ISSN 0947 - 8736
European Journal of Clinical Research
THE OPTIMAL LONG TERM TREATMENT OF DEEP VENOUS THROMBOSIS
Prandoni, MD, PhD,
of Medical and Surgical Sciences,
Chair of Internal Medicine University of Padua,
Randomized controlled trials have established that
patients with deep-vein thrombosis (DVT) of lower extremities who are treated
with an initial course of heparin therapy have a very high rate of recurrence
unless effective anticoagulant therapy is continued for weeks or months after
hospital discharge (1,2). A less intense warfarin regimen (targeted therapeutic
range, INR 2.0-3.0) is as effective in preventing recurrent venous
thromboembolism but is associated with a lower risk of bleeding than the
standard full-dose warfarin regimen (INR > 3.0) (3). Subcutaneous heparin,
adjusted to maintain the mid-interval APTT determined 6 hours after injection at
1.5 times the control value, is as effective as full-dose oral anticoagulants in
preventing recurrent thromboembolism, but is associated with a significantly
lower risk of bleeding (4). Finally, recent investigations suggest that for this
indication oral anticoagulants can be effectively and safely replaced by
low-molecular-weight heparins in fixed doses (5-9). Both standard and
low-molecular-weight heparin are highly recommendable in patients in whom oral
anticoagulants are contraindicated (i.e., during pregnancy) and in those who for
any reason cannot undergo the regular determination of INR.
Three months or less?
The optimal duration of oral anticoagulant therapy after a first episode of DVT is still controversial. For most patients it is recommended that warfarin be continued for three months (10). For many years this approach, that has recently received the support from a decision analysis model balancing the risk of recurrent thromboembolism against that of hemorrhagic complications (11), has represented the standard of referee for the secondary prevention of DVT. A number of investigators have evaluated shorter durations of warfarin treatment (12-15), but the results have been inconclusive because of the small number of patients or suboptimal study design. Furthermore, three major studies have provided in recent years a convincing evidence against the generalized shortening of the duration of oral anticoagulant treatment.
The British Thoracic Society performed a study evaluating the optimal duration of oral anticoagulant therapy for venous thromboembolism (VTE), in which patients with DVT or pulmonary embolism (PE) were randomized to receive either four or 12 weeks of therapy (16). They found a considerably higher recurrence rate of VTE in patients who were treated for four weeks (7.8%) rather than for 12 weeks (4.0%), during an unspecified period of follow-up. Post hoc analysis suggested a qualitative difference between "postoperative" and "medical" cases of VTE; regardless of whether four or 12 weeks of anticoagulation were given, only 1 of 116 patients with postoperative VTE had a recurrent event, whereas 4.0% of medical patients treated for 12 weeks, and 9.1% of medical patients treated for four weeks, experienced a recurrence. Even if this study has been criticized, because objective confirmation of the initial diagnosis was not obtained for all patients and because less than half of the presumed recurrences were confirmed, its results suggest that four weeks of anticoagulation may be adequate for VTE which occurs as a complication of surgery but is inadequate for VTE that occurs under other circumstances.
Basing on the hypothesis that a normal impedance plethysmography (IPG) following DVT defines a group of patients at low risk of recurrent VTE, Levine et al. conducted a prospective controlled double-blind trial to evaluate the efficacy of only fours weeks of warfarin in patients with an already normalized IPG test at that time (17). During the eight weeks following randomization, 9 (8.6%) of the 105 placebo patients developed recurrent VTE compared to 1 (0.9%) of the 109 warfarin patients (P=0.009). In 301 patients with proximal-vein thrombosis who were given warfarin for three months and then followed for an additional nine months (including the 109 who were randomized and 192 who presented with an abnormal IPG test after four weeks), there were 26 recurrent thromboembolic events in 212 patients who had either permanent risk factors or idiopathic DVT (12.3%), but there were none in 89 patients with transient, reversible risk factors. The results of this study are consistent with those of the British Thoracic Society, and suggest that patients with an identifiable reversible risk factor have low rates of recurrences, whereas patients without a reversible risk factor have high rates of recurrence after three months of oral anticoagulation.
