Rivaroxaban Plus Acetylsalicylic Acid Versus Standard of Care for Arterial and Venous Cardiovascular Prevention After Hip Fracture Surgery in Patients With Myocardial Injury: a Pilot Randomized Trial
Phase: PHASE3
Conditions: Hip Fracture Surgery, Cardiovascular Prevention, Venous Thromboembolism (VTE)
Sponsor: McMaster University

 
 
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Rivaroxaban plus Acetylsalicylic Acid Versus Standard of Care for Arterial 
and Venous Cardiovascular Prevention After Hip Fracture Surgery in 
Patients with Myocardial Injury: a Pilot Randomized Trial (HIPSTER-Pilot) 
 
Protocol Number: HIPSTER-2024 
Sponsor: Dr. Federico Germini, MD, McMaster University 
Name and title of the person(s) authorized to sign the protocol: Dr. Federico Germini, MD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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CONFIDENTIAL 
 
DECLARATION AND SIGNATURE PAGE 
Title: Rivaroxaban plus Acetylsalicylic Acid Versus Standard of Care for Arterial and Venous 
Cardiovascular Prevention After Hip Fracture Surgery in Patients with Myocardial Injury: a 
Pilot Randomized Trial (HIPSTER-Pilot) 
 
The study will be conducted in accordance with the International Council for Harmonisation  
Guidelines for Good Clinical Practice and applicable local and federal regulations. The study will 
not commence without the prior written approval of a properly constituted Research Ethics 
Board (REB), Institutional Review Board (IRB) or Independent Ethics Committee (IEC). No 
changes will be made to the study protocol without the prior written approval of the Sponsor 
and the REB, IRB or IEC, except where necessary to eliminate an immediate hazard to the 
subjects. 
 
Sponsor Signature: _____________________________               __________________________ 
        Dr. Federico Germini, MD 
 
       Date 
 
 
I have read, understood and agree to abide by all the conditions and instructions contained in 
this protocol. 
Responsible Investigator of the local study centre: ____________________________________ 
 
 
 
 
 
 
 
Name, Title 
___________________________      _________________________    ______________________ 
Institution 
 
 
          Signature 
 
 
   Date 
 

 
 
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ABSTRACT .................................................................................................................................. 4 
LIST OF ABBREVIATIONS ............................................................................................................. 5 
SYNOPSIS.................................................................................................................................... 7 
INTRODUCTION .......................................................................................................................... 8 
METHODS ................................................................................................................................. 17 
TRIAL REGISTRATION ................................................................................................................. 30 
FUNDING ................................................................................................................................... 30 
REFERENCES .............................................................................................................................. 31 
TABLES ...................................................................................................................................... 36 
FIGURES .................................................................................................................................... 37 
 
 

 
 
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Abstract 
Background: A third of patients undergoing surgery for a hip fracture develop a myocardial 
injury (i.e., an elevated troponin measurement), and these patients are at substantial risk of 
death and morbidity. Current prophylaxis strategies focus on preventing venous 
thromboembolism (VTE); however, arterial events are more common and carry a poor 
prognosis. The association of acetylsalicylic acid (ASA) 75-100 mg once daily and rivaroxaban 
2.5 mg twice a day (the regimen used in the COMPASS trial) might prevent both VTE and 
arterial cardiovascular events. 
Objective: Among patients who have undergone hip fracture surgery and have evidence of 
myocardial injury, to explore the feasibility of a randomized controlled trial (RCT) comparing 
rivaroxaban 2.5 mg twice daily + low-dose ASA (75-100 mg) for 90 days, with standard VTE 
thromboprophylaxis for 30 days, for prevention of major cardiovascular events. 
Methods: The HIPSTER-Pilot is a multicenter, international, open-label, pilot RCT with blinded  
outcome adjudication. A total of 100 participants aged ≥45 years who received hip fracture 
surgery and experienced a myocardial injury will be randomized to receive either rivaroxaban 
2.5 mg twice daily plus ASA 75-100 mg daily for 90 days or standard VTE prophylaxis with an 
anticoagulant for 30 days. The primary feasibility outcome will be the recruitment rate. Other 
feasibility measures include completeness of follow-up and adherence to the treatment. 
Exploratory clinical outcomes will be assessed.  
Conclusion: This pilot trial will provide information on the feasibility of conducting a larger RCT 
to evaluate the efficacy and safety of the COMPASS regimen for preventing arterial and venous 
thrombotic events after hip fracture surgery in patients who have had myocardial injury. The 
results of this feasibility study will inform the design of the full-scale trial. 
Funding: Canadian Venous Thromboembolism Research Network 
Registration: This study will be registered on ClinicalTrials.gov. 
 

 
 
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List of abbreviations 
AE: Adverse reaction 
ASA: acetylsalicylic acid 
ASH: American Society of Hematology 
BIMS: bleeding associated with mortality after non-cardiac surgery 
BID: bis in die (twice daily) 
CanVECTOR: Canadian Venous Thromboembolism Research Network 
CI: confidence interval 
CRF: case report form 
CV: cardiovascular 
CYP3A4: Cytochrome P450 3A4 
DOAC: direct oral anticoagulant 
DVT: deep vein thrombosis 
EDI: equity, diversity, and inclusion 
FTE: full-time equivalent 
HIPSTER: HIP fracture Surgery Thromboembolism prevention Randomized controlled trial 
HR: hazard ratio 
ICH-GCP: International Council for Harmonisation- Good Clinical Practice 
ISTH: International Society on Thrombosis and Haemostasis 
LMWH: low molecular weight heparin 
MI: myocardial infarction 
MINS: myocardial injury after non-cardiac surgery 
NICE: National Institute for Health and Care Excellence 
OD: once daily 
OR: odds ratio 
PE: pulmonary embolism 
P-gp: P-glycoprotein 
PI: principal investigator 
POD: postoperative day 
PreOD: preoperative day 
RCT: randomized controlled trial 
REB: Research Ethics Board 
REDCap: Research Electronic Data Capture 

 
 
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SAE: Serious adverse reaction 
SOP: standard operating procedure 
SUADR: serious unexpected adverse drug reactions 
UFH: unfractionated heparin 
VTE: venous thromboembolism 
 
 

 
 
