Thrombosis, Venous
Conditions
Keywords
Haemorrhage, Thromboprophylaxis
Brief summary
Arixtra (fondaparinux sodium) was the first selective Factor Xa inhibitor to be marketed. As with all anticoagulants, an important adverse event associated with Arixtra use is haemorrhage. Previous studies using clinical trial and observational data show no difference in the risk of haemorrhage in patients treated with Arixtra compared to (low molecular weight heparins) LMWHs. This study will assess the risk of haemorrhage in major orthopaedic surgery patients (hip fracture surgery and/or hip/knee replacement surgery) treated with either Arixtra or LMWH for thromboprophylaxis and will provide additional observational data from a European country to strengthen the comprehensive review of haemorrhage and the post-marketing safety of Arixtra. All patients age 18 years and older with a primary discharge diagnosis for hip fracture surgery and/or a hospitalization for hip and/or knee replacement surgery from the PHARMO RLS database in the Netherlands are eligible for participation. For study inclusion patients must receive either Arixtra or LMWH as initial in-hospital thromboprophylactic agent and have at least three months in the PHARMO RLS database before cohort entry date. Patients with a history of hospitalization for haemorrhage, renal failure or liver failure in the past 3 months will be excluded. Descriptive statistics, including gender, age, length of treatment, co-morbidities, concomitant medications, and other covariates will be calculated. Data for this study were obtained from different registers in the PHARMO medical record linkage system (PHARMO RLS) in the Netherlands. The PHARMO medical record linkage system is a population-based patient-centric data tracking system that includes high quality and complete information of patient demographics, drug dispensing, and hospital morbidity records of approximately 2.3 million community-dwelling inhabitants of 48 geo-demographic areas in the Netherlands. The PHARMO registers are linked on a patient level and contain unprecedented accurate and complete information required for the study. The out patient database contains drug dispensing data in the U-Expo database are encoded according to standards based upon the Z-Index drug database (www.z-index.nl). Therefore, it is possible to identify and classify drug use in time, both on the basis of national and international classification schemes as well as on the basis of individual active ingredients and administration forms. Of each dispensed drug, the Anatomical Therapeutic Chemical (ATC) code, the dispensing date, the prescriber, the prescribed dosage regimen, the dispensed quantity, the cost and the estimated legend duration of use are available. The hospital pharmacy database comprises hospital pharmacy data collected in a growing number of non-academic hospitals in the Netherlands. Currently, data are collected on patient level for more than one million patients from a representative sample of non-academic hospital pharmacies scattered over the Netherlands. The hospital pharmacy database includes data on in-patient medication orders such as type of drug, dose, and time of administration and duration of use. The Dutch Medical Register (LMR) is the data source comprising all hospital admissions in the Netherlands (www.prismant.nl). These records include detailed information concerning the primary and secondary discharge diagnoses, diagnostic, surgical and treatment procedures, type and frequency of consultations with medical specialists and dates of hospital admission and discharge. All diagnoses are coded according to the International Classification of Diseases, 9th edition (ICD-9-CM). Currently, data until December 2008 are available.
Detailed description
Patients were not recruited for nor enrolled in this study. This study is a retrospective observational study. Data from medical records or insurance claims databases are anonymised and used to develop a patient cohort. All diagnoses and treatment are recorded in the course of routine medical practice.
Interventions
Fondaparinux sodium for thromboprophylaxis (ATC: B01AX05)
LMWH including: dalteparin, nadroparin, enoxaparin or tinzaparin (ATC:B01AB (excluding B01AB01))
Sponsors
GlaxoSmithKline
Study design
Observational model
COHORT
Time perspective
RETROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age 18 years and older; Treatment with either Arixtra or LMWH as initial in-hospital thromboprophylactic agent; At least three months history in the PHARMO RLS database before cohort entry date
Exclusion criteria
* Hospitalization for haemorrhage, renal failure or liver failure in the 3 months before cohort entry date
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With the Indicated Types of Haemorrhages During Hospitalization or Follow-up for Major Orthopaedic Surgery of Lower Limbs (MOSLL) | Follow-up continued until the date of first event, death, end of initial therapy, hospital discharge, end of follow-up in PHARMO RLS, or 60 days after discharge, whichever came first | Haemorrhages during MOSLL hospitalization or follow-up as identified by ICD-9-CM codes were measured. The PHARMO medical record linkage system (RLS), in the Netherlands, is a population-based patient-centric data tracking system that includes high quality/ complete information of patient demographics, drug dispensing, and hospital morbidity records of approximately 2.3 million inhabitants in the Netherlands. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With the Indicated Haemorrhages During Hospitalization for Major Orthopaedic Surgery of Lower Limbs (MOSLL) | Follow-up continued until the date of first event, death, end of initial therapy, hospital discharge, end of follow-up in PHARMO RLS, or 60 days after discharge, whichever came first. | Haemorrhages during MOSLL hospitalization or follow-up as identified by ICD-9-CM codes were measured. The PHARMO medical record linkage system (RLS), in the Netherlands, is a population-based patient-centric data tracking system that includes high quality/ complete information of patient demographics, drug dispensing, and hospital morbidity records of approximately 2.3 million inhabitants in the Netherlands. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Fondaparinux All dosages of fondaparinux | 1,559 |
