Venous Thromboembolism, Postpartum
Conditions
Keywords
postpartum, low molecular weight heparin, venous thromboembolism, prophylaxis, Dalteparin Sodium
Brief summary
The purpose of this study is to determine if it is feasible to conduct a multi-center randomized trial to determine whether a blood thinner, low-molecular-weight-heparin (LMWH), is effective at preventing blood clots, thromboembolism (VTE), in postpartum women at risk.
Detailed description
The PROPSER pilot is a randomized, open-label pilot study comparing prophylactic low molecular weight heparin (LMWH) to saline placebo. The PROSPER pilot study will assess the feasibility of conducting a full trial as measured by the number of subjects recruited per center per month. In addition, clinical data will be collected to determine an estimate of the primary outcome event rate (symptomatic VTE or asymptomatic proximal deep vein thrombosis (DVT) and major bleeding event rate for the full trial in LMWH and control groups. If our pilot results indicate that no substantial changes are needed to the study design, we will include the pilot data in the primary and secondary outcome analyses for the full trial (i.e. a Vanguard trial or internal pilot trial). Eligible consenting women at risk of postpartum thrombosis will be randomized within 36 hours after delivery of the placenta and will be equally allocated to 2 trial arms, either the treatment group: prophylactic-dose LMWH, subcutaneously once daily for 10 days (+/-3 days), or the control group. At 10 days (+/- 3 days), all women will have a study visit to assess for study outcomes, including bilateral leg ultrasound screening for VTE and a D-dimer test. A final telephone follow-up will occur at 90 days for outcome assessment of subsequent VTE, bleeding or other adverse events.
Interventions
5,000 IU/0.2ml (anti-Xa) administered once daily in prefilled glass syringes.
Sponsors
Canadian Institutes of Health Research (CIHR)
Ottawa Hospital Research Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Women must be at high risk for thromboembolism for one of the following reasons: 1. Known low risk thrombophilia (Known = diagnosed prior to enrollment and low risk thrombophilia includes heterozygous factor V Leiden or prothrombin gene variant or protein C deficiency or protein S deficiency. If not previously tested then assumed not to have thrombophilia). 2. Immobilization (defined as \>90% of waking hours in bed, of a week or more at any point in the antepartum period). OR any two of the following reasons: 1. Postpartum infection (fever (temperature\>38.5oC) and clinical signs/symptoms of infection and elevated neutrophil count (higher than local lab normal)) 2. Postpartum hemorrhage (Estimated blood loss \>1000 ml during delivery and postpartum) 3. Pre-pregnancy BMI \>25 kg/m2 4. Emergency cesarean birth (emergency = not planned prior to onset of labour) 5. Smoking \>5 cigarettes per day prior to pregnancy 6. Preeclampsia (blood pressure ≥ 140mmHG systolic and/or ≥90 mmHg diastolic on at least one occasion and proteinuria (1+ on urine dipstick or 300mg/dl or total excretion of 300mg/24 hours) or typical end-organ dysfunction. 7. Infant birth weight (adjusted for sex and gestational age) \<3rd percentile (i.e., small for gestational age).