Schulman et al. performed a multicenter trial comparing six weeks of oral anticoagulant treatment with six months of such therapy in 897 patients who had had a first episode of VTE (18). After two years of follow-up, there were 80 recurrences among the 443 patients randomized to the 6-week group (18.1%), and 43 among the 454 randomized to the 6-month group (9.5%). The odds ratios for recurrence in the 6-week group was 2.1 (95% CI, 1.4 to 3.1). This trial showed, therefore, a substantial reduction in the risk for recurrent thromboembolism among patients six months of anticoagulation. However, there was no difference in the incidence of recurrent events in the two groups from six to 24 months after the initial episode in both groups of patients. In both groups, there was a linear increase in the cumulative risk, corresponding to 5 to 6% annually. Furthermore, although there was a trend toward a higher rate of recurrence among patients with temporary risk factors in the six-week group than in the six-month group (8.6% vs. 4.8%), the overall rate of recurrence after two years was much lower among patients with temporary risk factors than among those with permanent risk factors (6.6% vs. 18%).
As a result of these three major studies, the generalized reduction of overall anticoagulation beyond the currently recommended three months is not acceptable. Patients with reversible risk factors for VTE, such as surgery, trauma, or temporary immobilization, might require a shorter course (19,20). However, before introducing this approach into clinical practice, the results of proper randomized clinical trials should be awaited.
Three months or longer?
In order to assess the risk for recurrent thromboembolic events in patients suffering the first episode of DVT, we observed prospectively 528 consecutive symptomatic patients until eight years (21,22). A surprisingly high risk of recurrent venous thromboembolic disease that persisted after the period of treatment was found and resulted in a cumulative incidence of these complications of 5.6 after three months, and 9.5% after six months. This incidence gradually increased to 17.2% after two years, 24.3% after five years, and almost 30% after eight years of follow-up. Of the 101 patients who experienced at lest one recurrent thrombotic event, 47 (46.6%) occurred in a leg initially involved, 33 (32.7%) in the contralateral leg and 21 (20.8%) were pulmonary emboli, which were fatal in 11 (10.9%) patients. These results are fully consistent with those reported by other studies (23,24). Of the evaluated potential risk factors and clinical characteristics, the presence of malignancy and of impaired coagulation inhibition increased the risk of recurrent venous thromboembolism (RR=1.48 and 2.0, respectively). In contrast, surgery and recent trauma or fracture were associated with a diminished risk of recurrent venous thromboembolism (RR=0.65 and 0.39, respectively).
After the publication of the randomized study by Schulman et al (18), other recent studies have addressed the potential for prolonged anticoagulation in selected categories of patients. Kearon et al randomised consecutive patients to receive three months or two years of oral anticoagulant therapy following an episode of acute venous thromboembolism (25). A prespecified interim analysis led to early termination of the trial after 162 patients had been enrolled for an average of 10 months. Of 83 patients assigned to continue to receive placebo, 17 had a recurrent episode of venous thromboembolism (27% per patient-year), as compared with 1 of 79 patients assigned to receive warfarin (1.3% patient-year). Warfarin resulted in a 95% reduction in the risk of recurrent venous thromboembolism. There was a non-significant trend toward a higher risk of (nonfatal) major bleeding in patients assigned to warfarin as compared to those assigned to placebo group (3.8% vs. 0% per patient-year; P=0.09).
In a recent Italian multicenter study, 267 patients with a first episode of idiopathic proximal DVT who had completed three months of anticoagulant treatment were randomized either to withdraw anticoagulation or to continue for nine additional months (26). Of the 134 patients assigned to extended anticoagulation, 21 had a recurrence of venous thromboembolism (5.0% per patient-year, average follow-up 37.8 months) as compared with 21 of the 133 patients randomized to withdrawal of anticoagulation (5.1% per patient-year, average follow-up 37.2 months). Four patients had nonfatal major bleeding during extended anticoagulant treatment (3.0%). The results of this study suggest that extending to one year the three-month course of anticoagulant treatment in patients with idiopathic proximal deep-vein thrombosis is not associated with long-term clinical benefit.