| Low Molecular Weight Heparins (LMWHs) All dosages of LMWH, including Enoxaparin, Dalteparin, Nadroparin, and Tinzaparin | 11,883 |
| Total | 13,442 |
Baseline characteristics
| Characteristic | Low Molecular Weight Heparins (LMWHs) | Fondaparinux | Total |
|---|---|---|---|
| Age, Customized 18-64 years | 2962 Participants | 478 Participants | 3440 Participants |
| Age, Customized 65-74 years | 3433 Participants | 568 Participants | 4001 Participants |
| Age, Customized >=75 years | 5488 Participants | 513 Participants | 6001 Participants |
| Number of participants hospitalized because of hip surgery and knee surgery Hip surgery | 8810 participants | 1145 participants | 9955 participants |
| Number of participants hospitalized because of hip surgery and knee surgery Knee surgery | 3073 participants | 414 participants | 3487 participants |
| Number of participants with the indicated duration of follow-up 1-14 days | 4331 participants | 790 participants | 5121 participants |
| Number of participants with the indicated duration of follow-up 15-28 days | 1196 participants | 477 participants | 1673 participants |
| Number of participants with the indicated duration of follow-up 29-42 days | 2232 participants | 127 participants | 2359 participants |
| Number of participants with the indicated duration of follow-up >=43 days | 4124 participants | 165 participants | 4289 participants |
| Number of participants with the indicated duration of their in-hospital stay 0-7 days | 4826 participants | 994 participants | 5820 participants |
| Number of participants with the indicated duration of their in-hospital stay 11-14 days | 1608 participants | 75 participants | 1683 participants |
| Number of participants with the indicated duration of their in-hospital stay >=15 days | 2484 participants | 62 participants | 2546 participants |
| Number of participants with the indicated duration of their in-hospital stay 8-10 days | 2965 participants | 428 participants | 3393 participants |
| Number of participants with the indicated major risk factors or other key characteristics Cardiovascular disease | 2923 participants | 378 participants | 3301 participants |
| Number of participants with the indicated major risk factors or other key characteristics Hospitalization for cancer | 100 participants | 7 participants | 107 participants |
| Number of participants with the indicated major risk factors or other key characteristics Hospitalization for cerebrovascular disease | 30 participants | 1 participants | 31 participants |
| Number of participants with the indicated major risk factors or other key characteristics Hospitalization for hypercoagulable state | 0 participants | 0 participants | 0 participants |
| Number of participants with the indicated major risk factors or other key characteristics Hospitalization for thrombocytopenia | 0 participants | 1 participants | 1 participants |
| Number of participants with the indicated major risk factors or other key characteristics Hypertension | 5645 participants | 764 participants | 6409 participants |
| Number of participants with the indicated major risk factors or other key characteristics PAU: Fondaparinux | 0 participants | 2 participants | 2 participants |
| Number of participants with the indicated major risk factors or other key characteristics PAU: Heparin | 1 participants | 0 participants | 1 participants |
| Number of participants with the indicated major risk factors or other key characteristics PAU: LMWHs | 42 participants | 3 participants | 45 participants |
| Number of participants with the indicated major risk factors or other key characteristics PAU: Multiple agents | 11 participants | 0 participants | 11 participants |
| Number of participants with the indicated major risk factors or other key characteristics PAU: Vitamin K Antagonist (VKA) | 351 participants | 30 participants | 381 participants |
| Number of participants with the indicated major risk factors or other key characteristics Use of ns-NSAIDs | 2717 participants | 395 participants | 3112 participants |
| Number of participants with the indicated major risk factors or other key characteristics Use of platelet inhibitors | 2610 participants | 293 participants | 2903 participants |
| Sex: Female, Male Female | 8280 Participants | 1098 Participants | 9378 Participants |
| Sex: Female, Male Male | 3603 Participants | 461 Participants | 4064 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 0 / 0 | 0 / 0 |
Outcome results
Primary
Number of Participants With the Indicated Types of Haemorrhages During Hospitalization or Follow-up for Major Orthopaedic Surgery of Lower Limbs (MOSLL)
Haemorrhages during MOSLL hospitalization or follow-up as identified by ICD-9-CM codes were measured. The PHARMO medical record linkage system (RLS), in the Netherlands, is a population-based patient-centric data tracking system that includes high quality/ complete information of patient demographics, drug dispensing, and hospital morbidity records of approximately 2.3 million inhabitants in the Netherlands.
