|Year : 2016 | Volume
| Issue : 3 | Page : 657-661
The optimum duration of treatment for first time lower limb proximal deep vein thrombosis
Hatem A Saleh1, Asem F Mostafa2, Mostafa I Saad3
1 Department of Vascular Surgery, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Vascular Surgery, Alexandria Main University Hospital, Alexandria University, Alexandria, Egypt
3 Department of Vascular Surgery, Sharq El-Madina Hospital, Alexandria, Egypt
|Date of Submission||01-Apr-2015|
|Date of Acceptance||04-May-2015|
|Date of Web Publication||23-Jan-2017|
Mostafa I Saad
Department of Vascular Surgery, Sharq El Madina Hospital, Alexandria, 215119
Source of Support: None, Conflict of Interest: None
The aim of this study was to define the optimum duration required for treatment of first time proximal lower limb deep vein thrombosis (DVT).
DVT refers to the formation of one or more blood clots in one of the body's deep veins, most commonly in the lower limbs (proximal lower limb veins such as iliac, femoral or popliteal veins and distal lower limb veins such as calf veins). The optimal duration of treatment for first time proximal DVT is still controversial. The aim of this study was to define the optimal duration required for the treatment of first time proximal lower limb DVT.
Materials and methods
We reviewed papers on the optimal duration required for treatment of first time proximal lower limb DVT from Medline databases (Pub Med, Medscape, and ScienceDirect) and also from materials available in the Internet. We used optimal duration/treatment/first time proximal lower limb DVT as searching terms. The search was performed in the electronic databases from 2000 to 2014.
Three months of therapy is an efficient and a safe method for the treatment of first attack of proximal lower limb DVT and thus there is no need for extending the duration of therapy.
Keywords: deep vein thrombosis, optimal duration, venous thromboembolism
|How to cite this article:|
Saleh HA, Mostafa AF, Saad MI. The optimum duration of treatment for first time lower limb proximal deep vein thrombosis. Menoufia Med J 2016;29:657-61
|How to cite this URL:|
Saleh HA, Mostafa AF, Saad MI. The optimum duration of treatment for first time lower limb proximal deep vein thrombosis. Menoufia Med J [serial online] 2016 [cited 2020 Feb 17];29:657-61. Available from: http://www.mmj.eg.net/text.asp?2016/29/3/657/198750
| Introduction|| |
Venous thromboembolism (VTE) is a condition in which a blood clot (a thrombus) forms in a vein, most commonly in the deep veins of the legs or pelvis. This is known as deep vein thrombosis (DVT). The thrombus can dislodge and travel in the blood, particularly to the pulmonary arteries. This is known as pulmonary embolism (PE). The term 'VTE' includes both DVT and PE  .
Most thrombi are asymptomatic and are confined to the deep veins of the calf. About 20-30% of untreated calf vein thrombi extend proximally into the thigh, where, if untreated, they pose a 40-50% risk of PE and a mortality rate of about 25%. Autopsy studies indicate that many PEs are clinically undetected and likely contribute to additional morbidity and mortality  .
DVT and PE are two aspects of one disease process known as VTE. In DVT, a thrombus (blood clot) forms in the deep veins of the leg or pelvis where it may cause pain, tenderness, and swelling of the leg. In PE, some or all of the thrombus becomes detached and moves from the vein through the right side of the heart to lodge in one or more pulmonary arteries. PE may cause shortness of breath, bloody sputum, chest pain, faintness, and heart failure. Massive PE leads to death  .
Risk factors for VTE
According to Heit et al., 2002 following are the risk factors for VTE.
- Previous DVT or family history of thrombosis
- Coagulation abnormalities, including positive factor V Leiden, positive prothrombin 20210A, elevated serum homocysteine, protein C deficiency, protein S deficiency, or excessive plasminogen activator inhibitor
- Age over 40 years (incidence increases with age).
- Obesity (BMI >25 kg/m 2 ).