In a recent multicenter trial addressing the comparison between 3 and 6 months of anticoagulation in patients with proximal DVT, and that between 6 and 12 weeks in patients with isolated calf DVT, Pinede et al. failed to show appreciable differences between the study groups in terms of recurrent thromboembolic complications after a 12-month follow-up period (27).
In a multicentre trial addressing the optimal duration of oral anticoagulant therapy after a second episode of DVT or PE, Schulman et al found a considerable reduction in the risk for recurrent thromboembolism (from 21% to 3%) in patients allocated to receive four years as compared to six months of warfarin (28). This benefit was surprisingly offset by a remarkably higher incidence of major bleeding (8.6% versus 2.7%).
What do these findings imply for the management of patients with DVT? The observed difference in recurrence rates between patients with and without reversible risk factors is relevant to the issue of optimal duration of oral anticoagulant therapy. The long-term prognosis of patients in whom DVT occurs following exposure to temporary risk factors (namely, recent surgery, trauma or fracture, puerperium, hormonal therapy) is excellent. Accordingly, they do not require further anticoagulation following the initial six-to-twelve week period.
On the contrast, in patients with malignancy or other medical ilnesses requiring prolonged immobilization the long-term prolongation of oral anticoagulation should be considered, as well as in patients with multiple episodes of spontaneous thrombotic episodes and in those with antiphospholipid antibody syndrome, AT, protein C and S deficiency, double heterozygosity for factor V Leiden and G20210A prothrombin variant, homozygosity for either defect exibiting one or more spontaneous episodes of DVT. At present, long-term anticoagulant therapy remains a clinical judgement in the individual patient.
A 6-month period of anticoagulation is currently recommended for patients with the first episode of idiopathic DVT, even in the presence of a heterozygosity for factor V Leiden and G20210A prothrombin variant. As these patients might require a longer period of anticoagulation, further studies are needed for exploring the benefit-to-risk of different drugs or different intensities of anticoagulation.
1. Hull R, Delmore T, Genton E, et al. Warfarin sodium versus low-dose heparin in the long-term treatment of venous thrombosis. N Engl J Med 1979; 301: 855-8.
CI, Olsson CG, Fagher BO, Oqvist BW, Albrechtsson U. Need for long-term
anticoagulant treatment in symptomatic calf-vein thrombosis. Lancet 1985; 2:
3. Hull R,
Hirsh J, Jay R, et al. Different intensities of oral anticoagulant therapy in
the treatment of proximal-vein thrombosis. N Engl J Med 1982; 307: 1676-81.
4. Hull R,
Delmore T, Genton E, et al. Adjusted subcutaneous heparin versus warfarin sodium
in the long-term treatment of venous thrombosis. N Engl J Med 1982; 306: 189-94.
5. Pini M, Aiello S, Manotti C, et al. Low molecular weight heparin versus warfarin in the prevention of recurrences after deep vein thrombosis. Thromb Haemostas 1994; 72: 191-7.
6. Monreal M,
Lafoz E, Olive A, del Rio L, Vedia C. Comparison of subcutaneous unfractionated
heparin with a low molecular weight heparin (Fragmin) in patients with venous
thromboembolism and contraindications to coumarin. Thromb Haemostas 1994; 71:
7. Gonzales-Fajardo JA, Arreba E, Castrodeza J, et al. Venographic
comparison of subcutaneous low-molecular-weight heparin with oral anticoagulant
therapy in the long-term treatment of deep venous thrombosis. J
Vasc Surg 1999; 30: 283-92.
8. Lopaciuk S,
Bielska-Falda H, Noszczyk W et al.. Low molecular weight heparin versus
acenocoumarol in the secondary prophylaxis of deep vein thrombosis. Thromb
Haemost 1999; 81: 26-31.
