Venous Leg Ulcer
Conditions
Keywords
Venous ulcer, varicose ulcer, gravitational ulcer, aspirin
Brief summary
Venous leg ulcers (VLU) are the most common leg ulcer, can be painful, and limit work, lifestyles and activity, especially in older patients. There are few effective treatments - compression therapy (tight bandaging or stockings) helps healing, but about half the people with a VLU remain unhealed even after 12 weeks of treatment. Research suggests taking aspirin as well as using compression may speed up healing for VLU, but the current evidence is not enough to change clinical practice. We will conduct a randomised controlled trial to test whether using low dose aspirin (150 mg daily or placebo) really does speed up healing.
Detailed description
A pragmatic, community based, double-blind, placebo-controlled, randomised trial to determine whether low dose aspirin accelerates venous leg ulcer healing at 24 weeks when used in addition to compression. Participants in have compression therapy (system of choice guided by patient and/or clinical preference) as delivered through district nursing services at the study centres as a background treatment. Low dose aspirin (150 mg) or placebo will be taken once daily as an oral capsule. Participants will be district nursing service patients in five study centres in New Zealand with prevalent or incident venous leg ulcers. A venous leg ulcer will be defined as a wound on the lower leg that has remained unhealed for 4 or more weeks, appears to be primarily venous in aetiology with other causative diseases ruled out. If the participant has two or more venous leg ulcers, the largest ulcer will be the reference ulcer. Participants will receive three visits from the research nurse - visit 1 to screen for eligibility, visit 2 to consent and randomise the participant, visit 3 to collect outcome data. District nurses will continue to visit the participant (about weekly or more frequently if required) to provide routine care between research nurse visits. Block randomisation will be used, stratified by study centre and prognostic index (ulcer size greater than 5cm2 and ulcer duration greater than 6 months) to ensure a balance of participants within study centres and for participants likely to be slow healers. Research nurses in the study centres will contact a central telephone answering service, provide information on inclusion criteria, exclusion criteria, and relevant clinical history on consented participants. Randomised participants will receive a bottle of 168 capsules of study medication identified only by unique code and will take the capsule until the reference ulcer heals or up to 24 weeks, whichever occurs sooner. Participants will take the study medication for up to 24 weeks or until the reference ulcer heals. If the participant has a serious adverse event, needs to start taking aspirin, or must stop taking aspirin to use other medications, they will be withdrawn from treatment, although they will still be followed up at 24 weeks.
Interventions
DRUGAspirin
150 mg aspirin in capsule form once daily for up to 24 weeks
DRUGPlacebo
Matching placebo capsule containing inert bulking agent
Sponsors
Health Research Council, New Zealand
University of Auckland, New Zealand
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Identical placebo with only difference being unique code on bottle containing product.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Aged 18 years or older * Determined to have a venous leg ulcer (clinical indications of venous ulceration, Ankle Brachial Index ≥ 0.8, and other causative aetiologies ruled out) * Able to tolerate compression therapy * Able to provide written informed consent * Confirmation with participant's general practitioner that the participant can take low dose aspirin or placebo.
Exclusion criteria
* Pregnant or breast-feeding women * History of myocardial infarction, stroke, transient ischaemic attack, angina or significant peripheral arterial disease * History of adverse effects related to aspirin use * Currently using aspirin, or other anti-platelet or anticoagulant therapy * Opinion of screening medical practitioner at National Institute of Health Innovation that participant has an existing condition or treatment that is a contraindication to use of aspirin or to participation in the trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Complete Healing of Reference Ulcer | 24 weeks | Time to event (complete healing defined as intact skin with absence of scab) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Healed Venous Leg Ulcers | 24 weeks | Number of participants in each arm with completely healed reference ulcers at 24 weeks |
| Change in Health-related Quality of Life (Short Form 36) | Baseline, 24 weeks | Mean difference in change in Short Form 36 (SF36) from baseline to 24 weeks. Crude subscale scores for each group are not shown (each crude subscale is scored 0 to 100 at baseline and 24 weeks); higher mean differences in change from baseline to 24 weeks within groups indicate greater change on the subscales for that group. |
| Change in Health-related Quality of Life (EuroQol-5D 3L) | Baseline, 24 weeks | Mean difference in change measured by EuroQol 5D (EQ5D 3L) from baseline to 24 weeks. Crude health state scores for each group are not shown (health state is scored 0 to 100 at baseline and 24 weeks); higher mean differences in change from baseline to 24 weeks within groups indicate greater change on health state for that group. |
| Change in Estimated Ulcer Area | Baseline, 24 weeks | Change in estimated ulcer area from baseline to 24 weeks |
| Number of Participants With Adherence to Treatment | 24 weeks | Adherence to study medication as measured by pill counts (agreement between expected number of tablets remaining after healing and days to healing) |
| Incidence of Adverse Events at 24 Weeks | 24 weeks | Total number of different types of adverse events in participants who reported with any untoward medical event |
| Change in Health-related Quality of Life (Charing Cross Venous Ulcer Questionnaire) | 24 weeks | Mean difference in change in Charing Cross Venous Ulcer Questionnaire (CXVUQ)) from baseline to 24 weeks. Crude subscale scores for each group are not shown (each crude subscale is scored 0 to 100 at baseline and 24 weeks); higher mean differences in change from baseline to 24 weeks within groups indicate greater change on the subscales for that group. |
Participant flow
Recruitment details
Participants were screened and recruited from five study sites in New Zealand
Pre-assignment details
Enrolled participants were required to have their family physician confirm they could safely participate in the trial ie had no conditions that required treatment with aspirin and no conditions that contraindicated use of aspirin.
