ANZCTR - Registration

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Trial registered on ANZCTR

Registration number

ACTRN12618001879257

Ethics application status

Approved

Date submitted

13/11/2018

Date registered

19/11/2018

Date last updated

30/11/2022

Date data sharing statement initially provided

19/11/2018

Date results information initially provided

29/06/2021

Type of registration

Prospectively registered

Titles & IDs

Public title

A clinical trial to determine if aspirin is as effective and safe as low molecular weight heparin in preventing lung and leg clots after total hip or knee replacement surgery

Scientific title

A cluster randomised, crossover, non-inferiority trial of aspirin compared to low molecular weight heparin for venous thromboembolism prophylaxis and safety in hip or knee arthroplasty, a registry nested study

Secondary ID [1]

None

Universal Trial Number (UTN)

Trial acronym

CRISTAL

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Venous Thromboembolic Events (VTE) after Total Hip Arthroplasty (THA) and Total Knee Arthroplasty (TKA)

Condition category

Condition code

Blood

Clotting disorders

Surgery

Other surgery

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Aspirin at a dose of 85-150mg, administered once daily, orally, to all patients undergoing primary or revision THA or TKA as VTE chemoprophylaxis. The dose used is based on availability, some hospitals or surgeons have a dose of 100mg more readily available, whilst others have 150mg more readily available.

Patients undergoing THA will receive this for 35 days and patients undergoing TKA will receive this for 14 days, commencing within 24 hours postoperatively. This timing window of within 24 hours is used based on the surgeon's discretion as to when the procedure is performed (e.g. in the morning, evening) and how much bleeding is perceived to have occurred. The exact duration is based on the investigators' discretion. Adherence will be monitored by a patient questionnaire performed at 90 days postoperatively.

This dose and duration of aspirin was chosen as it is recommended by the recent United Kingdom National Institute for Health and Care Excellence (NICE) guidelines (2018).

The Crossover trial refers to the crossover of hospitals from one treatment arm to the second (e.g. one hospital will prescribe all patients aspirin only for a 9 month period and then low molecular weight heparin only for a second 9 month period), rather than patients crossing over from one treatment to the second. Therefore, there will be no 'wash-out' period for patients.

Intervention code [1]

Prevention

Comparator / control treatment

Low molecular weight heparin (LMWH), in the form of enoxaparin, at a dose of 40mg, administered once daily, via subcutaneous injection, to all patients undergoing primary or revision THA or TKA as VTE chemoprophylaxis. Patients undergoing THA will receive this for 35 days and patients undergoing TKA will receive this for 14 days.

This dose of enoxaparin was chosen as it is the recommended VTE prophylactic dose based on pharamcological studies, provided in the product information guide. The duration of enoxaparin therapy was chosen as it is recommended by the recent United Kingdom National Institute for Health and Care Excellence (NICE) guidelines (2018). The exact duration of the intervention is determined at the investigators' discretion.

Control group

Active

Outcomes

Primary outcome [1]

Symptomatic VTE after primary elective THA and TKA for osteoarthritis in patients receiving either aspirin or LMWH. This outcome will be assessed by a study-specific questionnaire. All patients who record a positive VTE result on the questionnaire will have this verified by AOANJRR staff by by contact with treating surgeons. This questionnaire has been specifically designed for this study.

Timepoint [1]

90 days from THA or TKA

Secondary outcome [1]

Symptomatic VTE after all THA and TKA (elective primary and revision, performed for any reason) in patients receiving either aspirin or LMWH. This outcome will be assessed by a study-specific questionnaire. All patients who record a positive VTE result on the questionnaire will have this verified by AOANJRR staff by contact with treating surgeons. This questionnaire has been specifically designed for this study.

Timepoint [1]

90 days from THA or TKA

Secondary outcome [2]

Symptomatic VTE after revision THA and TKA in patients receiving either aspirin or LMWH. This outcome will be assessed by a study-specific questionnaire. All patients who record a positive VTE result on the questionnaire will have this verified by AOANJRR staff by contact with treating surgeons. This questionnaire has been specifically designed for this study.

