Anticoagulant Treatment after VTE in the Netherlands: A Retrospective Cohort Study
DVT: Deep Venous Thrombosis;
PE: Pulmonary Embolism;
LMWH: Low-Molecular-Weight Heparin;
VKA: Vitamin K Antagonists;
GP: General Practitioner;
SD: Standard Deviation;
IQR: Interquartile Range
General characteristics and incidence of VTE
The study cohort included 1,581 VTE patients: 1,053 (67%) with DVT and 528 (33%) with PE. The incidence of VTE in the source population (linked GP and pharmacy data) was 1.10 per 1,000 person-years (95% CI 1.05-1.16); 0.73 per 1,000 person-
years (95% CI 0.69-0.78) for DVT and 0.37 per 1,000 person- years (95% CI 0.34-0.40) for PE. A cancer diagnosis was identified for 109 DVT patients (10%), 403 patients (38%) had a provoking risk factor and for 621 (59%) no risk factor was identified (‘unprovoked’). Among PE patients, 87 (16%) had a cancer diagnosis, 225 (43%) a provoking risk factor and 283 (54%) had unprovoked PE. Proportions of patients with provoking factors were similar for DVT and PE patients; non-active cancer (19 and 22%), recently hospitalized (12 and 13%), use of oestrogens (8 and 10%), recent surgery (7 and 8%), pregnancy/delivery (2%) and recent trauma (2 and 1%). Note that the cancer and provoked cohorts overlap as patients could have cancer as well as another risk factor.
The mean age (±SD) was 60 (±18) years for provoked DVT or PE and 61 (±16) years for unprovoked DVT or PE (Table 1). Patients with cancer were 68 (±13) years at DVT or PE diagnosis.
In the provoked cohort most patients were female (64%) as pregnancy and use of oestrogens was part of the cohort definition.
Anticoagulant treatment of VTE
Among 109 DVT patients with cancer, 92 (84%) had a dispensing record of LMWH or VKA within 90 days of DVT diagnosis (Table 2). Corresponding figures were 332 of 403 (82%) for provoked DVT and 434 of 621 (70%) for unprovoked DVT, and results were similar for PE patients: 75 of 87 (86%) in the cancer cohort, 190 of 225 (84%) in the provoked PE cohort and 217 of 283 (77%) in the unprovoked PE cohort.
Not all patients had records of both VKA and LMWH dispensings. More VKA only and relatively shorter treatment periods were observed among unprovoked VTE compared to provoked VTE (see below) and among patients with PE compared to DVT, which indicates missing information on initial in-hospital treatment. In the overall cancer cohort, both VKA and LMWH dispensing were observed for 30% of patients, LMWH but no VKA dispensing were observed for 36% and only VKA dispensing were observed for 20%. In the overall provoked cohort 42% had records of LMWH as well as VKA dispensing, 17% of LMWH only and 24% of VKA only. In the overall unprovoked cohort these respective percentages were 39%, 3% and 30%.
Persistence with anticoagulant treatment was in general higher among PE patients than among DVT patients and highest in the unprovoked cohorts. The median duration of anticoagulant treatment in the group with both LMWH and VKA dispensing within 90 days of the index date was 1.2 months among DVT patients with cancer, 3.8 months among patients with provoked DVT and 3.6 months among patients with unprovoked DVT (Table 2). Corresponding figures were 2.1, 2.1
Note: cohort numbers do not add up to the total of DVT or PE patients as the cancer and provoked cohorts are not mutually exclusive.
SD = standard deviation, VTE = venous thromboembolism, DVT = deep venous thrombosis and PE = pulmonary embolism
Table 1. General characteristics of patients diagnosed with DVT or PE, stratified by cohort
IQR = interquartile range, VTE = venous thromboembolism, DVT = deep venous thrombosis, PE = pulmonary embolism,
LMWH = low-molecular-weight heparin and VKA = vitamin K antagonists
Table 2. Anticoagulant treatment of first DVT or PE, stratified by cohort
and 5.2 months for PE patients. The median duration of LMWH treatment was 0.4 months (about 12 days) for these patients.Persistence was similar for patients with only VKA dispensings within 90 days.
The median duration of LMWH treatment in the group without VKA dispensing was 2.4 months among DVT patients with cancer, 1.8 months in the provoked cohort and 1.2 months in the unprovoked cohort. Among PE patients, median durations ofLMWH treatment were 5.5, 3.5 and 1.0 months in the respective cohorts.