Time frame: Follow-up continued until the date of first event, death, end of initial therapy, hospital discharge, end of follow-up in PHARMO RLS, or 60 days after discharge, whichever came first
Population: From the PHARMO RLS, all patients \>=18 years of age with in-hospital pharmacy data, a primary discharge diagnosis for hip fracture and/or a hospitalization for MOSLL, and follow-up between January 2003 (introduction of Arixtra) and December 2008.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Fondaparinux | Number of Participants With the Indicated Types of Haemorrhages During Hospitalization or Follow-up for Major Orthopaedic Surgery of Lower Limbs (MOSLL) | Intracranial bleeds | 0 participants |
| Fondaparinux | Number of Participants With the Indicated Types of Haemorrhages During Hospitalization or Follow-up for Major Orthopaedic Surgery of Lower Limbs (MOSLL) | Urinary tract bleeding | 1 participants |
| Fondaparinux | Number of Participants With the Indicated Types of Haemorrhages During Hospitalization or Follow-up for Major Orthopaedic Surgery of Lower Limbs (MOSLL) | Bleeding or hematoma as complication of a surgery | 7 participants |
| Fondaparinux | Number of Participants With the Indicated Types of Haemorrhages During Hospitalization or Follow-up for Major Orthopaedic Surgery of Lower Limbs (MOSLL) | Epistaxis | 0 participants |
| Fondaparinux | Number of Participants With the Indicated Types of Haemorrhages During Hospitalization or Follow-up for Major Orthopaedic Surgery of Lower Limbs (MOSLL) | Gastrointestinal bleeds | 0 participants |
| Fondaparinux | Number of Participants With the Indicated Types of Haemorrhages During Hospitalization or Follow-up for Major Orthopaedic Surgery of Lower Limbs (MOSLL) | Hemarthrosis | 0 participants |
| Low Molecular Weight Heparins (LMWHs) | Number of Participants With the Indicated Types of Haemorrhages During Hospitalization or Follow-up for Major Orthopaedic Surgery of Lower Limbs (MOSLL) | Gastrointestinal bleeds | 9 participants |
| Low Molecular Weight Heparins (LMWHs) | Number of Participants With the Indicated Types of Haemorrhages During Hospitalization or Follow-up for Major Orthopaedic Surgery of Lower Limbs (MOSLL) | Intracranial bleeds | 1 participants |
| Low Molecular Weight Heparins (LMWHs) | Number of Participants With the Indicated Types of Haemorrhages During Hospitalization or Follow-up for Major Orthopaedic Surgery of Lower Limbs (MOSLL) | Epistaxis | 3 participants |
| Low Molecular Weight Heparins (LMWHs) | Number of Participants With the Indicated Types of Haemorrhages During Hospitalization or Follow-up for Major Orthopaedic Surgery of Lower Limbs (MOSLL) | Urinary tract bleeding | 1 participants |
| Low Molecular Weight Heparins (LMWHs) | Number of Participants With the Indicated Types of Haemorrhages During Hospitalization or Follow-up for Major Orthopaedic Surgery of Lower Limbs (MOSLL) | Hemarthrosis | 2 participants |
| Low Molecular Weight Heparins (LMWHs) | Number of Participants With the Indicated Types of Haemorrhages During Hospitalization or Follow-up for Major Orthopaedic Surgery of Lower Limbs (MOSLL) | Bleeding or hematoma as complication of a surgery | 10 participants |
Secondary
Number of Participants With the Indicated Haemorrhages During Hospitalization for Major Orthopaedic Surgery of Lower Limbs (MOSLL)
Haemorrhages during MOSLL hospitalization or follow-up as identified by ICD-9-CM codes were measured. The PHARMO medical record linkage system (RLS), in the Netherlands, is a population-based patient-centric data tracking system that includes high quality/ complete information of patient demographics, drug dispensing, and hospital morbidity records of approximately 2.3 million inhabitants in the Netherlands.
Time frame: Follow-up continued until the date of first event, death, end of initial therapy, hospital discharge, end of follow-up in PHARMO RLS, or 60 days after discharge, whichever came first.
Population: From the PHARMO RLS, all patients \>=18 years of age with in-hospital pharmacy data, a primary discharge diagnosis for hip fracture and/or a hospitalization for MOSLL, and follow-up between January 2003 (introduction of Arixtra) and December 2008.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Fondaparinux | Number of Participants With the Indicated Haemorrhages During Hospitalization for Major Orthopaedic Surgery of Lower Limbs (MOSLL) | Bleeding or hematoma as complication of a surgery | 1 participants |
| Fondaparinux | Number of Participants With the Indicated Haemorrhages During Hospitalization for Major Orthopaedic Surgery of Lower Limbs (MOSLL) | Epistaxis | 0 participants |
| Low Molecular Weight Heparins (LMWHs) | Number of Participants With the Indicated Haemorrhages During Hospitalization for Major Orthopaedic Surgery of Lower Limbs (MOSLL) | Bleeding or hematoma as complication of a surgery | 0 participants |
| Low Molecular Weight Heparins (LMWHs) | Number of Participants With the Indicated Haemorrhages During Hospitalization for Major Orthopaedic Surgery of Lower Limbs (MOSLL) | Epistaxis | 1 participants |