Timepoint [2]

90 days from THA or TKA

Secondary outcome [3]

The rate of non-VTE complications between aspirin and LMWH groups . This is a composite outcome. These will specifically include hospital readmission (and reason for this), need for re-operation on the same joint (and nature of this - infection, dislocation of joint, manipulation under anaesthesia, fracture treatment, wound repair, implant loosening or migration), need for re-operation not related to the joint replacement (and nature of this), major bleeding (defined as any bleeding resulting in readmission, reoperation or death) and death. These complications will be assessed by a patient specific questionnaire and all positive answers will be verified by AOANJRR staff by contact with treating surgeons. This questionnaire has been specifically designed for this study. All deaths are automatically linked to the AOANJRR database and data relating to deaths will be obtained through registry related data-linkage.

Timepoint [3]

90 days from THA or TKA for readmission and major bleeding only.

90 days and 6 months from THA or TKA for reoperation and death.

Secondary outcome [4]

The cost effectiveness of aspirin to LMWH after primary elective THA and TKA for osteoarthritis. If aspirin is found to be inferior to LMWH, a cost effectiveness analysis of aspirin compared to LMWH will be performed from a health system perspective. Data for resource use associated with treatments and complications will be taken from trial data within the AOANJRR. Survival at one year and quality of life measured using EQ5D at baseline and 6 months will allow calculation of differences in quality adjusted life years (QALYs) between groups. We will calculate the cost per QALY for each treatment comparison as the difference in mean costs divided by the difference in mean outcomes (quality adjusted survival as QALYs) over the duration of the trial, using regression analysis to adjust for differences at baseline and clustering by site.

Timepoint [4]

6 months from THA and TKA

Secondary outcome [5]

An extension of the primary analysis for THA and TKA separately. This outcome will be assessed by a study-specific questionnaire. All patients who record a positive VTE result on the questionnaire will have this verified by AOANJRR staff by contact with treating surgeons. This questionnaire has been specifically designed for this study.

Timepoint [5]

90 days from THA or TKA.

Secondary outcome [6]

An extension of the primary analysis for unilateral versus bilateral arthroplasty. This outcome will be assessed by a study-specific questionnaire. All patients who record a positive VTE result on the questionnaire will have this verified by AOANJRR staff by contact with treating surgeons. This questionnaire has been specifically designed for this study.

Timepoint [6]

90 days from THA or TKA

Secondary outcome [7]

An extension of the primary analysis for below-knee DVT, above-knee DVT and PE separately. This outcome will be assessed by a study-specific questionnaire. All patients who record a positive VTE result on the questionnaire will have this verified by AOANJRR staff by contact with treating surgeons. This questionnaire has been specifically designed for this study.

Timepoint [7]

90 days from THA or TKA

Secondary outcome [8]

A second sub-study comparing the incidence of persistent wound drainage (defined as persistent, ongoing wound drainage beyond 72 hours postoperatively) and wound disturbance (defined as wound haematoma requiring readmission, wound blistering, prolonged drainage for greater than 7 days postoperatively and need for re-operation due to wound complications) between the aspirin and LMWH groups will be performed at two high volume hospitals (the Institute of Rheumatology and Orthopaedics and Fairfield Hospitals in New South Wales) participating in the CRISTAL trial. Data will be collected via data collection sheets designed specifically for this sub-study from patient notes at the time of surgery.

Timepoint [8]

90 days from THA or TKA

Secondary outcome [9]

To compare patient-reported pain, function and health status at 6 months via the Oxford Knee Score (OKS) between the two treatment groups in patients undergoing TKA

Timepoint [9]

6 months from TKA

Secondary outcome [10]

To compare patient-reported pain, function and health status at 6 months via the Oxford Hip Score (OHS) between the two treatment groups in patients undergoing THA

Timepoint [10]

6 months from THA

Secondary outcome [11]

To compare patient-reported pain, function and health status at 6 months between the two groups via the EuroQol EQ-5D Score

Timepoint [11]

6 months from THA or TKA

Secondary outcome [12]

To compare patient-reported pain, function and health status at 6 months via the EQ-VAS score

Timepoint [12]

6 months from THA or TKA

Secondary outcome [13]

To compare patient-reported pain, function and health status at 6 months via a 0-10 joint pain score.

