potentially eligible patients will be screened and documented as (1) eligible and included, (2) eligible and missed, or (3) excluded. The study coordinator will obtain informed consent for participation in the study using the approved IRB Informed Consent forms. All patients will provide written informed consent and will understand that by entering in the study they may receive placebo and not tranexamic acid. Participation in the study is voluntary and their decision to participate will not affect any other aspect of their care in case of refusal. Patients will have the right to withdraw from the study at any point. 16.) Allocation (lines 257-265) a.)Sequence generation

After the patient consents and is enrolled in the study, the institution’s investigational pharmacist will assign the patient to either receive TXA or placebo via computer generated randomization. Patients will be randomized in blocks of 20. b.)Concealment The packaging of the injections will be performed by the investigational pharmacy and will be identical for both TXA and placebo. All clinicians, except for the pharmacist, will remain blinded until the data is analyzed.

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c.)Implementation After the patient consents and is enrolled in the study, the institution’s investigational pharmacist will perform the randomization and assign the patient to either receive TXA or placebo. Patients will be randomized in blocks of 20. The packaging of the injections will be performed by the investigational pharmacy and will be identical for both TXA and placebo. All clinicians, except for the pharmacist, will remain blinded until the data is analyzed. 17.) Blinding (lines 257-265) a.) Masking The patient, the surgeon, the anesthesiologist and the hospitalist will all be blinded to the assignment of intervention. Therefore, the decision to transfuse a patient will be made independent of the intervention. b.)Emergency unblinding Unblinding of intervention assignment will only be allowed in exceptional circumstances if knowlegde of treatment is crucial to further management of the patient. An example of this is if a patient becomes unstable during drug administration in the operating room. The allocation will not be disclosed to the surgeon or the patient or other study personnel who are not directly treating the patient at that time. All code breaks will be reported and documented. 18.) Methods (line 248-255) a.) Data collection methods Baseline assessment includes sex, birth date, height and weight, mechanism of injury, time from injury to presentation to the emergency room, American Society of Anesthesiologists (ASA) classification, Charlson Comorbidity Index, comorbidities including diabetes, peripheral vascular disease, dementia, hypertension, and history of smoking. The hemoglobin and hematocrit will be recorded at the time of admission and on the morning of surgery, if applicable. Blood transfusion criteria will remain consistent with hospital standards (Hb<8 g/dL or symptomatic anemia) as determined by an independent, blinded medical team who will follow the patient throughout the hospital stay and number of blood transfusions received will be documented upon patient discharge. Hematocrit and hemoglobin will be recorded in all patients while they are in the hospital, for a minimum of 2 days postoperatively. Further monitoring will be conducted based on need as determined by the independent medical team. Estimated blood volume will be calculated from these values and used to estimate blood loss. After discharge, patients will undergo routine follow-up at 2wk, 6wk, 3mo, 6mo and 1 yr after surgery. Each will be questioned regarding possible adverse events that

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may have occurred since their previous visit. Further, electronic inpatient records will be reviewed at the 1 year follow-up appointment to determine if any undocumented adverse events may have occurred and patients will also be called at that time if they fail to attend their 1 year follow-up appointment. 19.) Data Management All data will be entered electronically into a Microsoft Excel database that will be password protected on an institutional computer. Any identifying health information will be removed or, if needed, coded when data is summarized in a spreadsheet format for statistical analysis purposes. 20.) Statistical Analysis (lines 351-370) a.) Outcomes Descriptive analyses of the patient population will include reporting means (with standard deviations) for continuous variables and frequencies (with percentages) for categorical or discrete variables. Following the descriptive analysis, a chi-square analysis will be conducted to evaluate the superiority of tranexamic acid in reducing the rate of transfusion versus the placebo control group. The analysis and reporting of the results of the clinical outcomes will follow the CONSORT guidelines (www.consort-statement.org). We will conduct a multiple logistic regression model to determine if type of fracture (intertrochanteric or femoral neck), comorbidities, Charlson comorbidity index, age, time to surgery, and mechanism of injury are related to transfusion administration. Similarly we will conduct a multiple linear regression model to determine if patient comorbidities, age, time to surgery, and mechanism of injury are related to blood loss. We will also conduct subgroup analyses to determine if the effect of TXA is modified by fracture type (intertrochanteric or femoral neck). All analyses will be performed using Stata 14.0 software (Stata Corporation, College Station, TX, USA). b.)Additional analyses Our a priori hypothesis, based on retrospective data, 6 is that patients with intertrochanteric fractures incur more blood loss than femoral neck fractures and will have a higher rate of transfusion. If these subgroup analyses are underpowered, the subgroup data will be used to generate further hypotheses to be tested in the future.

c.)Analysis population and missing data

Not applicable- as there will largely be no compliance breakdowns given that the intervention is a one-time administration of a drug during a surgical procedure.