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Synopsis 
Title 
Rivaroxaban plus acetylsalicylic acid versus standard of care for arterial and venous 
cardiovascular prevention after hip fracture surgery in patients with myocardial injury: a 
pilot randomized trial (HIPSTER-Pilot) 
Study objective 
To determine the feasibility of a randomized controlled trial (RCT) on the use of 
rivaroxaban 2.5 mg twice daily + low-dose acetylsalicylic acid (ASA 75-100 mg) compared 
with standard thromboprophylaxis for cardiovascular prevention after surgery for hip 
fracture in patients with myocardial injury. 
Study design 
Multicenter, international, pilot RCT, open label, with blinded outcome adjudication. 
Sample size 
100 participants. 
Study population 
Inclusion criteria: 
- 
Age ≥45 years, 
- 
Received surgery for a hip fracture due to a low-energy mechanism, and 
- 
myocardial injury (i.e., an elevated troponin measurement) 
Main exclusion criteria: 
- 
Contraindications to the use of rivaroxaban or ASA; 
- 
Indication for full dose anticoagulation; or for dual antiplatelet therapy or a 
P2Y12 inhibitor; 
- 
Patients already on rivaroxaban 2.5 mg twice daily + ASA before the fracture 
Bleeding diathesis;Previous participation in HIPSTER trial. 
Study intervention 
Rivaroxaban 2.5 mg twice daily + low-dose ASA (75-100 mg) for 90 days or standard 
prophylaxis for venous thromboembolic events for 30 days. 
Outcomes 
The primary feasibility outcome will be recruitment rate. Other feasibility measures 
include completeness of follow-up and adherence to the treatment. 
We will also undertake exploratory measurement of clinical outcomes. 
Follow-up 
In hospital and at 30 and 90 days after randomization. 
 
 
 

 
 
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1. Introduction 
1.1 Background and rationale 
More than 1.6 million persons worldwide and almost 30,000 Canadians experience hip 
fractures each year.1,2 The incidence of hip fractures is expected to increase dramatically, from 
1.6 million cases in 2000 to an estimated 6.3 million by 2050, largely due to an aging global 
population.3 A study analyzing postoperative mortality from hip fracture surgeries in Denmark 
(2000-2014) using national health registries revealed mortality rates of 9.6% at 30 days, 16.2% at 
90 days, and 26.8% at one year, with stable risk over time.4 The HIP ATTACK-1 trial, a multi-center 
study across 69 hospitals in 17 countries, enrolled 2970 patients to compare the outcomes of 
accelerated surgery (within 6 hours of diagnosis) versus the standard of care for hip fracture. 5 
After 90 days from the surgery, the all-cause mortality across both groups was 9.5%. The 
following major vascular complications occurred within 90 days: vascular death 5.5% of patients, 
myocardial infarction (MI, fatal and non-fatal) 5.5% of participants, and myocardial injury not 
fulfilling the universal definition of myocardial infarction 30.3% of patients. In contrast, the rate 
of venous thromboembolism (VTE) was low, at 1.1%. 
Despite the high frequency of arterial cardiovascular (CV) events and their poor prognosis, 
research has mainly focused on preventing VTE, the combination of deep vein thrombosis (DVT) 
and pulmonary embolism (PE), rather than on CV morbidity and mortality in general. Patients 
with hip fractures face a risk of VTE driven by a combination of factors, including regional tissue 
injury from the fracture and the surgery, comorbidities, prolonged immobility, and systemic 
complications associated with the intervention. In the absence of thromboprophylaxis, the 

 
 
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estimated risk of PE and proximal DVT is about 1% and 3%, respectively.67Pharmacological 
thromboprophylaxis has been shown to significantly reduce this risk, with relative risks of 0.49 
[95% confidence interval (CI) 0.33-0.72] for symptomatic PE and 0.51 (95% CI 0.38-0.69) for 
symptomatic proximal DVT, although there is very low certainty around these estimates due to 
risk of bias and imprecision. These benefits must be weighed against the bleeding risk. The 
baseline risk of major bleeding events in this population is approximately 5%.8 Pharmacological 
prophylaxis can increase this risk by an estimated 24% (relative increase, 95% CI 12-37%; very 
low certainty evidence due to risk of bias and indirectness or imprecision).7,9 
The American Society of Hematology (ASH) guidelines recommend using low-molecular-
weight heparin (LMWH) or unfractionated heparin (UFH) for VTE prophylaxis in hip surgery 
patients, based on very low certainty of evidence.10 The National Institute for Health and Care 
Excellence (NICE) guidelines propose offering VTE prophylaxis for a duration of one month to 
individuals with fragility fractures of the pelvis, hip, or proximal femur, provided the risk of VTE 
exceeds the risk of bleeding.11 Suggested prophylactic options include LMWH (initiated 6 to 12 
hours postoperatively), or fondaparinux sodium (administered 6 hours postoperatively, 
contingent on low bleeding risk).11 Consideration should be given to preoperative VTE 
prophylaxis in cases of delayed surgery beyond the day following admission. In this population, 
there is a lack of trials that directly compare these agents with each other, or  with alternatives 
such as the antiplatelet agent, acetylsalicylic acid (ASA) or direct oral anticoagulants (DOACS) 
inhibiting thrombin (dabigatran) or factor Xa (rivaroxaban, apixaban, and edoxaban).10 

 
 
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A few trials have evaluated the effects on venous or arterial thrombotic/ischemic events 
of antithrombotic agents other than LMWH or fondaparinux (i.e., antiplatelets or other 
anticoagulants) in this patient population. In the Pulmonary Embolism Prevention (PEP) trial, a 
total of 13,356 patients with hip fractures were randomized to receive ASA or placebo for the 
prevention of venous and arterial thrombotic events.9 The study drug was started before the 
surgery, as soon as possible after admission. Concomitant discretionary use of UFH or LMWH 
occurred in 43.8% of participants. VTE occurred in 105 participants (1.6%) in the intervention 
group and 165 (2.5%) in the control group, with a hazard ratio (HR) of 0.64 (95% CI 0.50-0.81). 
Fatal and non-fatal MI occurred in 105 (1.6%) assigned to ASA and 79 (1.2%) assigned to placebo 
(HR 1.33; 95% CI 1.00-1.78). There was no statistically significant difference in the risk of stroke, 
death from vascular or non-vascular causes between the two groups. The incidence of major 
bleeds was similar, although there was an increase in postoperative bleeds requiring 
transfusions, occurring in 197 (2.9%) patients assigned ASA and 157 (2.4%) assigned placebo, with 
an absolute (standard error) increase of 6 (3) per 1000 and a relative increase of 24% (95% CI 1; 
53). 
The POISE-2 and MANAGE studies were international, randomized, blinded, placebo-
controlled trials that investigated the efficacy of perioperative or postoperative antithrombotic 
therapy for the prevention of CV events in non-cardiac surgery.12,13 The POISE-2 trial had a 2-by-
2 factorial design, assessing the effect of ASA versus placebo and clonidine versus placebo in 
patients undergoing non-cardiac surgery. The study included 10,010 patients at risk for vascular 
complications, divided into an initiation stratum (n=5,628, not taking ASA before the trial) and a 