Timepoint [13]

6 months from THA or TKA

Eligibility

Key inclusion criteria

Adults (age 18 and older) receiving elective primary or revision TKA or THA

Minimum age

18 Years

Maximum age

No limit

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

- Departments that perform less than 250 THA or TKA proecedures per year
- The following patients will be excluded from the primary analysis: patients receiving partial joint replacements, revision surgery, non-osteoarthritis diagnosis, use of warfarin/NOAC/dual antiplatelet therapy pre-operatively

Study design

Purpose of the study

Prevention

Allocation to intervention

Randomised controlled trial

Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)

Allocation concealment will be blinded. Hospitals will be randomised via a computer generated random sequence, held by the AOANJRR. Hospitals will contact the AOANJRR to determine which form of prophylaxis (aspirin or LMWH) will be administered during the first study time period. Study investigators will be blinded to the allocation of each hospital.

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Randomisation will occur at the hospital level (clusters). Each site will be randomised to either aspirin or LMWH for a defined time period, unique to each hospital, based on volume of joint replacements each hospital performs. Randomisation will be via a 1:1 allocation with a computer generated random sequence. Simple randomisation will be used (no blocks or stratification).

Masking / blinding

Open (masking not used)

Who is / are masked / blinded?

Intervention assignment

Crossover

Other design features

We consider the trial a crossover trial. Randomisation will occur at the hospital level, rather than the patient level. Hospitals will prescribe aspirin or enoxaparin only (based on the randomisation sequence) for a given time period (determined by the volume of joint replacements performed by each hospital) and then crossover to the other drug for the second time period.

Phase

Phase 4

Type of endpoint/s

Efficacy

Statistical methods / analysis

Sample size
A recent large cohort study of 1900 THA and TKA patients from 19 institutions across Australia showed an incidence of symptomatic VTE within 90 days of THA and TKA of 2.6% (manuscript under preparation). A recent randomised trial of aspirin versus rivaroxaban used a minimum clinically important difference of 1%, based on a survey of thromboembolism experts and orthopaedic surgeons (Anderson et al, 2018).

For the sample size calculation in the CRISTAL study, we used an estimated overall event rate of 2% (a conservative estimate based on the recent Australian cohort study and the current available literature - Kulshrestha et al, 2013 and Bawa et al, 2018), the same non-inferiority margin of 1% from the recent randomised controlled trial (an event rate of 2.5% for aspirin and 1.5% for LMWH, Anderson et al, 2018), a power of 90% and a one-sided significance level of 0.025. For an individual randomised trial, this yields a sample size of 4,117 per treatment group or a total of 8,234 patients. For a cluster randomised crossover trial, the sample size must account for correlations within clusters during the same time period (intracluster correlation) and between study periods in the same cluster (interperiod correlation). Assuming an intracluster correlation of 0.01, an interperiod correlation of 0.008 and 31 clusters, the sample size required increases to 11,160 patients. From each cluster, we will aim to recruit 251 registered patients from each group (a total of 15,562 patients), which will allow a 27% loss to follow-up.

Due to uncertainty around the exact event rate and to allow for a smaller non-inferiority margin, we trialed different event rates and concluded that the trial will be adequately powered using a non-inferiority margin of 1%, for an event rate up to 3% at 80% power and for an event rate up to 2% at 90% power, provided that loss to follow-up is less than 17%. As a secondary measure, after 1,000 patients have completed the 90-day follow-up, we will obtain a preliminary symptomatic VTE rate for the whole sample and a loss to follow-up rate (without performing any comparative statistical analyses and maintaining blinding) to determine whether the estimates for the primary event rate (2%) and loss to follow-up rate (27%) are accurate and adjust the sample size accordingly if the primary event rate is greater than 3%, whilst accounting for loss to follow-up.