Participants by arm
| Arm | Count |
|---|---|
| Aspirin 150 mg capsule once daily for up to 24 weeks
Aspirin: 150 mg aspirin in capsule form once daily for up to 24 weeks | 125 |
| Placebo Matching inert capsule once daily for up to 24 weeks
Placebo: Matching placebo capsule containing inert bulking agent | 126 |
| Total | 251 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 2 | 0 |
| Overall Study | Lost to Follow-up | 0 | 3 |
| Overall Study | Moved out of area | 0 | 1 |
| Overall Study | Transferred to palliative care | 0 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 0 |
Baseline characteristics
| Characteristic | Aspirin | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 60.1 Years STANDARD_DEVIATION 17.1 | 56.2 Years STANDARD_DEVIATION 16.1 | 58.2 Years STANDARD_DEVIATION 16.7 |
| Ankle Brachial Index | 1.1 Ratio of SBP ankle/SBP arm STANDARD_DEVIATION 0.1 | 1.1 Ratio of SBP ankle/SBP arm STANDARD_DEVIATION 0.1 | 1.1 Ratio of SBP ankle/SBP arm STANDARD_DEVIATION 0.1 |
| Compression system High compression | 105 Participants | 102 Participants | 207 Participants |
| Compression system Hosiery | 8 Participants | 13 Participants | 21 Participants |
| Compression system Light compression | 11 Participants | 11 Participants | 22 Participants |
| Compression system Other | 1 Participants | 0 Participants | 1 Participants |
| Highest educational attainment None | 0 Participants | 1 Participants | 1 Participants |
| Highest educational attainment Postgraduate | 21 Participants | 11 Participants | 32 Participants |
| Highest educational attainment Primary school | 9 Participants | 6 Participants | 15 Participants |
| Highest educational attainment Secondary school | 66 Participants | 74 Participants | 140 Participants |
| Highest educational attainment Undergraduate | 9 Participants | 17 Participants | 26 Participants |
| Highest educational attainment Vocational/technical | 20 Participants | 17 Participants | 37 Participants |
| Medical history Diabetes | 13 Participants | 13 Participants | 26 Participants |
| Medical history Lower limb joint replacement | 16 Participants | 19 Participants | 35 Participants |
| Medical history Prior DVT | 11 Participants | 7 Participants | 18 Participants |
| Medical history Prior lower limb fracture | 18 Participants | 23 Participants | 41 Participants |
| Medical history Prior treatment for varicosities | 35 Participants | 33 Participants | 68 Participants |
| Race/Ethnicity, Customized Asian | 4 Participants | 5 Participants | 9 Participants |
| Race/Ethnicity, Customized Māori | 21 Participants | 16 Participants | 37 Participants |
| Race/Ethnicity, Customized NZ European/Pākehā | 77 Participants | 74 Participants | 151 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Pasifika | 23 Participants | 30 Participants | 53 Participants |
| Reference ulcer area | 2.6 square centimetres | 2.3 square centimetres | 2.5 square centimetres |
| Sex: Female, Male Female | 60 Participants | 58 Participants | 118 Participants |
| Sex: Female, Male Male | 65 Participants | 68 Participants | 133 Participants |
| Smoking status Current smoker | 16 Participants | 19 Participants | 35 Participants |
| Smoking status Former smoker | 47 Participants | 44 Participants | 91 Participants |
| Smoking status Never smoked | 62 Participants | 63 Participants | 125 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 125 | 0 / 126 |
| other Total, other adverse events | 20 / 125 | 18 / 126 |
| serious Total, serious adverse events | 11 / 125 | 10 / 126 |
Outcome results
Primary
Time to Complete Healing of Reference Ulcer
Time to event (complete healing defined as intact skin with absence of scab)
Time frame: 24 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Aspirin | Time to Complete Healing of Reference Ulcer | 77 days |
| Placebo | Time to Complete Healing of Reference Ulcer | 69 days |