Recurrent VTE was observed for 7 of 96 (7%) cancer patients with at least one year follow-up, 33 of 428 (8%) patients withprovoked VTE and 44 of 687 (6%) patients with unprovoked VTE (Table 3). None of the patients had a new entry within 30 days after the first event. Most recurrent events occurred after discontinuation of anticoagulant treatment. Most recurrentevents during initial treatment were observed among patients with unprovoked PE. Median duration of treatment was 1-3 months for patients with a recurrence after treatment compared to 1-7 months for patients who did not have a recurrenceduring the study period.
IQR = interquartile range, VTE = venous thromboembolism, DVT = deep venous thrombosis and PE = pulmonary embolism
Table 3. VTE recurrence after first DVT or PE in relation to anticoagulant treatment, stratified by cohort, among patients with at least one year follow-up
This study describes initial anticoagulant treatment after a first DVT or PE in the Netherlands during 2007-2011 related to the underlying risk factors, guidelines and recurrence rates. In this population based cohort study the incidence of DVT and PE in primary care corresponded well with previous studies in the Netherlands [15, 16].
VTE patients were classified in cohorts of underlying risk factors. Proportions of patients with cancer were 10% for DVT and 16% among patients with PE. Some previously reported cancer proportions were higher than in our study [5,17]. One of the reasons might be limited sensitivity in our database due to underreporting of cancer diagnoses in hospital and GP registrations.Furthermore, studies differed in study definitions and study design. In other previous reports comparable proportions of patients with VTE and cancer and with provoked VTE were found [18, 19].
For up to one third of the patients and mainly among unprovoked VTE patients, no dispensing record of either LMWH or VKA was observed within 90 days of diagnosis. Some of the patients who did not have a record of anticoagulant treatment may actually have missed treatment, but in a healthcare database study there are several reasons why treatment may goundetected. First, the date of diagnosis, which may in our database also be the date when the GP recorded the VTE diagnosis,might have been misclassified and the time window of observation therefore not correct. Second, patients may have obtained their drugs from another source than the out-patient pharmacy, such as a hospital pharmacy. Among PE patients, for example, a larger proportion had VKA dispensings but no LMWH dispensings, as compared to DVT patients. These patients likely received LMWH during hospital admission in the first week after diagnosis and in many cases will have completed LMWH bridging to VKA treatment prior to discharge. Third, some patients with superficial or distal VT, which may be untreated, were coded (misclassified) as DVT.
The guidelines at the time of the study advised treatment for three months for DVT patients with a clear trigger, and sixmonths for unprovoked thrombosis. In our study, we found that patients with provoked DVT or PE were treated for about 2 to 4 months which is according to the guidelines. The treatment duration of PE was likely underestimated as information on initial in-hospital treatment was not collected. In addition, the more recent guidelines  make the distinction between 3 months and long-term treatment instead of 6 months.
For unprovoked DVT and PE, the observed persistence with anticoagulant treatment when including VKA treatment was slightly shorter than recommended: about 3.5 to 5 months. However, as for PE overall, it should be noted that because information on initial in-hospital treatment was not collected, actual treatment durations, in particular LMWH treatment, were likely longer.
For patients with VTE without cancer, LMWH is advised only for initial treatment until INR is stable. In the provoked andunprovoked VTE cohorts the observed median duration of LMWH treatment was 0.4 months (about 12 days) for patients who also received VKA, which means that one of every two patients was treated with LMWH for more than two weeks outside of the hospital. The duration of LMWH treatment among patients who were hospitalized after diagnosis may be underestimated as mentioned before. On the other hand, out-patient treatment duration may have been overestimated because not all medication that was dispensed was actually used, i.e. ‘use’ in this study actually refers to the period covered by anticoagulant dispensings.
Among patients for whom only LMWH dispensing was observed in the first 90 days, the median treatment duration was 1.1 months for unprovoked VTE and 2.3 months for provoked VTE. Why we did not observe VKA treatment is unclear. Part of this will be explained by the overlap between the cancer cohort and provoked cohort; 55% of provoked patients were also in the cancer cohort and treated accordingly.
Treatment with LMWH for at least six months is recommended for cancer patients. In all subgroups, however the medianduration of LMWH treatment was shorter (0.5 to 5.5 months), which might be due to the short follow-up among cancer patients.
Recurrent VTE occurred in general after discontinuation of anticoagulant treatment. When comparing patients with recurrenceafter treatment and patients without recurrence, longer treatment durations were observed among patients without recurrence in all cohorts. This could be an indication that the treatment duration after a VTE should be longer than observed in real-life. However, the analysis was performed on a subcohort with few patients and limited follow-up and must be interpretedcautiously.