9. Veiga F,
Escribà A, Maluenda MP, et al. Low molecular weight heparin (enoxaparin) versus
oral anticoagulant therapy (acenocoumarol) in the long-term treatment of deep
venous thrombosis in the elderly: a randomised trial. Thromb Haemost 2000;
10. Hyers TM,
Agnelli G, Hull RD, et al. Antithrombotic therapy for venous thromboembolic
disease. Chest 1998;114 (Suppl): 561-78.
11. Sarasin F,
Bounameaux H. Duration of oral anticoagulant therapy after proximal deep vein
thrombosis: a decision analysis. Thromb Haemostas 1994; 71: 286-91.
12. Fennerty AG, Dolben J, Thomas P, et al. A comparison of 3 and 6 weeks' anticoagulation in the treatment of venous thromboembolism. Clin Lab Haemat 1987; 9: 17-22.
13. Holmgren K, Andersson G, Fagrell B, et al. One-month versus six-month therapy with oral anticoagulants after symptomatic deep vein thrombosis. Acta Med Scand 1985; 218: 279-84.
14. Petitti M, Strom BL, Melmon KL. Duration of warfarin anticoagulant therapy and the probabilities of recurrent thromboembolism and haemorrhage. Am J Med 1986; 81: 255-9.
Schulman S, Lockner D, Juhlin-Dannfelt A The duration of oral anticoagulation
after deep vein thrombosis. Acta Med Scand 1985; 217: 547-52.
Research Committee of the British Thoracic Society. Optimum duration of
anticoagulation for deep-vein thrombosis and pulmonary embolism. Lancet
1992; 340: 873-6.
17. Levine MN, Hirsh J, Gent M, et al. Optimal duration of oral anticoagulant therapy: a randomized trial comparing four weeks with three months of warfarin in patients with proximal deep vein thrombosis. Thromb Haemostas 1995; 74:606-611.
Schulman S, Rhedin AS, Lindmarker P, et al. A comparison of six weeks with six
months of oral anticoagulant therapy after a first episode of venous
thromboembolism. N Engl J Med 1995; 332:1661-1665.
Hirsh J. The optimal duration of anticoagulant therapy for venous thrombosis. N
Engl J Med 1995; 332: 1710-1711.
20. Chesterman CN. After a first episode of venous thromboembolism. BMJ 1995; 311:700-701.
21. Prandoni P, Lensing AWA, Cogo A, et al. The long-term clinical course of acute deep venous thrombosis. Ann Intern Med 1996; 125: 1-7.
Prandoni P, Villalta S, Bagatella P, et al. The clinical course of deep-vein
thrombosis. Prospective long-term follow-up of 528 symptomatic patients.
Haematologica 1997; 82: 423-8.
UK, Schalch I, Jager KA, Schneider E, Grimm J, Bollinger A. Prospective 12-year
follow-up of clinical and hemodynamic sequelae after deep vein thrombosis in
low-risk patients (Zurich Study). Circulation 1996; 93: 74-9.
PO, Sorbo J, Eriksson H. Recurrent venous thromboembolism after deep vein
thrombosis. Incidence and risk factors. Arch Intern Med 2000; 1260: 769-74.
25. Kearon C, Gent M, Hirsh J et al. A comparison of three months ofanticoagulation with extended anticoagulation for a first episode of idiopathic
venous thromboembolism. N Engl J Med 1999; 340: 901-7.
26. Agnelli G,
Prandoni P, Santamaria MG, et al. Three months versus one year of oral
anticoagulant therapy for idiopathic deep venous thrombosis. N Engl J Med 2001;
27. Pinede L,
Ninet J, Duhaut P, 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: 2453-60.
28. Schulman S, Granqvist S, Holmstrom M et al. The duration of oralanticoagulant therapy after a second episode of venous thromboembolism. NEngl J Med 1997; 336: 393-8.