 
 
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continuation stratum (n=4,382, taking ASA before the trial). Patients in the initiation stratum 
received a 200 mg dose of ASA/placebo just before surgery, followed by 100 mg daily for 30 days. 
Those in the continuation stratum had to stop ASA at least three days before randomization, and 
they were then given ASA/placebo for seven days after the surgery before resuming their regular 
regimen. We don’t have details about the proportion of participants with a hip fracture, but 7.2% 
required urgent surgery, and 38.7% of surgeries were classified as orthopedic procedures. The 
primary composite outcome of death or nonfatal MI showed an HR of 0.99 (95% CI 0.86-1.15) 
between the ASA and placebo groups. Secondary and tertiary outcomes, including overall death, 
CV death, nonfatal MI, nonfatal stroke, and a combination of these, also showed no statistically 
significant benefit from ASA, with HRs close to 1. There was no statistically significant difference 
in life-threatening bleeding events, but major bleeding occurred in 230 (4.6%) participants on 
ASA and 188 (3.8%) on placebo, with an HR of 1.23 (95% CI 1.01-1.49). The definition of major 
bleeding represented severe bleeding.  
 The MANAGE trial investigated the effect of dabigatran on major vascular complications 
in patients who experienced myocardial injury after non-cardiac surgery (MINS).12 Participants 
(≥45 years, within 35 days of MINS diagnosis) were given either dabigatran (110 mg twice daily) 
or placebo for a median duration of 474 days. The primary outcome was a composite of major 
vascular events that included vascular mortality and non-fatal MI, non-hemorrhagic stroke, 
peripheral arterial thrombosis, amputation, and symptomatic VTE. The median number of days 
from surgery to dabigatran initiation was six, 38.2% of participants received orthopedic surgery. 
Dabigatran significantly reduced the risk of major vascular events, with an HR of 0.72 (95% CI 

 
 
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0.55-0.93). The HR for the primary safety outcome (a composite of life-threatening, major, and 
critical organ bleeding) was 0.92 (95% CI 0.55-1.53). Therefore, the MANAGE trial highlighted the 
potential for oral anticoagulation to prevent CV events in the postoperative period. Fifty-eight 
percent of patients (in both groups) were on ASA before randomization, and, during the study 
period, 74% took ASA or a P2Y12 inhibitor, which suggest that a combination of anticoagulation 
and ASA could be safe long-term in patients with a recent history of major non-cardiac surgery. 
The participants’ mean age in MANAGE was 70 years and patients were excluded if their 
estimated glomerular filtration rate was <35 mL/min. 
Moving outside the postoperative setting, the COMPASS trial was a randomized 
controlled trial (RCT) that compared the efficacy and safety of rivaroxaban 2.5 mg twice daily (bis 
in die, BID) plus ASA  100 mg once daily (OD) - from now on referred to as the “COMPASS 
regimen” -, rivaroxaban 5 mg BID, or ASA 100 mg OD for secondary CV prevention in 27,395 
participants with stable atherosclerotic vascular disease.14 The primary outcome was a composite 
of CV death, stroke, or MI. The trial was stopped early for efficacy, with the primary composite 
outcome occurring in 4.1% of participants receiving the COMPASS regimen compared with 5.4% 
in those receiving ASA alone, with an HR of 0.76 (95% CI 0.66-0.86). The COMPASS regimen 
resulted in increased major bleeding events [International Society on Thrombosis and 
Haemostasis (ISTH) definition in non-surgical patients]15 compared with ASA alone, 3.1% vs. 1.9%; 
HR 1.70 (95% CI 1.40-2.05). Notably, a mortality benefit was seen with the COMPASS regimen, 
3.4% vs. 4.1%; HR 0.82 (95% CI 0.71-0.96).14 The trial was not designed to compare the COMPASS 
regimen with rivaroxaban 5 mg BID on its own. However, rivaroxaban 5 mg BID is a dose that can 

 
 
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be considered equivalent to the 10 mg OD dose currently used for VTE prophylaxis. This 
comparison is of interest to us, as it can provide an indirect estimate of the possible benefits of 
the use of the COMPASS regimen as compared with rivaroxaban alone for thromboprophylaxis 
and CV prevention in people undergoing surgery for hip fracture. We extrapolated crude odds 
ratios (ORs) for this comparison using published data from the COMPASS trial, reported in Figure 
1. This analysis suggests that the COMPASS regimen, compared with rivaroxaban 5 mg BID, 
reduced the likelihood of CV complications such as death, stroke, or MI, as indicated by an OR of 
0.84 (95% CI 0.73-0.96), and death from any cause, with an OR of 0.85 (95% CI 0.73-0.99). There 
was a potential trend toward reduced CV mortality (OR 0.81, 95% CI 0.66-1.01) and VTE (OR 0.69; 
95% CI 0.41-1.15). However, the COMPASS regimen increased the risk of minor bleeding events 
(OR 1.14; 95% CI 1.03-1.26), and there was a potential trend for an increase in major bleeding 
(OR 1.13, 95% CI 0.95-1.34).  
The COMPASS regimen was used in the postoperative setting in the VOYAGER PAD trial, 
an RCT that compared the efficacy and safety of the COMPASS regimen with ASA alone in a 
blinded manner in patients with peripheral artery disease who had undergone lower-extremity 
revascularization.16 The three-year incidence of the primary composite outcome of acute limb 
ischemia, major amputation, MI, ischemic stroke, or CV death was 17.3% in the intervention 
group and 19.9% in the control group (HR 0.85; 95% CI 0.76-0.96). There was an increase in major 
bleedings as defined using the ISTH criteria, the incidence at 3 years being 5.9% with rivaroxaban 
and 4.1% with placebo (HR 1.42; 95% CI 1.10-1.84).16 The VTE rate in participants on the 
COMPASS regimen was 0.8%.16 The COMPASS regimen is approved for the prevention of stroke, 

 
 
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myocardial infarction (MI) and cardiovascular (CV) death; and the prevention of acute limb 
ischemia and mortality in patients with coronary artery disease (CAD) and/or peripheral artery 
disease (PAD) at high-risk with small regulatory differences in Canada, Europe, and the United 
States.17–19 
The benefits of the COMPASS regimen observed in the COMPASS and VOYAGER trials may 
extend to the high-risk population of people with hip fractures. Compared with the current 
standard of care for VTE prophylaxis, the COMPASS regimen might offer comparable or better 
VTE prevention, prevention of arterial CV events, improvement in quality of life and treatment 
adherence because of oral administration instead of daily subcutaneous injection of LMWH (the 
current standard of care according to guidelines), as well as cost savings over injectables. 
Considering the clinical characteristics of this patient population, including older age, 
comorbidities such as dementia, and the need for urgent surgical treatment, it is crucial to 
determine the feasibility of enrolling and retaining such patients in a trial. Additionally, a 
feasibility study will allow us to evaluate the acceptability of using the COMPASS regimen after 
surgery, identifying potential compliance issues or concerns. Our goal is to establish a new, more 
effective and comprehensive approach to thrombosis prevention in hip fracture patients with 
myocardial injury by simultaneously preventing venous and arterial CV events. 
Before designing this study, we conducted a survey to assess physician practices 
surrounding VTE prophylaxis for patients undergoing hip fracture surgery to define the current 
standard of care. Unpublished data from the survey showed that of the 204 physicians from 28 
countries who completed the survey, 175 (85.8%) were responsible for prescribing postoperative 