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Should a patient consent and be enrolled in the trial and decide to unenroll prior to drug administration they will not be taken into account for the analysis. In the event of missing data, ie missing hemoglobin levels postoperatively, we do not plan on using an imputing method but rather analyzing only the data collected given that these missing data points will likely be randomly arranged throughout the study. 21.) Methods: Monitoring (lines 372-375) a.)Formal Committee The data safety monitoring board (DSMB) has been established to monitor the trial and renew the study biannually. This board is independent of the trial and free of conflicts with any of the investigation team. b.)Interim analysis Data will be analyzed every six months throughout the study by the study investigators.

22.) Harms (lines 312-334)

The secondary outcomes of this study including adverse outcomes and events. These events will be monitored for after the subject has provided consent and has been enrolled in the study. If a subject experiences an adverse event after the informed consent document is signed (entry) but the subject has not yet received the intervention in the operating room, the event will be reported as not related to study drug. Adverse events during hospitalization will be recorded and patients will be asked about adverse events during their follow-up appointments. Adverse events will be reported to the DSMB as well.

23.) Auditing (lines 372-375)

The data safety monitoring board (DSMB) has been established to monitor the trial and renew the study biannually. This board is independent of the trial and free of conflicts with any of the investigation team.

24.) Research ethics approval (lines 77-80)

The protocol and site specific consent forms have been approved by our institutional review board (IRB) with respect to scientific content and compliance with applicable research and human subjects regulations.

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25.) Protocol amendments

See attached.

26.) Consent or assent (lines 214-218)

a.) Consent

Informed consent will be obtained by research associated personnel at the time of patient presentation. Written consent will be obtained from the patient when possible, or from the health care proxy if the patient is unable to consent for themselves.

Each patient will be provided the written informed consent form to read and will have the opportunity to ask any questions related to the research protocol/methods to the researcher obtaining consent.

b.)Ancillary studies

not applicable

27.) Confidentiality

Data is only recorded electronically and will be kept in the Principal Investigator’s locked office on a password-protected computer. Only research personnel will have access to electronic files kept in the PIs locked office, and only research personnel will know the password needed to access research files. Patients will be numbered sequentially on the data collection sheet. Numbers will be associated with names and medical records, which will be stored in a separate file by the research coordinator.

28.) Declaration of interests

None of the authors of the study or study personnel have any financial relationships

related to the nature of the study.

29.) Access to data

n/a – single institution study

30.) Ancillary and post-trial care (lines 436)

n/a- this is a privately funded study with no study-specific insurance policy.

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31.) Dissemination policy

a.) Trial results

The results from the trial will be reviewed by the authors and following editing from each member a manuscript will be prepared for publication in a peer reviewed journal. b.)Authorship

The authors currently listed will be included as authors on the final manuscript submitted for publication according to their maintained involvement. New authors will be required by meet guidelines for authorship as stated previously. c.)Reproducible research

n/a

32.) Informed consent material

see attached

33.) Biological specimens

n/a

References







Emerg Surg. 2015.

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2001;15(1):34-39.



2015;46(4):703-708.


Surg Br. 2006;88(8):1053-1059.



Trauma. 2003;54(5):908-914.



230.






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696.


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101, 1101.e1-2.

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Anaesth. 2004;51(1):31-37.












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2014;186(1):318-327.



Bone Joint J. 2015;97-B(4):458-462.

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2015;46(10):1978-1982.









Appendix






follows:

Pre-op RBC volume loss = PBV x (Admit Hct – Day of surgery Hct) Operative RBC volume loss = PBV x (Day of surgery Hct – PACU Hct)

If a patient requires a pre-op or intraoperative transfusion, the calculation will be adjusted as follows:

Pre-op RBC volume loss = [PBV x (Admit Hct – Day of surgery Hct)]+ (No. of Units Transfused x 0.285) / (Admit Hct – Day of surgery Hct) / 2)Operative RBC volume loss = [PBV x (Day of surgery

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Hct – PACU Hct)] +)]+ (No. of Units Transfused x 0.285) / (Day of surgery Hct – Post-op Hct) / 2

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Documents

Tranexamic Acid in Hip Fracture Patients: a protocol for a ...bmjopen.bmj.com/content/bmjopen/6/6/e010676.draft-revisions.pdf · For peer review only 5 95 Of the five studies investigating