- Immobility, such as bed rest or sitting for long periods
- Major trauma (<1 month)
- Acute spinal cord injury (<1 month)
- Recent surgery (<1 month)
- Stroke (<1 month)
- Limb trauma and/or orthopedic procedures
- Limb immobilized with plaster cast (<1 month)
- Previous or current cancer
- Cancer therapy (hormonal, chemotherapy, or radiotherapy)
- Serious lung disease, including pneumonia (<1 month)
- Abnormal pulmonary function (chronic obstructive pulmonary disease)
- Indwelling central venous catheter
- nflammatory bowel disease
- Acute infection (<1 month)
- Cardiac dysfunction, including heart failure (<1 month)
- Severe sepsis
- Nephrotic syndrome
- Autoimmune disease, including systemic lupus erythematosus
- Myeloproliferative disorders
- Varicose veins
- Swollen legs (current)
- Hormone therapy or oral contraceptives
- Pregnancy or postpartum period.
The most common risk factors are obesity, previous VTE, malignancy, surgery, and immobility. Each is found in 20-30% of patients. Hospitalized and nursing home patients often have several risk factors and account for one-half of all DVT (with an incidence of one case per 100 hospitalized population)  . Among the multiple cardiac-related risk factors for DVT, acute coronary syndrome and unstable angina are not considered risk factors for DVT  .
The aim of this study was to define the optimal duration required for treatment of first time proximal lower limb DVT.
| Materials and methods|| |
We reviewed papers on the optimal duration required for treatment of first time proximal lower limb DVT from Medline databases (Pub Med, Medscape, ScienceDirect) and also from materials available in the Internet. We used optimal duration/treatment/first time proximal lower limb DVT as searching terms. The search was performed in the electronic databases from 2000 to 2014.
All studies were independently assessed for inclusion. They were included if they fulfilled the inclusion criteria.
Inclusion criteria for the published studies
- Published in English language
- Published in peer-reviewed journals
- Focused on treatment of proximal first time DVT
- Discussed the optimal duration required for treatment of first time proximal DVT
- Latest publication giving the most relevant data in case of a study having several publications on certain aspects.
If the studies did not fulfill the above criteria, they were excluded, such as studies on recurrent DVT, DVT during pregnancy, and proximal DVT.
The analyzed publications were evaluated on the basis of evidence-based medicine (EBM) criteria using the classification of the US Preventive Services Task Force and UK National Health Service protocol for EBM in addition to the Evidence Pyramid ([Figure 1]).
Classification according to the US Preventive Services Task Force.
- Level I: evidence obtained from at least one properly designed randomized controlled trial
- Level II-1: evidence obtained from well-designed controlled trials without randomization
- Level II-2: evidence obtained from well-designed cohort or case-control analytic studies, preferably from more than one center or research group
- Level II-3: evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled trials might also be regarded as this type of evidence
- Level III: opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees.
The quality of all studies was assessed. Important factors included study design, attainment of ethical approval, evidence of a power calculation, specified eligibility criteria, appropriate controls, and adequate information and specified assessment measures. It was expected that confounding factors would be reported and controlled for and appropriate data analysis made, in addition to an explanation of missing data.
A structured systematic review was performed with the results tabulated.
| Results|| |
Study selection and characteristics
A total of 70 potentially relevant publications were identified; 64 articles were excluded as they did not meet our inclusion criteria ([Figure 2]). A total of six studies were included in the review as they were deemed eligible by fulfilling the inclusion criteria. The six studies were human studies.
The results of the six studies are tabulated in [Table 1] representing the optimal duration required for the treatment of first time proximal DVT.
|Table 1 Studies investigating the optimal duration required for the treatment of first time proximal lower limb deep vein thrombosis |
Click here to view
The optimal duration required for the treatment of first time proximal lower limb deep vein thrombosis was investigated in the following six studies.
The first one is the study by Campbell et al.  , which was a multicenter prospective randomized study, with level I (or level A) EBM.