 
 
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VTE prophylaxis and 172 (84.3%) supported the need for an RCT in this field. LMWH was the most 
frequently used VTE prophylaxis regimen (58.8%), DOACs (rivaroxaban or apixaban) (25.0%), ASA 
alone (9.8%), and sequential treatments (LMWH followed by either an oral anticoagulant or ASA, 
37.7%). Fondaparinux, dabigatran, and other regimens were less commonly used. As expected, 
the COMPASS regimen is not used for VTE prophylaxis.  
There was some variability in the duration of prophylaxis, with 58.9% of physicians 
prescribing the treatment for four weeks or 35 days, 9.8% until weight-bearing status, 10.3% until 
discharge from rehabilitation, and the remaining 21.0% spread among other options. While 30 
days are likely appropriate for VTE prophylaxis, the risk of arterial cardiovascular events remains 
high for at least 90 days.5 The COMPASS regimen can prevent cardiovascular events in this 
setting, but one should select a population with high risk of such events and try minimizing the 
risk of bleeding. People who develop ischemic myocardial injury (35% on the population with a 
low-energy hip fracture), are the ones at higher risk of a recurrent cardiovascular events at 90 
days:  29.6% as compared with 14.6% in people without myocardial injury.21 Targeting a similar 
group was a successful strategy in the MANAGE trial.12 However, approximately 80% of the initial 
myocardial injuries after non-cardiac surgery start off as supply-demand mismatch. 
Antithrombotic treatment is not only unlikely to prevent these events but may cause them 
through bleeding. This could explain the neutral effect of ASA on MI in the POISE-2 trial and the 
increased occurrence of MI in the ASA arm of the PEP trial. 12,13  The COMPASS regimen can be 
beneficial in people who had a myocardial injury on presentation to the hospital with their hip 

 
 
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fracture or in the days after their hip fracture surgery, if started not too soon after the surgery to 
reduce the risk of bleeding and administered for 90 days. 
1.2 Objectives 
Our primary objective is to determine the feasibility of an RCT comparing rivaroxaban 2.5 mg BID 
+ ASA 75 to 100 mg daily for 90 days with standard thromboprophylaxis with a low-dose 
anticoagulant for 30 days in people who received surgery for low-energy hip fracture and 
experienced a myocardial injury. Our secondary objective is to describe the frequency of clinical 
outcomes. 
Our research question in a PICOTS format: 
• 
Population: Individuals who received surgery for low energy hip fracture and experienced 
a myocardial injury. 
• 
Intervention: Oral rivaroxaban 2.5 mg BID + ASA 75 to 100 mg daily for 90 days. 
• 
Comparison: Institutional standard thromboprophylaxis with a low-dose anticoagulant 
for 30 days 
• 
Outcomes:  
o Feasibility: recruitment rate (primary), medication adherence, and retention of 
participants. 
o Exploratory: all-cause mortality, symptomatic VTE, arterial vascular events, and 
bleeding events. 
• 
Time of Follow-up: in hospital, 30 days and 90 days. 
• 
Setting: in-hospital and post discharge. 
 

 
 
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2. Methods 
2.1 Study design. 
This will be a pilot open-label RCT. The study design is described in Figure 2. 
2.2 Study setting 
We will enroll patients admitted to the hospital. 
2.3 Eligibility criteria 
2.3.1 Inclusion criteria 
We will include patients satisfying the following criteria: 
1. Age ≥45 years; 
2. who received urgent surgery for a hip fracture due to a low energy mechanism; and, 
3. who had a myocardial injury (not meeting the diagnostic criteria for myocardial infarction) 
on presentation to the hospital with their hip fracture or in the first three days after their 
hip fracture surgery. 
2.3.2 Exclusion criteria 
We will exclude centers in which the standard of care for VTE prophylaxis after hip fractures is 
ASA, alone or in combination with other drugs. 
We will exclude patients based on the following criteria: 
1. Renal Function: Measured or estimated glomerular filtration rate (GFR) <15 mL/min. 
2. Drug interactions and conditions that prevent the use of the standard of care or 
intervention: 
a. Known allergy to the study drugs; 

 
 
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b. Pregnancy; 
c. An indication for anticoagulation, for dual antiplatelet therapy, for a P2Y12 
inhibitor; 
d. Already on rivaroxaban 2.5 mg twice daily + ASA before the fracture; 
e. Bleeding diathesis that in the judgment of the investigator precludes the use of 
anticoagulant prophylaxis; 
f. History of significant hepatic disease (Child-Pugh B or C, see supplementary 
material) or any other condition that, in the judgment of the investigator, 
precludes the use of the intervention. We will collect information about the 
specific reason; 
g. Concomitant use of drugs that are strong inhibitors or strong inducers of P-
glycoprotein (P-gp, e.g., systemic azole antimycotics, such as ketoconazole, and 
human immunodeficiency virus [HIV]-protease inhibitors, such as ritonavir) 
and/or Cytochrome P450 3A4 (CYP3A4). 
3. Other Factors:  
a. Expected requirement for major surgery post-arthroplasty within 90 days; 
b. Persons of childbearing potential who are not abstinent or do not use appropriate 
contraception or are breast-feeding; 
c. Patient is unable or unwilling to consent; 
d. Previous participation in the HIPSTER trial; 
e. Participation in another anticoagulant or antiplatelet study.  