Exclusion criteria
1. Less than 6 hours or more than 36 hours since delivery at the time of randomization 2. Need for anticoagulation as judged by the local investigator, may include but not limited to: 1. Personal history of previous provoked or unprovoked VTE (DVT or PE) 2. Continuation of LMWH that was started in the antenatal period for VTE prophylaxis 3. Mechanical heart valve 4. Known high-risk thrombophilia (Known = diagnosed prior to enrolment and high-risk thrombophilia includes deficiency of antithrombin (at least 1 abnormal lab result), persistently positive anticardiolipin antibodies (\> 30U/ml on two measurements a minimum of six weeks apart), persistently positive Anti B2 glycoprotein antibodies (\> 20U/ml on two measurements a minimum of six weeks apart), persistently positive lupus anticoagulant (positive on two measurements a minimum of six weeks apart), homozygous factor V Leiden (FVL), homozygous prothrombin gene mutation (PGM), compound heterozygosity factor V Leiden (FVL) and prothrombin gene mutations (PGM), more than 1 thrombophilia (any combination of 2 or more: FVL, PGM, protein C deficiency, protein S deficiency). If not previously tested then assumed not to have thrombophilia). 3. Contraindication to heparin therapy, including: 1. History of heparin induced thrombocytopenia (HIT) 2. Platelet count of less than 80,000 x 106/L on postpartum Complete Blood Count(CBC) 3. Hemoglobin ≤ 75 g/L on postpartum CBC 4. Active bleeding at any site (not resolved prior to randomization) 5. Excessive postpartum vaginal bleeding (\>1 pad per hour prior to randomization). 6. Documented gastrointestinal ulcer within 6 weeks prior to randomization 7. History of heparin or LMWH allergy 8. Severe postpartum hypertension (systolic blood pressure (SBP) \> 200mm/hg and/or diastolic blood pressure (DBP) \> 120mm/hg) 9. Severe hepatic failure (INR \>1.8 if liver disease suspected) 4. Have received more than one dose of heparin or LMWH since delivery 5. \< age of legal majority in local jurisdiction (age \<18 in Canada) 6. Prior participation in PROSPER 7. Unable or refused to consent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Feasibility of Recruitment and Trial Operations. | 4 months | The average number of subjects that are recruited per site per month during a 4 month active recruitment phase at each site. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Late Symptomatic Venous Thromboembolism | From Day 10 to Day 90 | This includes symptomatic Deep Vein Thrombosis or Pulmonary Embolism. Suspected outcomes will be adjudicated by a blinded adjudication committee. |
| Venous Thromboembolism in the Early Postpartum Period. | From randomization to Day 10 | This includes symptomatic Deep Vein Thrombosis (DVT) or pulmonary embolism (PE) in the interval between randomization and the last dose of study drug (10 days +/- 3 days) OR asymptomatic proximal DVT detected by compression ultrasound of both legs done within 24hrs of the last dose of study drug (10 days (+/- 3 days) postpartum). Compressed and non-compressed images will be obtained from the calf trifurcation to the inguinal ligament. All suspected outcomes will be adjudicated by a blinded expert adjudication committee. |
| Death From Venous Thromboembolism | From Randomization to Day 90 | If a subject dies between randomization and late postpartum follow up (Day 90 +/- 7 days) the death will be adjudicated as certain, highly probable, probable, or unlikely due to Pulmonary Embolism (PE) using the following criteria. Certain: hypotension, hypoxia, cardiac arrest with no other explanation other than PE and autopsy or radiographic confirmation Highly probable: criteria for certain but another disease could have caused the death Probable: other cause suspected based on clinical evidence but 100% certainty not available Unlikely: all other cases. |
| Major Bleeding or Clinically Relevant Non-major Bleeding | From Randomization to Day 90 | Major bleeding meets at least one of the following: Fatal bleeding; Symptomatic bleeding in a critical area or organ (intracranial, intraspinal, retroperitoneal, etc.); Bleeding causing a fall in hemoglobin level of 20 g L-1 (1.24 mmol L-1) or more, or leading to transfusion of two or more units of whole blood or red cells . Clinically Relevant Non-major Bleeding does not meet the criteria for major bleeding but meets at least one of the following: Hospitalization; Medical intervention; Unscheduled contact with a physician; Discomfort (pain, or impairment of activities of daily life). |
| Heparin Induced Thrombocytopenia | From Randomization to Day 90 | All subjects who develop thrombocytopenia (platelets less than 80 x 109/L and/or with \>50% decrease from baseline) will be investigated for Heparin Induced Thrombocytopenia (HIT) by having ELISA and serotonin release assays to confirm or refute a diagnosis of HIT. HIT will be diagnosed with a positive PF4 (platelet factor 4) HIT ELISA assay. |
Countries
Canada, United States
Participant flow
Recruitment details
Potential subjects were initially approached by a member of the health care team providing their care (physician, nurse, care facilitator, etc.). If the patient agreed to being contacted, the Investigator or designate provided detailed information regarding the study and assessed the individual's eligibility for the study.
Participants by arm
| Arm | Count |
|---|---|
| Low Molecular Weight Heparin Prophylactic-dose (5000 IU/0.2ml)low molecular weight heparin (LMWH), administered subcutaneously once daily in pre-filled glass syringes for 10 days (+/- 3 days) for a total of 10 (+/-3) study drug injections.
