eMedicine Specialties > Emergency Medicine > Cardiovascular

Deep Venous Thrombosis and Thrombophlebitis: Treatment & Medication

Author: Donald Schreiber, MD, CM, Associate Professor of Surgery (Emergency Medicine), Stanford University School of Medicine
Contributor Information and Disclosures

Updated: Aug 5, 2009

Treatment

Emergency Department Care

The primary objectives for the treatment of deep venous thrombosis (DVT) are to prevent pulmonary embolism (PE), reduce morbidity, and prevent or minimize the risk of developing the postphlebitic syndrome.   The current guidelines recommend short-term anticoagulation with LMWH SC (Grade 1A), unfractionated heparin IV (Grade 1A), fixed-dose unfractionated heparin SC (Grade 1A), or fondaparinux SC (Grade 1A). Initial treatment with LMWH, unfractionated heparin, or fondaparinux should continue for at least 5 days and until the INR is >2 for 24 hours (Grade 1C). A vitamin K antagonist such as warfarin should be initiated together with LMWH, unfractionated heparin, or fondaparinux on the first treatment day (Grade 1A).¹¹

Anticoagulation

Heparin

Anticoagulation remains the mainstay of the initial treatment for DVT. Regular unfractionated heparin was the standard of care until the introduction of low-molecular-weight-heparin (LMWH) products. Heparin prevents extension of the thrombus and has been shown to significantly reduce (but not eliminate) the incidence of fatal and nonfatal pulmonary emboli as well as recurrent thrombosis. The primary reason for the persistent, albeit reduced, risk of PE is primarily due to the fact that heparin has no effect on preexisting nonadherent thrombus. Heparin does not affect the size of existing thrombus and has no intrinsic thrombolytic activity.

Heparin therapy is associated with complete lysis in fewer than 10% of patients studied with venography after treatment.

Heparin therapy has little effect on the risk of developing the postphlebitic syndrome. The original thrombus causes venous valvular incompetence and altered venous return leading to a high incidence of chronic venous insufficiency and postphlebitic syndrome.

The anticoagulant effect of heparin is directly related to its activation of antithrombin III. Antithrombin III, the body's primary anticoagulant, inactivates thrombin and inhibits the activity of activated factor X in the coagulation process.

Heparin is a heterogeneous mixture of polysaccharide fragments with varying molecular weights but with similar biological activity. The larger fragments primarily interact with antithrombin III to inhibit thrombin. The low-molecular-weight fragments exert their anticoagulant effect by inhibiting the activity of activated factor X. The hemorrhagic complications attributed to heparin are thought to arise from the larger higher-molecular-weight fragments.

Warfarin therapy is overlapped with heparin for 4-5 days until the international normalized ratio (INR) is therapeutically elevated to 2-3. Heparin must be overlapped with oral warfarin because of the initial transient hypercoagulable state induced by warfarin. This effect is related to the differential half-lives of protein C, protein S, and the vitamin K–dependent clotting factors II, VII, IX, and X. Long-term anticoagulation is definitely indicated for patients with recurrent venous thrombosis and/or persistent or irreversible risk factors.

When intravenous unfractionated heparin is initiated for DVT, the goal is to achieve and maintain an elevated activated partial thromboplastin time (aPTT) of at least 1.5 times control. Heparin pharmacokinetics are complex; the half-life is 60-90 minutes. A protocol for IV heparin use is as follows:

1. Give an initial bolus of 80 U/kg
2. Initiate a constant maintenance infusion of 18 U/kg.
3. Check the aPTT or Heparin Activity level 6 hours after the bolus and adjust the infusion rate accordingly.
4. Continue to check the aPTT or heparin Activity level every 6 hours until 2 successive values are therapeutic.
5. Monitor the aPTT or Heparin Activity level, hematocrit, and platelet count every 24 hours.

Heparin-induced thrombocytopenia is not infrequent. In this condition, platelet aggregation induced by heparin may trigger venous or arterial thrombosis with significant morbidity and mortality. Unfortunately, it is not possible to predict which subset of patients will develop thrombosis. All patients who develop thrombocytopenia while taking heparin are at risk. Alternatives include the substitution of porcine for bovine heparin, the use of LMWH, or initiation of therapy with warfarin alone.

Traditionally, heparin has been used only for admitted patients with DVT. In a recent study by Kearon et al, fixed-dose subcutaneous unfractionated heparin was evaluated for outpatient treatment of DVT.¹² In this randomized, primarily outpatient, open-label, adjudicator-blinded, noninferiority trial of 708 adult patients with objectively confirmed DVT fixed-dose subcutaneous unfractionated heparin (UFH) was compared to LMWH (enoxaparin or dalteparin). In the UFH group, 333 units/kg of unfractionated heparin was administered subcutaneously initially followed by a fixed dose of 250 units/kg twice daily. This was overlapped with oral warfarin for 5 days until the INR was considered therapeutic. In the LMWH group, 100 IU/kg of the LMWH was administered twice daily.