 
 
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2.4 Trial intervention 
Intervention Arm: Patients randomized to the intervention will receive rivaroxaban 2.5 mg orally 
BID and ASA 75-100 mg OD for 90 days, to be started between postoperative day (POD) three 
and five. The exact dose of ASA will depend on local formulary and clinical practice at each 
participating site. A maximum of four postoperative days of any anticoagulant (LMWH, UFH, 
fondaparinux or a DOAC) will be allowed in the meantime.  
Control Arm: Patients in the control arm will receive the institution's standard of care for 
thromboprophylaxis for up to 30 days. While the study team will encourage a 30-day duration to 
align with guideline recommendations and ensure consistency with the intervention arm, it will 
not be mandated as there are variations in the duration of postoperative VTE prophylaxis across 
institutions. Actual practices at each site will be documented and analyzed. The following 
regimens are provided as guidance only, and actual clinical practices will be recorded and 
analyzed. 
• Low-molecular-weight heparin (LMWH) 
- 
Enoxaparin: 40 mg subcutaneously OD (or 30 mg subcutaneously BID); 
- 
Dalteparin: 5000 IU subcutaneously OD (or alternative dosing based on institutional 
protocol); 
- 
Tinzaparin: 4500 IU subcutaneous OD; 
• Fondaparinux: 2.5 mg subcutaneously OD; or 
• Direct oral anticoagulant (DOAC): Rivaroxaban 10 mg OD or apixaban 2.5 mg BID, started 
after surgery or after a period of LMWH.  

 
 
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2.4.1 People already on ASA: 
For people already on ASA at the time of the hip fracture diagnosis, who are eligible for the study, 
we will suggest holding it preoperatively. In the intervention arm, ASA will be restarted as 
planned after randomization. In the control arm, if the indication to ASA is confirmed, it can be 
restarted at physician’s discretion. 
2.5 Standardization of co-interventions 
To minimize the potential for co-interventions and detection bias, we will promote adherence to 
evidence-based perioperative management in accordance with national and international 
guidelines, as summarized below. Data on co-interventions will be collected, but non-adherence 
to these measures will not be considered a protocol violation. Where available, the perioperative 
and thrombosis services will continue to follow patients as per routine clinical practice. This 
includes assessment of signs and symptoms of VTE, arterial cardiovascular events, and bleeding. 
For the duration of the study period, the study team will follow patients.  The study team will 
assume the responsibility for initiating and managing the assigned thromboprophylaxis in the 
interventional arm. The study team will remain in communication with the treating team.  
2.5.1 Preoperative VTE prophylaxis 
The American Society of Hematology (ASH) 2019 guidelines and American College of Chest 
Physicians recommend - Prophylactic UFH or LMWH before surgery. The last dose should be 
administered at least four hours before the procedure.7,19 

 
 
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2.5.2 Intra-operative bleeding prevention 
The NICE guideline recommend that all patients should receive 1 g of tranexamic acid 
intravenously at the beginning of the surgery and 1 g at wound closure.22,23  Patients with an 
absolute contraindication to its use will not receive it and the reason will be documented. 
2.5.3 Measuring Troponins for Cardiac Risk Assessment 
We will suggest measuring troponin (I or T, high-sensitivity or not, as available to the institution) 
after hip fracture diagnosis (before surgery) and daily after surgery (POD 1 to 3), for the detection 
of myocardial injury.24,25 
2.5.4 Postoperative VTE prophylaxis 
The American Society of Hematology (ASH) 2019 guidelines recommend that patients should 
receive daily VTE prophylaxis with LMWH or a DOAC starting ~12-24 hours after the surgery up 
to randomization.7 The study team will provide the required prescriptions, medications, and 
instructions prior to discharge, in consultation with the thrombosis service where available. 
2.5.5 Pregnancy test  
Pregnancy is an exclusion criterion, and rivaroxaban is contraindicated in pregnancy.26 Therefore, 
pregnancy testing will be mandated for all individuals of child-bearing potential, prior to 
enrollment, unless it has already been performed for clinical reasons as part of standard of care.  
2.6 Outcomes  
2.6.1 Feasibility outcomes 
The primary feasibility outcome will be the recruitment rate. Other feasibility outcomes will be 
complete 30 and 90 days follow up, treatment adherence. We will also measure the working time 

 
 
HIPSTER pilot protocol - version 1.4, June 23, 2025 
22 
for the research coordinator and research assistant, to obtain a precise estimate of the time 
commitments for the full-scale trial. 
2.6.2 Progression criteria. 
We will adopt a traffic light system for our feasibility outcomes: green (go) indicates that the 
criteria have been met and we should proceed, amber (amend) indicates that some changes 
should be made to proceed to the larger trial, and red (major amendments or stop) indicates that 
we should not move forward with the full-scale trial without major amendments.27 Table 1 
reports the formula for calculating the feasibility outcomes with the thresholds for progression. 
For recruitment rate, we aim at recruiting two (one) patients per month per site. For the 30 and 
90 days follow up, we aim at 95% (85%) of the patients. For treatment adherence we aim at 85% 
(75%).  
2.6.3 Exploratory clinical outcomes 
The primary clinical outcome will be a composite of all-cause mortality, MI, non-hemorrhagic 
stroke, peripheral arterial thrombosis, and symptomatic, objectively confirmed VTE (DVT and/or 
PE). These outcomes will be monitored from randomization and over the specified follow-up 
period and will also be analyzed as individual outcomes, with the addition of CV mortality. We 
will also collect data on the length of stay and on re-hospitalizations, as measures of resource 
utilization. 

 
 
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23 
2.6.4 Exploratory safety outcomes 
The primary safety outcome will be bleeding independently associated with mortality after non-
cardiac surgery (BIMS).28 Secondary safety outcomes will be major bleeding events as defined by 
the ISTH, clinically relevant nonmajor bleeding, and minor bleeding.29,30 
The appendix contains detailed outcomes definitions. 
Decisions regarding holding or discontinuing (and eventually restarting) either study drug rest 
with the attending physician and the patient.  If a patient experiences a life-threatening or 
clinically relevant bleed, study personnel will recommend that the patient have their trial 
medication(s) held until the bleeding is stabilized. If a patient experiences a minor bleed, 
physicians may continue, temporarily interrupt, or permanently discontinue the trial 
medication.  It is not a requirement, however, that the study medication is stopped for minor 
bleeding. The study personnel will be available for discussion about the best course of action. 
Participants will continue to be followed up for outcomes by the study team, unless they choose 
to withdraw from the study entirely.  
2.7 Recruitment 
Physicians and nurses working in the orthopedic, thrombosis and perioperative services (as 
appropriate and applicable for each site) will receive training on the HIPSTER study from the local 
investigators and study material prepared centrally. Health care providers who are part of the 
circle of care will identify potential participants, and if the potential participant provides 
permission to be approached for the study, the study team will be notified to seek informed 
consent. At sites where allowed by local  policies, trained study personnel will also screen patient 

 
 