Statistical analysis
The analysis for the primary objective will be limited to patients undergoing elective primary THA or TKA for a diagnosis of OA, excluding patients for whom the study drugs were contraindicated (e.g., allergy or need for alternative anticoagulant – warfarin, NOAC, dual antiplatelet, for a pre-existing condition). This analysis will test between-group difference in the proportion of cases developing VTE within 90 days for non-inferiority of aspirin at a margin of 1%, on an intention to treat basis.

The primary analysis will use cluster summary methods (Turner et al, 2007). These methods estimate the treatment effect using cluster level differences and have been shown to be appropriate for cluster randomised crossover trials with rare outcomes and the intracluster and interperiod correlation coefficients expected in this trial (Forbes et al, 2015).

Multiple imputation to account for missing outcome data will be investigated, using auxiliary variables gathered from routine AOANJRR data (including age, sex, baseline health, pain and function, diagnosis and surgical factors). Since VTE is rare, if prediction in the imputation models using these auxiliary variables is a problem, no imputation will be performed due to the possibility of bias (White et al, 2010). Since the most likely reason for loss to follow-up is difficulty in contacting patients postoperatively (rather than any association with treatment assignment or outcome), missing outcome data is expected to be missing completely at random, which will not cause bias in the estimates.

Secondary analyses will be performed for the primary outcome, to test for differences in treatment effect between subgroups of patients: THA only, TKA only and bilateral joint replacement. The analysis method will be the same as the primary outcome and will include an interaction term between subgroup and treatment group.

Further secondary analyses will include an extension of the primary analysis for patients undergoing all forms of HA and KA (total, revision, partial) for any indication (non-OA diagnoses) and will include patients for whom the study drug was contraindicated. This will assess the effect of implementing the protocol at a departmental (hospital) level. Other secondary analyses will include an analysis of the subcategories of VTE as the outcome; PE only, all DVT, above knee DVT only and below knee DVT only and non-VTE related complications (death, re-operation, readmission and major bleeding rates). Cluster summary methods will be used for all secondary analyses.

Interim Analysis
As the trial is comparing two commonly used medications which are considered standard treatment for VTE prophylaxis following THA and TKA in Australia and the United States with a non-inferiority design, an interim analysis was not initially planned.

However, due to a concern regarding safety of one of the study drugs at one participating institution, a data safety and monitoring board (DSMB) was convened after the meeting of the CRISTAL Trial Management Committee (TMC) on the 4 August 2020. The DSMB convened consisted of a statistician, orthopaedic surgeon and haematologist, all of whom were independent to the trial.

The DSMB were advised to conduct an interim analysis. In liaison with the DSMB (prior to the interim analysis), the TMC applied the Haybittle-Peto stopping rule of a significance level of 0.001. This stopping rule was chosen as it does not require adjustment of the significance threshold for the final analysis and allows further interim analyses using the same threshold.

Secondary Studies
If aspirin is found to be inferior to LMWH, a cost effectiveness analysis of aspirin compared to LMWH will be performed from a health system perspective. Data for resource use associated with treatments and complications will be taken from trial data within the AOANJRR. Survival at one year and quality of life measured using EQ5D at baseline and 6 months will allow calculation of differences in quality adjusted life years (QALYs) between groups. We will calculate the cost per QALY for each treatment comparison as the difference in mean costs divided by the difference in mean outcomes (quality adjusted survival as QALYs) over the duration of the trial, using regression analysis to adjust for differences at baseline and clustering by site.

A secondary study comparing death within 90 days and revision joint surgery within 90 days and 6 months (defined as reoperation requiring change of any implanted prosthesis) for patients allocated to aspirin and those allocated to enoxaparin will be conducted. This will include all patients undergoing any hip or knee arthroplasty procedure at participating CRISTAL hospitals during the course of the trial. The aim of this will be to compare the effect of implementing the trial protocol at the hospital level.

A sub-study comparing rates of PWD between aspirin and LMWH groups at two sites participating in the CRISTAL trial will be performed. The analysis for this study will test the between-group difference in the proportion of cases developing PWD postoperatively, using the chi-square statistic and a logistic regression model, accounting for confounding patient and surgical factors (age, body mass index, sex, American Society of Anaesthesiologists grading, diabetes, rheumatoid arthritis, liver disease, cardiac disease, peripheral vascular disease, cerebrovascular disease, type of joint replacement, tourniquet use, tranexamic acid use and method of skin closure).

