Current guidelines for the treatment of deep vein thrombosis (DVT) recommend initial treatment with low molecular weight heparin (LMWH) or unfractionated heparin (UFH), followed by treatment with vitamin K antagonist (VKA) for at least 3 months . Additional treatment with catheter-directed thrombolysis (CDT) is recommended in selected patients with extensive proximal DVT, to prevent post-thrombotic syndrome (PTS) .
A substantial number of patients develop recurrent venous thrombosis (VT) after discontinuation of anticoagulation. Prolonged anticoagulation can prevent recurrence, but at the expense of increased risk of bleeding . The presence of residual vein thrombosis on ultrasonography is associated with an increased risk of recurrence, providing a rationale for prolonged treatment . PTS is a long-term complication of DVT that is associated with substantial morbidity and impact on quality of life (QoL) .
As residual vein thrombosis may be a risk factor for recurrent VT, and because additional CDT may provide more efficient clot lysis, we hypothesized that additional CDT would reduce recurrent VT as compared with anticoagulation alone. The present study was aimed at determining the rate of recurrent VT and the frequency of PTS, and their association with lysis grade and health-related QoL (HRQoL) following treatment with additional CDT.
Patients with previous severe proximal DVT who had received additional CDT during the period 1999–2006 were identified from the registries of four Norwegian hospitals. Treatment comprised catheter-directed administration of a 5-mg bolus of alteplase followed by continuous infusion of 0.01 mg/kg alteplase and UFH, followed by LMWH and VKA. The duration of VKA administration was decided by the responsible physician. The study was approved by the Regional Ethics Committee.
Patients were interviewed and examined for assessment of study outcomes. Lysis was determined by reviewing venography images and/or reports, with a method described elsewhere . The primary outcome was defined as objectively verified recurrent VT. PTS was assessed with the modified Villalta scale. A Villalta score of 5–9 was classifed as mild PTS, a score of 10–14 as moderate PTS, and a score of > 15 or the presence of a venous ulcer as severe PTS .
HRQoL assessment was assessed with the generic EQ-5D and the disease-specific VEINES-QOL/Sym questionnaires in patients and controls. Patients were asked to give the HRQoL questionnaires to two friends or relatives of the same sex and age with no previous history of VT. Kaplan–Meier curves were plotted to assess the time-dependent risk of recurrent VT. The evaluated time interval spanned from the day following withdrawal of VKA to the last available day of follow-up. Scores for VEINES-QOL/Sym were computed with standard scoring algorithms .
In total, 127 patients were identified; five were dead, 13 were not contactable, and two had axillary vein thrombosis. Twenty-six of 107 invited patients did not respond, eight declined, and two had not received CDT. The median duration of follow-up for 71 enrolled patients (median age 41 years; 54 females) was 6.3 years (interquartile range [IQR] 4.8–8.3 years). All except two patients had first-time DVT; 63 iliofemoral, five iliac and three femoral vein thromboses. Forty-nine (69%) patients had provoked DVT (surgery/immobilization during the last 8 weeks [n = 9]; oral contraceptives/hormone therapy [n = 27]; delivery within 4 weeks [n = 13]). Twenty-two patients (31%) had unprovoked DVT.
Grade III (> 90%) lysis was achieved in 44 patients (62%), grade II (50–90%) in 25 (35%), and grade I (< 50%) in two. Objectively verified recurrent VT occurred in 14 patients: 13 DVTs and one PE. Recurrence was ipsilateral in 10 and contralateral in three. Four recurrences occurred in patients receiving ongoing anticoagulation. The median duration of anticoagulation in patients who discontinued anticoagulation (n = 50) was 0.7 years (IQR 0.5–1.1 years). Ten of these developed recurrent VT. The 10-year probability of recurrent VT was 25% (95% confidence interval 10–40) (Fig. 1). There was no difference in the rate of recurrence according to the grade of lysis, as recurrence was encountered in seven of 35 patients (20%) with > 90% lysis and in three of 15 (20%) with < 90% lysis. The 8-year probability (Fig. 2) of recurrence after discontinuation of anticoagulation was significantly lower for provoked DVT (17%) than for unprovoked DVT (49%) (log-rank test, P = 0.002).
Twenty-six (37%) patients had manifestations of PTS, graded as mild in 15 (21%), moderate in eight (11%), and severe in three (4%). No association was found between the occurrence of PTS and the lysis grade (P = 0.2); PTS occurred in 13 of 25 patients (52%) with > 90% lysis and in 12 of 25 (48%) with < 90% lysis. Elastic compression stockings were used in 63 patients (91%).