Comparison: Placebo group = reference groupp-value: 0.24695% CI: [0.64, 1.13]Log Rank
Secondary
Change in Estimated Ulcer Area
Change in estimated ulcer area from baseline to 24 weeks
Time frame: Baseline, 24 weeks
Population: Ulcer area estimated using maximum width and length of the ulcer to calculate the area of an ellipse. We have previously shown this approach to be highly correlated with digital calculation of measured area (r=0.92).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aspirin | Change in Estimated Ulcer Area | 4.1 square centimetres | Standard Error 0.4 |
| Placebo | Change in Estimated Ulcer Area | 4.8 square centimetres | Standard Error 0.4 |
p-value: 0.2595% CI: [-1.9, 0.5]ANCOVA
Secondary
Change in Health-related Quality of Life (Charing Cross Venous Ulcer Questionnaire)
Mean difference in change in Charing Cross Venous Ulcer Questionnaire (CXVUQ)) from baseline to 24 weeks. Crude subscale scores for each group are not shown (each crude subscale is scored 0 to 100 at baseline and 24 weeks); higher mean differences in change from baseline to 24 weeks within groups indicate greater change on the subscales for that group.
Time frame: 24 weeks
Population: Only participants that provided both baseline and endpoint data were included in the analysis. Hence the number of participants included in this analysis is less than the number randomised.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Aspirin | Change in Health-related Quality of Life (Charing Cross Venous Ulcer Questionnaire) | Domestic activities | -6.6 score on a scale | Standard Error 1.1 |
| Aspirin | Change in Health-related Quality of Life (Charing Cross Venous Ulcer Questionnaire) | Emotional status | -9.4 score on a scale | Standard Error 1.8 |
| Aspirin | Change in Health-related Quality of Life (Charing Cross Venous Ulcer Questionnaire) | Cosmesis | -6.1 score on a scale | Standard Error 1.6 |
| Aspirin | Change in Health-related Quality of Life (Charing Cross Venous Ulcer Questionnaire) | Overall | -7.3 score on a scale | Standard Error 1.2 |
| Aspirin | Change in Health-related Quality of Life (Charing Cross Venous Ulcer Questionnaire) | Social function | -6.2 score on a scale | Standard Error 1.3 |
| Placebo | Change in Health-related Quality of Life (Charing Cross Venous Ulcer Questionnaire) | Overall | -5.5 score on a scale | Standard Error 1.2 |
| Placebo | Change in Health-related Quality of Life (Charing Cross Venous Ulcer Questionnaire) | Social function | -4.7 score on a scale | Standard Error 1.3 |
| Placebo | Change in Health-related Quality of Life (Charing Cross Venous Ulcer Questionnaire) | Domestic activities | -5.2 score on a scale | Standard Error 1.2 |
| Placebo | Change in Health-related Quality of Life (Charing Cross Venous Ulcer Questionnaire) | Cosmesis | -4.9 score on a scale | Standard Error 1.6 |
| Placebo | Change in Health-related Quality of Life (Charing Cross Venous Ulcer Questionnaire) | Emotional status | -6.5 score on a scale | Standard Error 1.8 |
Comparison: Change in social functionp-value: 0.43895% CI: [-5.2, 2.2]Regression, Linear
Comparison: Change in domestic activitiesp-value: 0.40895% CI: [-4.5, 1.9]Regression, Linear
Comparison: Change in cosmesisp-value: 0.56895% CI: [-5.6, 3.1]Regression, Linear
Comparison: Change in emotional statusp-value: 0.25795% CI: [-8.1, 2.2]Regression, Linear
p-value: 0.27395% CI: [-5.2, 1.5]Regression, Linear
Secondary
Change in Health-related Quality of Life (EuroQol-5D 3L)
Mean difference in change measured by EuroQol 5D (EQ5D 3L) from baseline to 24 weeks. Crude health state scores for each group are not shown (health state is scored 0 to 100 at baseline and 24 weeks); higher mean differences in change from baseline to 24 weeks within groups indicate greater change on health state for that group.