Our study was designed to collect information during a fiveyear observational period on first VTE, VTE treatment and recurrent VTE from GP data, outpatient pharmacy data and hospitalization records. The PHARMO GP Database is a large data source with ‘real-life data’ which is routinely collected. The GP acts as a gatekeeper in the Dutch healthcare system and all VTE diagnoses should be captured in the GP records. However, as the GP information system was designed for clinical practice, some information relevant for our research may not be available from the GP records. In this study for example, the VTE incidence and recurrence might be underestimated as fatal PE may go undetected. Furthermore, assumptions had to be made for the treatment duration, as the dosing of VKA takes place at the anticoagulation clinics, and only out-patient treatment was collected in the database.
In conclusion, treatment after VTE as captured in observational healthcare data generally follows the Dutch guidelines, except for the duration of LMWH treatment, which was longer than recommended. The observation of shorter anticoagulant treatment among patients with recurrent VTE compared to patients with no recurrence may indicate that anticoagulant treatment was not optimal for these patients.
Ethics approval and consent to participate
Consent for publication
Availability of data and materials
Data will not be shared, due to privacy regulations.
Kerstin Folkerts and Luke Bamber are employees of Bayer HealthCare Pharmaceuticals. Irene Bezemer, Elsa van den Berg, Fernie Penning- van Beest and Ron Herings are employees of the PHARMO Institute. This independent research institute performs financially supported studies for government and related healthcare authorities and several pharmaceutical companies.
This study was funded by Bayer HealthCare Pharmaceuticals / Bayer Pharma AG.
IDB, EJB, KF and LB were involved in the study design. IDB and EJB performed the analysis and wrote the first draft of the manuscript. All authors were involved in critical review and subsequent amendment of the manuscript.
2. Silverstein MD, Heit JA, Mohr DN, Petterson TM, O’Fallon WM et al. 3rd. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Archives of internal medicine. 1998, 158(6): 585-593.
3. Oger E. Incidence of venous thromboembolism: a communitybased study in Western France. EPI-GETBP Study Group. Groupe d’Etude de la Thrombose de Bretagne Occidentale. Thrombosis and haemostasis. 2000, 83(5): n657-660.
4. Nordstrom M, Lindblad B, Bergqvist D, Kjellstrom T. A prospective study of the incidence of deep-vein thrombosis within a defined urban population. Journal of internal medicine. 1992, 232(2): 155-160.
5. Cushman M, Tsai AW, White RH, Heckbert SR, Rosamond WD et al. Deep vein thrombosis and pulmonary embolism in two cohorts: the longitudinal investigation of thromboembolism etiology. The American journal of medicine. 2004, 117(1): 19-25.
7. Heit JA, O’Fallon WM, Petterson TM, Lohse CM, Silverstein MD et al. Relative impact of risk factors for deep vein thrombosis and pulmonary embolism: a population-based study. Archives of internal medicine. 2002, 162(11): 1245-1248.
11. Buller HR, Agnelli G, Hull RD, Hyers TM, Prins MH et al. Antithrombotic therapy for venous thromboembolic disease: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004, 126(3): 401S-428S.
13. Herings RMC, Pedersen L. Pharmacy -based Medical Record Linkage Systems. Strom BL, Kimmel S.E., Hennessy, S., editor. Pharmacoepidemiology, 5th Edition. 5th Edition ed: John Wiley & Sons, Ltd. 2012, 270-286.
14. van Herk-Sukel MP, Lemmens VE, Poll-Franse LV, Herings RM, Coebergh JW. Record linkage for pharmacoepidemiological studies in cancer patients. Pharmacoepidemiology and drug safety. 2012, 21(1): 94-103.
16. Van der Linden MW WG, De Bakker DH, Schellevis FG. Tweede Nationale Studie naar ziekten en verrichtingen in de huisartspraktijk: klachten en aandoeningen in de bevolking en in de huisartspraktijk.2004.
17. Tagalakis V, Patenaude V, Kahn SR, Suissa S. Incidence of and Mortality from Venous Thromboembolism in a Real-World Population: The Q-VTE Study Cohort. The American journal of medicine. 2013, 126(99): 832.e13-21.
18. Blom JW, Doggen CJ, Osanto S, Rosendaal FR. Malignancies, prothrombotic mutations, and the risk of venous thrombosis. JAMA : the journal of the American Medical Association. 2005, 293(6): 715-722.
19. Martinez C, Cohen AT, Bamber L, Rietbrock S. Epidemiology of first and recurrent venous thromboembolism: A populationbased cohort study in patients without active cancer. Thrombosis and haemostasis. 2014, 112(2): 255-263.
20. Kearon C, Kahn SR, Agnelli G, Goldhaber S, Raskob GE et al. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008: 133(6): 454S-545S.