Recruitment

Recruitment status

Stopped early

Data analysis

Data analysis is complete

Reason for early stopping/withdrawal

Safety concerns
Other reasons/comments

Other reasons

First Interim Analysis
The DSMB completed the first interim analysis on the 9 September 2020 based on data collected from 5,812 procedures eligible for the primary outcome. After the first interim analysis, the DSMB found no strong evidence of a safety concern in the overall group of patients or the subgroup of patients with a prior history of VTE and recommended continuation of the trial with no change to the trial protocol. However, the DSMB requested a second interim analysis given that the last data extraction occurred in February 2020, to be conducted in November 2020.

Second Interim Analysis
In line with the DSMB's request, a second interim analysis was conducted on the 30 November 2020 on 8,296 eligible procedures undertaken before 31 July 2020 with follow-up until the 30 October 2020. The DSMB met on the 9 December 2020 and found a significant difference in the primary outcome between the two arms, at a significance level of less than 0.001, which was consistent across sites with well balanced baseline characteristics between the two arms. There was no evidence of a difference in other outcomes including major bleeding, death and further surgery. Based on this interim analysis, the DSMB recommended cessation of the trial in their report sent to the TMC on the 16 December 2020.

An emergency meeting of the TMC was convened on the 17 December 2020 and after clarifying the findings with the DSMB and in consultation with all investigators, the TMC made a decision on 18 December 2020 to cease recruitment as soon as possible. This was conveyed to all site investigators on the 18 December 2020.

Date of first participant enrolment

Anticipated

4/02/2019

Actual

15/04/2019

Date of last participant enrolment

Anticipated

31/08/2021

Actual

18/12/2020

Date of last data collection

Anticipated

1/06/2021

Actual

Sample size

Target

15562

Accrual to date

Final

9711

Recruitment in Australia

Recruitment state(s)

ACT,NSW,QLD,SA,TAS,WA,VIC

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

Medical Research Future Fund - National Health and Medical Research Council

Address [1]

16 Marcus Clarke St, Canberra ACT, 2601

Country [1]

Australia

Primary sponsor type

University

Name

University of New South Wales

Address

South West Sydney Clinical School, Goulburn Street, Liverpool, NSW, 2170

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Sydney Local Health District Ethics Review Committee (RPAH Zone) [EC00113]

Ethics committee address [1]

Research Ethics and Governance Office (REGO)
Royal Prince Alfred Hospital
Missenden Road
CAMPERDOWN NSW 2050

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

28/09/2018

Approval date [1]

11/12/2018

Ethics approval number [1]

X18-0424

Summary

Brief summary

Background
Total hip arthroplasty (THA) and total knee arthroplasty (TKA) are the two most costly procedures performed in Australia. Venous thromboembolism (VTE) – pulmonary embolism (PE) or deep venous thrombosis (DVT) remain serious complications of THA and TKA and there is current uncertainty regarding which drugs should be used as chemoprophylaxis. Low molecular weight heparin (LMWH) is the most commonly recommended and used, but many surgeons use aspirin as it is a safe, efficacious, easy to administer and a low cost alternative.

Study Aim
This study aims to compare LMWH and aspirin in VTE prevention in patients undergoing THA or TKA at hospitals contributing data to the Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR). It is hypothesised that aspirin will be non-inferior to LMWH in preventing symptomatic 90-day VTE.

Study Design and Intervention
The study will use the AOANJRR to perform a registry-nested, cluster randomised crossover trial. The intervention will be aspirin given orally (once daily, 85-150mg) and the comparator will be LMWH (enoxaparin, 40mg subcutaneously), both given for 35 days after THA and for 14 days after TKA.

Study Outcomes
The primary outcome is verified symptomatic VTE within 90 days in patients undergoing primary THA or TKA for osteoarthritis. Secondary outcomes will include a cost-effectiveness analysis, efficacy for all THA or TKA (revision, primary, performed for any diagnosis) and non-VTE complications between the two groups (including wound ooze as a sub-study).