HIPSTER pilot protocol - version 1.4, June 23, 2025 
24 
charts for potentially eligible patients and approach where appropriate. If an eligible patient is 
missed, the research staff will discuss with the relevant stakeholders to reduce the potential for 
this to reoccur. A screening log will be kept as allowed per local institutional practices to 
document missed patients. 
2.8 Participant timeline 
The study schedule is reported in Figure 3. 
Randomization will occur three to five days after surgery and will be timed to allow starting the 
intervention as soon as possible after allocation. The study personnel will follow patients 
throughout their hospital stay assessing the participants and reviewing their medical records, 
ensuring trial orders are followed, and noting any outcome. The study personnel will contact the 
patients via telephone (or in person, if the patient will not be discharged) 30 and 90 days after 
randomization and will obtain documentation as appropriate. 
2.9 Sample size 
For this study, we set the target of enrolling 100 patients as a pragmatic sample size. This will 
allow us to show a complete 90-day follow-up in 95% of participants with a 95% CI ranging from 
89% to 98%. We also calculated possible sample sizes for the full-scale trial. Table 2 reports the 
sample size for different scenarios. We used the rate of cardiovascular events reported in the 
HIP-ATTACK trial: 0.18 overall, 0.30 in the subgroup with myocardial injury. For the effect size, 
we used the one reported in the COMPASS study, adding a more conservative and a more 
optimistic estimate. This provides the rationale for only including people with myocardial injury. 

 
 
HIPSTER pilot protocol - version 1.4, June 23, 2025 
25 
2.10 Assignment of the interventions 
Participants will be randomized to a control or experimental group with a 1:1 ratio using a 
computer-generated randomization schedule. The allocation sequence will be generated by a 
statistician and imported into the web application Research Electronic Data Capture (REDCap), 
which will function as a web-based randomization system and data collection tool. Participants 
will be stratified by center and the use of ASA at baseline or at the time of enrolment (yes or no). 
The stratification will be implemented using permuted blocks of variable size in random order, 
to ensure allocation concealment. Randomization will occur after a patient is deemed eligible 
and provides informed consent.  
2.11 Blinding 
The care providers, on-site study personnel, and participants will not be blinded to the treatment 
allocation, the outcome adjudicators will be. 
2.12 Data collection and management 
 All data collection and management will be performed in accordance with International Council 
for Harmonisation - Good Clinical Practice (ICH-GCP) and applicable local privacy and personal 
health information protection regulations to maintain patient confidentiality and privacy. Each 
patient will be assigned a unique study ID and no direct patient identifiers will be collected as 
part of the study data. No patients will be recruited before institutional approval is obtained. 
The study personnel at participating sites will input the data into online CRFs through REDCap. 
REDCap is a browser-based, meta-driven electronic data capture (EDC) software and workflow 
methodology for designing clinical research databases. REDCap can be installed in a variety of 

 
 
HIPSTER pilot protocol - version 1.4, June 23, 2025 
26 
environments for compliance with standards such as Health Insurance Portability and 
Accountability Act (HIPAA) and FDA 21 CFR Part 11.  Within REDCap, user privileges are utilized 
to maintain data integrity and confidentiality (e.g. each user has an individual account with 
unique username and password; a site research coordinator will only be able to access data from 
their site).  REDCap implements authentication to validate the identity of end-users that log in to 
the system, as well as an auto-logout feature after a period of inactivity. REDCap has a built-in 
audit trail that automatically logs all user activity and logs all pages viewed by every user.  The 
Computer Services Unit at McMaster University has the appropriate license agreement and is 
password protected on a secure site and on a separate server.  Any hard copy documents will be 
stored in a locked, secure location at each site with access restricted to the study team only. 
2.13 Statistical analysis 
Baseline patient characteristics will be reported using means and standard deviations or medians 
and ranges as appropriate for continuous variables, and percentages with 95% CI for 
dichotomous and categorical variables. Feasibility and clinical outcomes will be reported using 
percentages with 95% CI.  We will not look at clinical outcomes by group, as data from this 
feasibility study will be included in the analysis of a later full-scale multicenter study if its design 
will not change. 
2.14 Monitoring 
 
Both rivaroxaban and ASA are approved for prevention of arterial and venous thrombosis and 
have been extensively used, and the combination of low dose rivaroxaban and ASA is approved 
for prevention of arterial thrombosis. The overall adverse profiles of each agent and in 

 
 
HIPSTER pilot protocol - version 1.4, June 23, 2025 
27 
combination have been well described in broad populations, with the most common side effect 
being bleeding.  Given the approved status and known risk profiles of rivaroxaban and ASA as 
well as the small sample size of this pilot study, we are not planning to set up a data monitoring 
committee, nor to implement formal interim analyses. However, at 50% recruitment, we will ask 
a person with expertise in cardiovascular medicine and clinical trials to review the event rates. 
This person will be independent of the study team. If there is a safety concern, the study will be 
paused and the protocol will be reconsidered. If there is no major concern, the study investigators 
will remain blinded.   
2.14.1 Documenting and Reporting of Adverse Events 
An Adverse Event (AE), as defined by GCP, is any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease having been absent at baseline, or, if present 
at baseline, appears to worsen and is temporally associated with medical treatment or 
procedure, regardless of the attribution (i.e., relationship of event to medical treatment or 
procedure). Because of the extensive safety data available on ASA, rivaroxaban, and their 
combination, AE collection in HIPSTER pilot is limited to changes in health status that require 
permanent drug discontinuation. This ensures that only those events the investigator thinks are 
related to the study medication are considered an adverse event. These AEs will be collected 
during the whole treatment period, and will be followed to resolution or stabilization. Data on 
AEs will be collected during the hospital stay and at the follow-up assessments. Moreover, study 
participants will be able to report AEs by contacting their local study team or the coordinating 
center. 

 
 
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28 
A serious adverse event (SAE) is classified as any untoward medical occurrence that, at any 
dose, results in death, is life-threatening, requires inpatient hospitalization or prolongation of 
existing hospitalization, results in persistent or significant disability / incapacity, is a 
congenital anomaly / birth defect and/or is another medically important serious event 
representing a significant hazard, which is comparable to the aforementioned criteria. 
All unexpected and related or possibly related SAEs will be reported by the site PI to their local 
REB within 7 business days of awareness. The sponsor will report these SAEs to HiREB within 15 
business days of awareness if they require a change to the research and/or informed consent 
form and/or requires immediate notification to participants for safety reasons. Follow-up reports 
will be submitted as required.  
2.14.2 Protocol-specific exceptions to expedited SAE reporting 
For the purpose of this trial, expected events will be captured on the CRFs as study outcome 
events only and will be exempted from the expedited reporting but will be included in the final 
study report. This includes: 
• 
Primary or secondary efficacy outcomes for the full trial: 
o Overall mortality 
o Cardiovascular mortality 
o All thrombosis or thromboembolism (arterial and venous) 
o Hospitalization 
• 
Safety outcomes: 
o Bleeding events  