Dalteparin Sodium: 5,000 IU/0.2ml (anti-Xa) administered once daily in prefilled glass syringes. | 30 |
| Control Group No treatment control group. | 32 |
| Total | 62 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Low Molecular Weight Heparin | Total | Control Group |
|---|---|---|---|
| Age, Continuous | 30.0 years | 30.8 years | 31.6 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 4 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 28 Participants | 58 Participants | 30 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 7 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 24 Participants | 51 Participants | 27 Participants |
| Region of Enrollment Canada | 27 participants | 55 participants | 28 participants |
| Region of Enrollment United States | 3 participants | 7 participants | 4 participants |
| Sex: Female, Male Female | 30 Participants | 62 Participants | 32 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 3 / 30 | 0 / 32 |
| serious Total, serious adverse events | 2 / 30 | 0 / 32 |
Outcome results
Primary
Feasibility of Recruitment and Trial Operations.
The average number of subjects that are recruited per site per month during a 4 month active recruitment phase at each site.
Time frame: 4 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Low Molecular Weight Heparin | Feasibility of Recruitment and Trial Operations. | 0.9 participants per site per month |
| Control Group | Feasibility of Recruitment and Trial Operations. | 0.9 participants per site per month |
Secondary
Death From Venous Thromboembolism
If a subject dies between randomization and late postpartum follow up (Day 90 +/- 7 days) the death will be adjudicated as certain, highly probable, probable, or unlikely due to Pulmonary Embolism (PE) using the following criteria. Certain: hypotension, hypoxia, cardiac arrest with no other explanation other than PE and autopsy or radiographic confirmation Highly probable: criteria for certain but another disease could have caused the death Probable: other cause suspected based on clinical evidence but 100% certainty not available Unlikely: all other cases.
Time frame: From Randomization to Day 90
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Low Molecular Weight Heparin | Death From Venous Thromboembolism | 0 Participants |
| Control Group | Death From Venous Thromboembolism | 0 Participants |
Secondary
Heparin Induced Thrombocytopenia
All subjects who develop thrombocytopenia (platelets less than 80 x 109/L and/or with \>50% decrease from baseline) will be investigated for Heparin Induced Thrombocytopenia (HIT) by having ELISA and serotonin release assays to confirm or refute a diagnosis of HIT. HIT will be diagnosed with a positive PF4 (platelet factor 4) HIT ELISA assay.
Time frame: From Randomization to Day 90
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Low Molecular Weight Heparin | Heparin Induced Thrombocytopenia | 0 Participants |
| Control Group | Heparin Induced Thrombocytopenia | 0 Participants |
Secondary
Late Symptomatic Venous Thromboembolism
This includes symptomatic Deep Vein Thrombosis or Pulmonary Embolism. Suspected outcomes will be adjudicated by a blinded adjudication committee.
Time frame: From Day 10 to Day 90
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Low Molecular Weight Heparin | Late Symptomatic Venous Thromboembolism | 0 Participants |
| Control Group | Late Symptomatic Venous Thromboembolism | 0 Participants |
Secondary
Major Bleeding or Clinically Relevant Non-major Bleeding
Major bleeding meets at least one of the following: Fatal bleeding; Symptomatic bleeding in a critical area or organ (intracranial, intraspinal, retroperitoneal, etc.); Bleeding causing a fall in hemoglobin level of 20 g L-1 (1.24 mmol L-1) or more, or leading to transfusion of two or more units of whole blood or red cells . Clinically Relevant Non-major Bleeding does not meet the criteria for major bleeding but meets at least one of the following: Hospitalization; Medical intervention; Unscheduled contact with a physician; Discomfort (pain, or impairment of activities of daily life).
Time frame: From Randomization to Day 90
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Low Molecular Weight Heparin | Major Bleeding or Clinically Relevant Non-major Bleeding | 3 Participants |
| Control Group | Major Bleeding or Clinically Relevant Non-major Bleeding | 1 Participants |
Secondary
Venous Thromboembolism in the Early Postpartum Period.
This includes symptomatic Deep Vein Thrombosis (DVT) or pulmonary embolism (PE) in the interval between randomization and the last dose of study drug (10 days +/- 3 days) OR asymptomatic proximal DVT detected by compression ultrasound of both legs done within 24hrs of the last dose of study drug (10 days (+/- 3 days) postpartum). Compressed and non-compressed images will be obtained from the calf trifurcation to the inguinal ligament. All suspected outcomes will be adjudicated by a blinded expert adjudication committee.
Time frame: From randomization to Day 10
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Low Molecular Weight Heparin | Venous Thromboembolism in the Early Postpartum Period. | 0 Participants |
| Control Group | Venous Thromboembolism in the Early Postpartum Period. | 0 Participants |