Study Timeline
Thirty-one institutions have commenced recruiting patients in 2019. Recruitment of patients for the CRISTAL trial will take at least 12 months for each treatment arm, yielding approximately 15,500 patients. It is estimated the study will take a further 12 months to complete for data analysis and manuscript preparation. This would provide a conservative estimate of 4 years for study completion.

Trial website

Trial related presentations / publications

Public notes

Primary aim of trial has been completed.

Completion of secondary studies is currently underway and is expected to be complete by August 2023.

Contacts

Principal investigator

Name

Prof Ian Harris

Address

Whitlam Orthopaedic Research Centre, Ingham Institute for Applied Medical Research, South West Sydney Clinical School, UNSW Sydney

1 Campbell Street, Liverpool, NSW, 2170

Country

Australia

Phone

+61287389254

Fax

+61296027187

[email protected]

Contact person for public queries

Name

Dr Verinder Sidhu

Address

Whitlam Orthopaedic Research Centre, Ingham Institute for Applied Medical Research, South West Sydney Clinical School, UNSW Sydney

1 Campbell Street, Liverpool, NSW, 2170

Country

Australia

Phone

+14843883371

Fax

[email protected]

Contact person for scientific queries

Name

Dr Verinder Sidhu

Address

The Ingham Institute
1 Campbell St, Liverpool NSW, 2170

Country

Australia

Phone

+14843883371

Fax

[email protected]

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

Yes

What data in particular will be shared?

De-identified datasets and dictionaries will be made available for further research after trial completion and dissemination of the results via peer-review journal publication, upon request from the Chief Investigator (IAH).

When will data be available (start and end dates)?

After data analysis and dissemination of data via peer-review publication. Data is now available as of 16th November, 2022. There is no end-date for data availability.

Available to whom?

To authors who request the data for ongoing research in this area

Available for what types of analyses?

For meta-analyses and systematic reviews

How or where can data be obtained?

Data can be obtained upon request by contacting the Principal Investigator

What supporting documents are/will be available?

No Supporting Document Provided

Results publications and other study-related documents

Documents added manually

Type	Is Peer Reviewed?	DOI	Citations or Other Details	Attachment
Study results article	Yes		Sidhu VS, Kelly TL, et al. Effect of Aspirin vs En... [More Details]
Plain language summary	No		In this cluster-randomized, crossover trial that i... [More Details]

Documents added automatically

Source	Title	Year of Publication	DOI
Embase	Time for an Update? A Look at Current Guidelines for Venous Thromboembolism Prophylaxis After Hip and Knee Arthroplasty and Hip Fracture.	2021	https://dx.doi.org/10.1016/j.artd.2021.06.015
Embase	CRISTAL (a cluster-randomised, crossover, non-inferiority trial of aspirin compared to low molecular weight heparin for venous thromboembolism prophylaxis in hip or knee arthroplasty, a registry nested study): statistical analysis plan.	2021	https://dx.doi.org/10.1186/s13063-021-05486-0
Embase	Effect of Aspirin vs Enoxaparin on Symptomatic Venous Thromboembolism in Patients Undergoing Hip or Knee Arthroplasty: The CRISTAL Randomized Trial.	2022	https://dx.doi.org/10.1001/jama.2022.13416
Embase	Effect of Aspirin vs Enoxaparin on 90-Day Mortality in Patients Undergoing Hip or Knee Arthroplasty: A Secondary Analysis of the CRISTAL Cluster Randomized Trial.	2023	https://dx.doi.org/10.1001/jamanetworkopen.2023.17838
Embase	CRISTAL: Protocol for a cluster randomised, crossover, non-inferiority trial of aspirin compared to low molecular weight heparin for venous thromboembolism prophylaxis in hip or knee arthroplasty, a registry nested study.	2019	https://dx.doi.org/10.1136/bmjopen-2019-031657

N.B. These documents automatically identified may not have been verified by the study sponsor.

Trial Review

Documents added manually

Documents added automatically