Significantly lower VEINES-QOL/Sym scores were found in patients than in controls (Table 1). Cases with PTS had significantly lower scores than those without PTS; the latter group had mean scores that were comparable to those of controls. HRQoL assessed by EQ-5D differed significantly between patients who reported worse outcome and controls in all dimensions except for self-care.
|VEINES-QOL (71 patients/58 controls)||46.5 (11.4)||54.3 (5.4)||< 0.001|
|VEINES-Sym (71 patients/58 controls)||46.2 (11.5)||54.2 (5.8)||< 0.001|
|VEINES-QOL in patients with PTS (N = 26)||38.1 (11.3)||< 0.001|
|VEINES-QOL in patients without PTS (N = 45)||51.3 (8.3)|
|VEINES-Sym in patients with PTS (N = 26)||36.8 (11.1)||< 0.001|
|VEINES-Sym in patients without PTS (N = 45)||51.6 (7.7)|
|EQ-5D dimension||Cases with problems*, n (%)||Controls with problems, *n (%)||P|
|Mobility (N = 71)||20 (28.2)||4 (6.5)||0.001|
|Self-care (N = 71)||6 (8.5)||2 (3.2)||0.28*|
|Usual activities (N = 71)||16 (22.5)||3 (4.8)||0.004|
|Pain/discomfort (N = 70)||38 (54.3)||15 (24.6)||0.001|
|Anxiety/depression (N = 71)||23 (32.4)||4 (6.5)||< 0.001|
In contrast to the majority of studies on additional CDT, which have focused on radiologic markers, such as early lysis and venous patency , our study explored the long-term functional outcomes. To our knowledge, our study is the largest to report on clinical outcomes, and has data on the longest follow-up time after CDT in the literature to date.
The 10-year probability of recurrent VT after discontinuation of warfarin was 25%. Recurrence was significantly higher in patients with unprovoked VT than in those with provoked VT. Thirty-seven per cent of the study population exhibited some degree of PTS; however, PTS was mostly mild to moderate. Neither recurrence nor PTS was found to be associated with the grade of initial lysis.
In the absence of a control group, it is difficult to draw firm conclusions on the risk of recurrence and/or PTS in patients who have received additional CDT as compared with treatment with anticoagulation alone. However, according to the literature, the 10-year rate of VT recurrence after anticoagulation alone ranges between 30% and 40% . Although the 10-year recurrence rate of 40% was higher in the large cohort that included proximal DVT and pulmonary embolism, the probabilities of recurrence in patients with unprovoked VT (52%) and provoked (22%) VT were comparable with our findings .
Accelerated removal of the venous thrombus and restoration of venous patency with thrombolytic agents should theoretically reduce the risk of PTS. Our study found complete lysis in 60%, which is similar to what has been found in other studies . PTS was encountered in 37%, but only 16% exhibited moderate to severe PTS. The prevalence of PTS in our study was comparable to that reported in the literature with the use of conventional anticoagulant treatment alone, which ranges from 25% to 45% . Considering the severity of thrombosis, the rates of PTS in our study look propitious. A few studies have investigated the long-term incidence of PTS after CDT. One study showed rates of mild and moderate PTS in 28 patients who were treated with CDT of 25% and 14%, respectively, and no manifestation of PTS in 60% .
The HRQoL was poorer in patients than in controls, both when assessed with the generic questionnaire and assessed with the disease-specific questionnaire. However, these differences seem to be mainly attributable to PTS, and this is particularly evident in the VEINES-QOL/Sym scores. Reduced HRQoL after DVT has been reported in several studies, and its association with PTS is well documented .
The strength of our study is the long follow-up, the use of the Villalta score for assessing PTS, the use of age-matched and sex-matched controls, and the use of validated HRQoL instruments for the evaluation of QoL. The main limitations are the retrospective design, the lack of a control group, preventing firm conclusions being drawn regarding the additional benefit of CDT in preventing recurrence and/or PTS, and the relatively high proportion of patients who did not participate in the study.
In conclusion, accelerated removal of the clot by CDT did not appear to prevent recurrence or PTS, and neither did it normalize the HRQoL. Results of ongoing randomized clinical trials will hopefully clarify the role of additional CDT in patients with proximal DVT.