Time frame: Baseline, 24 weeks
Population: Only participants that provided both baseline and endpoint data were included in the analysis. Hence the number of participants included in this analysis is less than the number randomised.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aspirin | Change in Health-related Quality of Life (EuroQol-5D 3L) | 7.4 score on a scale | Standard Error 1.6 |
| Placebo | Change in Health-related Quality of Life (EuroQol-5D 3L) | 4.0 score on a scale | Standard Error 1.7 |
p-value: 0.15695% CI: [-1.3, 8]Regression, Linear
Secondary
Change in Health-related Quality of Life (Short Form 36)
Mean difference in change in Short Form 36 (SF36) from baseline to 24 weeks. Crude subscale scores for each group are not shown (each crude subscale is scored 0 to 100 at baseline and 24 weeks); higher mean differences in change from baseline to 24 weeks within groups indicate greater change on the subscales for that group.
Time frame: Baseline, 24 weeks
Population: Only participants that provided both baseline and endpoint data were included in the analysis. Hence the number of participants included in this analysis is less than the number randomized.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Aspirin | Change in Health-related Quality of Life (Short Form 36) | Physical Functioning | 5.0 units on a scale | Standard Error 2.2 |
| Aspirin | Change in Health-related Quality of Life (Short Form 36) | Role Physical | 11.7 units on a scale | Standard Error 3.4 |
| Aspirin | Change in Health-related Quality of Life (Short Form 36) | Bodily Pain | 11.4 units on a scale | Standard Error 2.2 |
| Aspirin | Change in Health-related Quality of Life (Short Form 36) | General Health | -1.1 units on a scale | Standard Error 1.4 |
| Aspirin | Change in Health-related Quality of Life (Short Form 36) | Vitality | 3.9 units on a scale | Standard Error 1.6 |
| Aspirin | Change in Health-related Quality of Life (Short Form 36) | Social Functioning | 5.8 units on a scale | Standard Error 2.2 |
| Aspirin | Change in Health-related Quality of Life (Short Form 36) | Role Emotional | 10.5 units on a scale | Standard Error 3.1 |
| Aspirin | Change in Health-related Quality of Life (Short Form 36) | Mental Health | -1.2 units on a scale | Standard Error 1.4 |
| Placebo | Change in Health-related Quality of Life (Short Form 36) | Mental Health | 1.2 units on a scale | Standard Error 1.4 |
| Placebo | Change in Health-related Quality of Life (Short Form 36) | Physical Functioning | 3.8 units on a scale | Standard Error 2.2 |
| Placebo | Change in Health-related Quality of Life (Short Form 36) | Vitality | -0.3 units on a scale | Standard Error 1.6 |
| Placebo | Change in Health-related Quality of Life (Short Form 36) | Role Physical | 10.3 units on a scale | Standard Error 3.4 |
| Placebo | Change in Health-related Quality of Life (Short Form 36) | Role Emotional | 6.8 units on a scale | Standard Error 3.1 |
| Placebo | Change in Health-related Quality of Life (Short Form 36) | Bodily Pain | 9.0 units on a scale | Standard Error 2.2 |
| Placebo | Change in Health-related Quality of Life (Short Form 36) | Social Functioning | 4.9 units on a scale | Standard Error 2.2 |
| Placebo | Change in Health-related Quality of Life (Short Form 36) | General Health | -0.8 units on a scale | Standard Error 1.4 |
Comparison: Change in Physical Functioningp-value: 0.71495% CI: [-5, 7.2]Regression, Linear
Comparison: Change in Role Physicalp-value: 0.76895% CI: [-8, 10.8]Regression, Linear
Comparison: Change in Bodily Painp-value: 0.44995% CI: [-3.7, 8.4]Regression, Linear
Comparison: Change in General Healthp-value: 0.87395% CI: [-4.3, 3.6]Regression, Linear
Comparison: Change in Vitalityp-value: 0.05795% CI: [-0.1, 8.5]Regression, Linear
Comparison: Change in Social Functioningp-value: 0.75695% CI: [-5.1, 7]Regression, Linear
Comparison: Change in Role Emotionalp-value: 0.495% CI: [-4.9, 12.3]Regression, Linear
Comparison: Change in Mental Healthp-value: 0.23695% CI: [-6.2, 1.5]Regression, Linear
Secondary
Incidence of Adverse Events at 24 Weeks
Total number of different types of adverse events in participants who reported with any untoward medical event
Time frame: 24 weeks
Population: Only participants that reported any reported untoward medical event were included in this analysis.