Among the patients allocated to 3 months of treatment, two died from DVT or PE during or after treatment, compared with three in the 6-month group. During treatment, DVT or PE failed to resolve, extended, or recurred in six patients in the 3-month group without fatal consequences, compared with 10 in the 6-month group. After treatment, there were 23 nonfatal recurrences in the 3-month group and 16 nonfatal recurrences in the 6-month group. Therefore, for patients with DVT or PE and no known risk factors for recurrence, there seems to be little, if any, advantage in increasing the duration of anticoagulation from 3 to 6 months. Any possible advantage would be small and would need to be judged against the increased risk of hemorrhage associated with the longer duration of treatment with warfarin.
Second is a study by Pinede et al.  , which was a meta-analysis of randomized controlled trials, with level I (or level A) EBM.
The researchers stated that, after a first episode of VTE, a long-term treatment regimen (beyond 3 months) allows a significant reduction in the incidence of recurrences without increasing the incidence of bleeding events.
Third is a study by Agnelli et al.  , which was a randomized, multicenter, open trial with independent, blinded assessment of the outcome events, level I or (level A) EBM.
The primary intention-to-treat analysis showed that, of the 134 patients assigned to continued oral anticoagulant therapy after 3 months, 21 had recurrence of VTE compared with 21 of 133 patients assigned to the discontinuation of oral anticoagulant therapy, resulting in a relative risk of 0.99. During the initial 9 months after randomization (after all patients received 3 months of therapy), one patient had a recurrence when receiving oral anticoagulant therapy, compared with 11 patients assigned to the discontinuation of oral anticoagulant therapy. The incidence of recurrence after the discontinuation of treatment was 5.1% per patient-year in patients in whom oral anticoagulant therapy was discontinued after 3 months and 5.0% per patient-year in patients who received an additional 9 months of oral anticoagulant therapy. None of the recurrences were fatal. Four patients had nonfatal major bleeding during the extended period of anticoagulant therapy.
In conclusion, in patients with idiopathic deep venous thrombosis, the clinical benefit associated with extending the duration of anticoagulant therapy to 1 year is not maintained.
Fourth is a study by Wells et al.  , which was a double-blinded randomized study, with level I (or level A) EBM.
The study showed that, of the 83 patients assigned to continue to receive placebo, 17 had a recurrent episode of VTE, compared with one of 79 patients assigned to receive warfarin. Warfarin resulted in 95% reduction in the risk of recurrent VTE. Three patients assigned to the warfarin group had nonfatal major bleeding (two had gastrointestinal bleeding and one had genitourinary bleeding), compared with none in the placebo group.
It proved that patients with a first episode of idiopathic VTE should be treated with anticoagulant agents for longer than 3 months.
Fifth is a study by Kearon et al.  , which was a randomized double-blind study of level I (or level A) EBM.
In this study, of the 84 patients assigned to placebo, five had recurrent VTE, compared with three of 81 assigned to warfarin, resulting in an absolute risk difference of 2.3%. The incidence of recurrent VTE after discontinuation of warfarin was 6.8% per patient-year in those who received warfarin for 1 month and 3.2% per patient-year in those who received warfarin for 3 months. There were no major bleeding incidents in either group.
This study stated that the duration of anticoagulant therapy for VTE provoked by a transient risk factor should not be reduced from 3 to 1 month, as this is likely to increase recurrent VTE without achieving a clinically important decrease in bleeding.
Finally, sixth is a study by Boutitie et al.  that pooled analysis of individual participants' data from seven randomized trials.
The results of the study were as follows: recurrence was lower after isolated distal DVT than after proximal deep vein; it was similar after PE and proximal DVT and lower after thrombosis provoked by a temporary risk factor than after unprovoked thrombosis. Recurrence was higher if anticoagulation was stopped at 1.0 or 1.5 months compared with that when stopped at 3 months or later, and it was similar if treatment was stopped at 3 months compared with that when stopped at 6 months or later. High rates of recurrence associated with shorter durations of anticoagulation were confined to the first 6 months after stopping treatment.