 
 
HIPSTER pilot protocol - version 1.4, June 23, 2025 
29 
• 
Expected Events: Events that are expected to occur in high frequency in the population 
under study, including: 
o Planned hospitalization (e.g., surgery, rehabilitation, respite care) 
o Conditions e.g., chronic obstructive pulmonary disease, hypertension, diabetes 
and trauma  
The sponsor will report all serious unexpected adverse drug reactions (SUADRs) to the regulatory 
authorities and REB. If the SUADR is neither fatal nor life-threatening, the sponsor will report the 
SUADR to Health Canada within 15 calendar days of awareness. If the SUADR is fatal or life-
threatening, Health Canada will be advised within 7 calendar days of awareness. Follow-up 
reports will be submitted as required. In addition, as required by ICH-GCP, the sponsor will 
expedite reporting of all SUADRs to all concerned institutions and REBs. 
2.14.3 Audits and Inspections 
Authorized representatives of a regulatory authority and/or an REB may visit the sites to perform 
audits or inspections, including source data verification. The medical records of participating 
study subjects are considered confidential and disclosure to third parties other than those noted 
is prohibited. The ethics-approved informed consent form will clearly indicate  
that the subject’s medical records will be inspected by said parties, and permission for such  
review and use of personal information is a requirement for study participation. 
2.15 Ethics 
Research personnel will approach all eligible patients to obtain informed consent.  In accordance 
with the Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans – TCPS 2 

 
 
HIPSTER pilot protocol - version 1.4, June 23, 2025 
30 
(2022), if the patient is legally competent but not competent to provide informed consent, we 
will inform and obtain consent from a family member.  In case of legal incompetence, we will 
inform and obtain consent from the patient’s authorized representative. 
Study participants will have the possibility to withdraw from the study at any time they decide to 
do so, contacting their local study team or the coordinating center. They will have the possibility 
to withdraw from treatment but continue the follow-up, or to also stop the follow-up. They will 
decide if they want the study team to also delete the data already collected (right to be 
forgotten). These participants will not be replaced. 
2.16 Record retention 
The PI will retain and maintain all documentation relating to the study for a period of 15 years as 
per C.05.012 (4) of the Food and Drug Regulations (FDR). Any additional applicable regulatory 
requirements in other relevant jurisdictions will also be adhered to. 
3. Trial registration  
The trial will be registered on ClinicalTrials.gov. 
4. Funding 
This project received funding from the Canadian Venous Thromboembolism Research Network 
(CanVECTOR) pilot trial competition. 
 

 
 
HIPSTER pilot protocol - version 1.4, June 23, 2025 
31 
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3. 
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4. 
Gundel O, Thygesen LC, Gögenur I, Ekeloef S. Postoperative mortality after a hip 
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Borges FK, Bhandari M, Guerra-Farfan E, et al. Accelerated surgery versus standard care 
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Gao Y, Long A, Xie Z, et al. The compliance of thromboprophylaxis affects the risk of 
venous thromboembolism in patients undergoing hip fracture surgery. Springerplus. 
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7. 
Anderson DR, Morgano GP, Bennett C, et al. American Society of Hematology 2019 
guidelines for management of venous thromboembolism: Prevention of venous 

 
 
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thromboembolism in surgical hospitalized patients. Blood Adv. 2019;3(23):3898-3944. 
doi:10.1182/bloodadvances.2019000975 
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Borges FK, Bhandari M, Guerra-Farfan E, et al. Accelerated surgery versus standard care 
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9. 
Rodgers A, MacMahon S, Collins R, Prentice C. Prevention of pulmonary embolism and 
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trial. Lancet. 2000;355(9212):1295-1302. doi:10.1016/S0140-6736(00)02110-3 
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Anderson DR, Morgano GP, Bennett C, et al. American Society of Hematology 2019 
guidelines for management of venous thromboembolism: prevention of venous 
thromboembolism in surgical hospitalized patients. Blood Adv. 2019;3(23):3898-3944. 
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11. 
Venous Thromboembolism in over 16s: Reducing the Risk of Hospital-Acquired Deep 
Vein Thrombosis or Pulmonary Embolism NICE Guideline.; 2018. 
www.nice.org.uk/guidance/ng89 
12. 
Devereaux PJ, Duceppe E, Guyatt G, et al. Dabigatran in Patients with Myocardial Injury 
after Non-Cardiac Surgery (MANAGE): An International, Randomised, Placebo-
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Devereaux PJ, Mrkobrada M, Sessler DI, et al. Aspirin in Patients Undergoing 
Noncardiac Surgery. New England Journal of Medicine. 2014;370(16):1494-1503. 
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14. 
Eikelboom JW, Connolly SJ, Bosch J, et al. Rivaroxaban with or without Aspirin in Stable 
Cardiovascular Disease. New England Journal of Medicine. 2017;377(14):1319-1330. 
doi:10.1056/nejmoa1709118 
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Schulman S, Kearon C. Definition of major bleeding in clinical investigations of 
antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 
2005;3(4):692-694. doi:10.1111/J.1538-7836.2005.01204.X 
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Bonaca MP, Bauersachs RM, Anand SS, et al. Rivaroxaban in Peripheral Artery Disease 
after Revascularization. New England Journal of Medicine. 2020;382(21):1994-2004. 
doi:10.1056/nejmoa2000052 
17. 
Regulatory Decision Summary for Xarelto - Drug and Health Products Portal. Accessed 
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Xarelto | European Medicines Agency (EMA). Accessed January 21, 2025. 
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Food and Drug Administration (FDA). XARELTO (rivaroxaban) Label. Accessed January 
21, 2025. 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/215859s000lbl.pdf 
20. 
Borges FK, Bhandari M, Guerra-Farfan E, et al. Accelerated surgery versus standard care 
in hip fracture (HIP ATTACK): an international, randomised, controlled trial. Lancet. 
2020;395(10225):698-708. doi:10.1016/S0140-6736(20)30058-1 
21. 
Borges FK, Farfan EG, Bhandari M, Patel A. Myocardial injury in hip fractures: a HIP-
ATTACK randomized trial substudy. In peer review. 