| Arm | Measure | Category | Value (COUNT_OF_UNITS) |
|---|---|---|---|
| Aspirin | Incidence of Adverse Events at 24 Weeks | Respiratory | 3 Number of events |
| Aspirin | Incidence of Adverse Events at 24 Weeks | Psychiatric | 1 Number of events |
| Aspirin | Incidence of Adverse Events at 24 Weeks | Cardiovascular | 0 Number of events |
| Aspirin | Incidence of Adverse Events at 24 Weeks | Signs & symptoms | 7 Number of events |
| Aspirin | Incidence of Adverse Events at 24 Weeks | Genitourinary | 2 Number of events |
| Aspirin | Incidence of Adverse Events at 24 Weeks | Leg ulcer bleeding | 2 Number of events |
| Aspirin | Incidence of Adverse Events at 24 Weeks | Cancer | 6 Number of events |
| Aspirin | Incidence of Adverse Events at 24 Weeks | Leg ulcer infection | 2 Number of events |
| Aspirin | Incidence of Adverse Events at 24 Weeks | Skin & cutaneous | 1 Number of events |
| Aspirin | Incidence of Adverse Events at 24 Weeks | Extension of leg ulcer | 1 Number of events |
| Aspirin | Incidence of Adverse Events at 24 Weeks | Gastrointestinal | 8 Number of events |
| Aspirin | Incidence of Adverse Events at 24 Weeks | New leg ulcer | 1 Number of events |
| Aspirin | Incidence of Adverse Events at 24 Weeks | Accidental injury | 4 Number of events |
| Aspirin | Incidence of Adverse Events at 24 Weeks | Other | 2 Number of events |
| Placebo | Incidence of Adverse Events at 24 Weeks | Accidental injury | 4 Number of events |
| Placebo | Incidence of Adverse Events at 24 Weeks | Gastrointestinal | 4 Number of events |
| Placebo | Incidence of Adverse Events at 24 Weeks | Cancer | 1 Number of events |
| Placebo | Incidence of Adverse Events at 24 Weeks | Cardiovascular | 4 Number of events |
| Placebo | Incidence of Adverse Events at 24 Weeks | Respiratory | 0 Number of events |
| Placebo | Incidence of Adverse Events at 24 Weeks | Genitourinary | 0 Number of events |
| Placebo | Incidence of Adverse Events at 24 Weeks | Skin & cutaneous | 5 Number of events |
| Placebo | Incidence of Adverse Events at 24 Weeks | Other | 3 Number of events |
| Placebo | Incidence of Adverse Events at 24 Weeks | Psychiatric | 0 Number of events |
| Placebo | Incidence of Adverse Events at 24 Weeks | Signs & symptoms | 5 Number of events |
| Placebo | Incidence of Adverse Events at 24 Weeks | Leg ulcer bleeding | 2 Number of events |
| Placebo | Incidence of Adverse Events at 24 Weeks | Leg ulcer infection | 4 Number of events |
| Placebo | Incidence of Adverse Events at 24 Weeks | Extension of leg ulcer | 2 Number of events |
| Placebo | Incidence of Adverse Events at 24 Weeks | New leg ulcer | 3 Number of events |
p-value: 0.7195% CI: [0.7, 1.7]IRR test statistic
Secondary
Number of Participants With Adherence to Treatment
Adherence to study medication as measured by pill counts (agreement between expected number of tablets remaining after healing and days to healing)
Time frame: 24 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Aspirin | Number of Participants With Adherence to Treatment | 92 Participants |
| Placebo | Number of Participants With Adherence to Treatment | 92 Participants |
p-value: 0.91795% CI: [0.87, 1.17]Chi-squared
Secondary
Number of Participants With Healed Venous Leg Ulcers
Number of participants in each arm with completely healed reference ulcers at 24 weeks
Time frame: 24 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Aspirin | Number of Participants With Healed Venous Leg Ulcers | 88 Participants |
| Placebo | Number of Participants With Healed Venous Leg Ulcers | 101 Participants |
p-value: 0.07395% CI: [0.76, 1.01]Chi-squared