The study concluded that 3 months of treatment achieves a similar risk of recurrent VTE after stopping anticoagulation to a longer course of treatment. Unprovoked proximal DVT and PE have a high risk of recurrence whenever treatment is stopped.
| Discussion|| |
The duration of anticoagulant treatment following DVT and PE remains controversial. Nevertheless, several facts have been highlighted in the past two decades that should help establish guidelines on the basis of evidence rather than variable opinions of leaders in the field. Obviously, the duration of anticoagulation should be dictated by the balance between two risks: the risk of recurrent VTE with and without treatment and the risk of treatment-induced hemorrhage. In the present review, we used the terms idiopathic (or unprovoked) and secondary (provoked) to characterize thromboembolic events that occurred in the absence or in the presence of obvious provoking factors, such as surgery or trauma.
Reviewing the recent studies as regards the optimal duration required for the treatment of proximal first time lower limb DVT, we found that a duration of 3 months of therapy is sufficient for treatment. Extending the duration of therapy beyond 3 months can increase the risk of bleeding without beneficial effect in prevention of recurrence of DVT.
| Conclusion|| |
Three months of therapy is an efficient and a safe method for treatment of first attack of proximal lower limb DVT and thus there is no need for extending the duration of therapy, as it does not decrease the chance of recurrence and increases the risk of bleeding without a necessary reason.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Chong LY, Fenu E, Stansby G, Hodgkinson S. Managementof venous thromboembolic diseases and the role of thrombophilia testing: summary of NICE guidance. BMJ 2012; 344
Geerts WH, Bergqvist D, Pineo GF, Heit JA, Samama CM, Lassen MR, Colwell CW. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8 th
edition). Chest 2008; 133
Heit JA, O'Fallon WM, Petterson TM, Lohse CM, Silverstein MD, Mohr DN, Melton LJ 3 rd
. Relative impact of risk factors for deep vein thrombosis and pulmonary embolism: a population-based study. Arch Intern Med 2002; 162(11)
Reda AA, Abdelazez WF, Yaseen RI, Galal Elsawaf MM. Risk factor profile and in-hospital complications in patients admitted with acute coronary syndrome in Menoufia Governorate. Menoufia Med J 2014; 27
Campbell IA, Bentley DP, Prescott RJ, Routledge PA, Shetty HG, Williamson IJ. Anticoagulation for three versus six months in patients with deep vein thrombosis or pulmonary embolism, or both: randomised trial. BMJ 2007; 334(7595)
Pinede L, Ninet J, Duhaut P; Chabaud S, Demolombe-Rague S, Durieu I, et al.
Comparison of 3 and 6 months of oral anticoagulant therapy after a first episode of proximal deep vein thrombosis or pulmonary embolism and comparison of 6 and 12 weeks of therapy after isolated calf deep vein thrombosis. Circulation 2001; 103
Agnelli G, Prandoni P, Santamaria MG, Bagatella P, Iorio A, Bazzan M, et al.
Warfarin Optimal Duration Italian Trial Investigators. Three months versus one year of oral anticoagulant therapy for idiopathic deep venous thrombosis. Warfarin Optimal Duration Italian Trial Investigators. N Engl J Med 2001; 345(3)
Wells PS, MA Forgie, MA Rodger. Treatment of venous thromboembolism. JAMA 2014; 311
Kearon C, Ginsberg JS, Anderson DR, Kovacs MJ, Wells P, Julian JA, et al.
Comparison of 1 month versus 3 months of anticoagulation for a first episode of venous thromboembolis associated with transient risk factor. J Thromb Haemost 2004; 2
Boutitie F, Pinede L, Schulman S, Agnelli G, Raskob G, Julian J, et al.
Influence of preceding length of anticoagulant treatment and initial presentation of venous thromboembolism on risk of recurrence after stopping treatment: analysis of individual participants' data from seven trials. BMJ 2011; 342
[Figure 1], [Figure 2]