 
 
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22. 
Devereaux PJ, Marcucci M, Painter TW, et al. Tranexamic Acid in Patients Undergoing 
Noncardiac Surgery. New England Journal of Medicine. 2022;386(21):1986-1997. 
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23. 
National Institute for Health and Care Excellence (NICE). Joint Replacement (Primary): 
Hip, Knee and Shoulder Quality Standard. NICE; 2022. Accessed at 
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24. 
Duceppe E, Parlow J, MacDonald P, et al. Canadian Cardiovascular Society Guidelines on 
Perioperative Cardiac Risk Assessment and Management for Patients Who Undergo 
Noncardiac Surgery. Canadian Journal of Cardiology. 2017;33(1):17-32. 
doi:10.1016/j.cjca.2016.09.008 
25. 
Halvorsen S, Mehilli J, Cassese S, et al. 2022 ESC Guidelines on cardiovascular 
assessment and management of patients undergoing non-cardiac surgery. Eur Heart J. 
2022;43(39):3826-3924. doi:10.1093/eurheartj/ehac270 
26. 
Lameijer H, Aalberts JJJ, van Veldhuisen DJ, Meijer K, Pieper PG. Efficacy and safety of 
direct oral anticoagulants during pregnancy; a systematic literature review. Thromb 
Res. 2018;169:123-127. doi:10.1016/j.thromres.2018.07.022 
27. 
Avery KNL, Williamson PR, Gamble C, et al. Informing efficient randomised controlled 
trials: exploration of challenges in developing progression criteria for internal pilot 
studies. BMJ Open. 2017;7(2). doi:10.1136/BMJOPEN-2016-013537 
28. 
Roshanov PS, Eikelboom JW, Sessler DI, et al. Bleeding Independently associated with 
Mortality after noncardiac Surgery (BIMS): an international prospective cohort study 

 
 
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establishing diagnostic criteria and prognostic importance. Br J Anaesth. 
2021;126(1):163-171. doi:10.1016/J.BJA.2020.06.051 
29. 
Schulman S, Anger SU, Bergqvist D, Eriksson B, Lassen MR, Fisher W. Definition of major 
bleeding in clinical investigations of antihemostatic medicinal products in surgical 
patients. Journal of Thrombosis and Haemostasis. 2010;8(1):202-204. 
doi:10.1111/j.1538-7836.2009.03678.x 
30. 
Anderson DR, Dunbar M, Murnaghan J, et al. Aspirin or Rivaroxaban for VTE Prophylaxis 
after Hip or Knee Arthroplasty. N Engl J Med. 2018;378(8):699-707. 
doi:10.1056/NEJMOA1712746 
  
 
 

 
 
HIPSTER pilot protocol - version 1.4, June 23, 2025 
36 
Tables 
Table 1:calculation and progression criteria for the feasibility outcomes. 
Outcome 
Calculation 
No 
modifications 
Minor 
modifications 
Major 
modifications 
Recruitment 
rate 
(n of participants 
recruited)/month/site 
≥ 2/month 
1-2/month 
<1/month 
Screening to 
enrollment 
ratio 
(n of eligible 
participants)/(n enrolled) 
NA 
NA 
NA 
30 days FUP 
(n of participants with 
complete follow-up 
data)/(n of enrolled 
participants) 
≥ 95% 
95-85% 
< 85% 
90 days FUP 
≥ 95% 
95-85% 
< 85% 
Treatment 
adherence 
(n of pills/syringes 
prescribed – n of 
pills/syringes 
administered*)/(n of 
pills/syringes prescribed) 
≥ 85% 
85-75% 
< 75% 
FUP: follow-up, NA: not applicable. 
*Based on hospital records for the inpatient period and on patient-reported for the period after 
discharge. 
 
Table 2: effect size for the full-scale trial, for different event rates and effect sizes. 
 
Based on the composite outcome measured in the HIP-ATTACK study: all-cause mortality, non-
fatal myocardial infarction, non-fatal stroke, and non-fatal congestive heart failure. 0.30 was 
the event rate in people with baseline troponin elevation, 0.18 was the event rate in unselected 
patients with a baseline troponin measurement. 
HR: hazard ratio 
Power set at 0.80. 
Control event rate 
Effect size (HR) 
Sample size 
0.30 
0.70 
1215 
0.75 
1826 
0.80 
2967 
0.25 
0.70 
1409 
0.75 
2115 
0.80 
3434 
0.18 
0.70 
1860 
0.75 
2789 
0.80 
4524 

 
 
HIPSTER pilot protocol - version 1.4, June 23, 2025 
37 
Figures 
Figure 1: comparison of rivaroxaban 2.5 mg BID + ASA 100 mg OD with rivaroxaban 5 mg BID, data from the COMPASS trial 
 
CI: confidence interval; CV: cardiovascular. 
 
Figure 2: HIPSTER Pilot design 
 
1With low-molecular weight heparin (LMWH) or a direct oral anticoagulant (DOAC) 
2ASA 75-100 mg once daily + Rivaroxaban 2.5 mg twice daily 
Figure created with BioRender.com, dice by Marie Van den Broeck from Noun Project 
 
 

 
 
HIPSTER pilot protocol - version 1.4, June 23, 2025 
38 
Figure 3: study schedule. 
 
STUDY PERIOD 
 
 
Enrolment 
Allocation1 
Post-allocation 
Close-out 
TIMEPOINT** 
PreOD -1 to POD3 
POD 3-5 
POD 3-5 
POD 30 
 
POD 90 
tx2 
ENROLMENT: 
 
 
 
 
 
 
 
 
Eligibility screen 
 
X 
 
 
 
 
 
 
Troponin measurement3 
X 
X 
 
 
 
 
 
 
Informed consent  
 
X 
 
 
 
 
 
 
2 gr Tranexamic acid IV4 
X 
 
 
 
 
 
 
 
Allocation 
 
 
X 
 
 
 
 
 
INTERVENTIONS: 
 
 
 
 
 
 
 
 
Rivaroxaban 2.5 mg BID + ASA 75-100 mg daily 
 
 
 
 
 
 
 
 
Standard of Care5  
 
 
 
 
 
 
 
 
ASSESSMENTS: 
 
 
 
 
 
 
 
 
List baseline variables 
 
X 
 
 
 
 
 
 
Feasibility outcomes 
 
X 
X 
X 
X 
 
X 
X 
Efficacy outcomes 
 
 
 
X 
X 
 
X 
 
Safety outcomes 
 
 
 
X 
X 
 
X 
 
ASA: acetylsalicylic acid, BID: bis in die; POD: post operative day; PreOD: preoperative day. 
1 As close as possible to the start of the intervention. 
2 tx: 90 days after the enrolment of the last participant. 
3 At diagnosis and daily on POD 1-3 
4 1 g of tranexamic acid intravenously at the beginning of the surgery and 1 g at wound closure 
5 Standard of Care for Thromboprophylaxis: Includes low molecular weight heparin (e.g., enoxaparin 40mg daily/30mg BID, dalteparin 5000 IU daily, tinzaparin 
4500 IU daily), fondaparinux 2.5 mg daily, or direct oral anticoagulants (rivaroxaban 10 mg or Apixaban 2.5 mg BID) post-surgery or following low molecular 
weight heparin.