Recurrent venous thromboembolism (VTE) occurred in 13 patients in the UFH group (3.8%) compared with 12 patients in the LMWH group (3.4%; absolute difference 0.4%; 95% CI, -2.6% - 3.3%). Major bleeding during the first 10 days of treatment occurred in 1.1% of the UFH group versus 1.4% in the LMWH group (absolute difference -0.3%; 95% CI, -2.3% - 1.7%) The authors concluded that fixed-dose UFH is as safe and effective as LMWH in patients with acute DVT and is suitable for outpatient treatment.

Low-Molecular-Weight Heparin

LMWH is prepared by selectively treating unfractionated heparin to isolate the low-molecular-weight (<9,000 Da) fragments. Its activity is measured in units of factor X inactivation, and monitoring of the aPTT is not required. The dose is weight adjusted.

LMWH products are administered subcutaneously, and their half-life permits single- or twice-daily dosing. Its use in the outpatient treatment of DVT and PE has been evaluated in a number of studies.

At the present time, 4 LMWH preparations, enoxaparin, dalteparin, tinzaparin, and nadroparin, are available. Enoxaparin, dalteparin, and tinzaparin have received US Food and Drug Administration (FDA) approval for the treatment of DVT in the United States. Enoxaparin is approved for inpatient and outpatient treatment of DVT. Nadroparin is approved for DVT treatment in Canada.

The increased bioavailability and prolonged half-life of LMWH allows for outpatient treatment of DVT using once - or twice-daily subcutaneous treatment regimens. Outpatient treatment of acute DVT with LMWH has been successfully evaluated in a number of studies and is currently the treatment of choice if the patient is eligible. In general, outpatient management is not recommended if the patient has proven or suspected concomitant PE, significant comorbidities, extensive ileofemoral DVT, morbid obesity, renal failure, or poor follow-up (see exclusion criteria for outpatient management).

The efficacy and safety of LMWH for the initial treatment of DVT have been well established in several trials.

Mismetti and colleagues¹³ have conducted a systematic meta-analysis of the original source data to specifically address the question whether the efficacy and safety of enoxaparin, a LMWH, is modified by the presence or absence of initial PE at baseline. PE is recognized as a sequela of DVT, and most cases of PE are recognized to arise from DVT of the lower extremities. Previous meta-analyses of published trials could not evaluate the efficacy and safety of LMWH if PE was present in addition to DVT because they reviewed only published summarized data. The authors reanalyzed the original individual source data from 1503 patients in 3 randomized controlled trials. Efficacy was assessed through objectively confirmed recurrence of DVT and/or PE. The authors also used a well-established margin of noninferiority for the treatment effect that was calculated prior to data collection. Enoxaparin 1 mg/kg twice daily was found to be noninferior to UFH in the treatment of DVT with or without a coexisting PE. In addition, while not statistically significant, a trend favoring enoxaparin over UFH was also observed in the incidence of major bleeding and all-cause mortality at 3 months.

Although LMWH is noninferior to UFH in the treatment of DVT, the emergency physician must recognize that, despite adequate anticoagulant therapy, the recurrence rate for DVT and/or PE when enoxaparin was used was still 4.5%. With UFH, the recurrence rate for DVT, PE, or both was 4.4%, 1.8%, and 5.7%, respectively. The incidence of DVT and PE recurrence in patients presenting with DVT and an initial symptomatic PE is much higher, approaching 8.2% in the UFH group compared with 4.8% in patients with DVT alone. When comparing the efficacy of enoxaparin versus UFH, no significant difference between patients with and without an initial symptomatic PE was noted. However, the risk of recurrent PE was also higher in patients with an initial symptomatic PE despite adequate anticoagulant therapy. Therefore, a recurrent VTE event must be considered in patients who present to the emergency department with recurrent symptoms despite adequate anticoagulant therapy. Incidentally, the group of patients presenting with DVT and symptomatic PE were found more often to be women with a previous history of VTE, and thus, inherently at greater risk for VTE recurrence.

A Canadian study by Wells et al compared tinzaparin with dalteparin, the former being the only LMWH to have demonstrated statistical superiority to UFH in the prevention of DVT recurrence. Wells et al conducted this single-blind, randomized controlled trial of 505 outpatients with objectively proven DVT. In addition to subcutaneous LMWH, patients were simultaneously begun on warfarin using a standardized normogram. After 5 days and an INR of 2 or greater, the LMWH was stopped and oral anticoagulation was continued for 3 months. A composite end-point, combining both the risk of recurrent thrombosis or PE and the risk of hemorrhage, was used as the most appropriate assessment of the two pharmacotherapies.¹⁴ The existing literature had predicted outcomes in favor of tinzaparin by a minimal but clinically important 4% combined end-point. However, with combined event rates of 4.8% and 5.4% for dalteparin and tinzaparin, respectively, tinzaparin was not found to be superior to dalteparin, and both therapies provided safe and efficacious outpatient treatment of acute DVT and PE. However, in December 2008, the FDA issued a communication that recommended considering alternatives to tinzaparin for treatment of DVT in patients older than 70 years with renal insufficiency, because of increased risk of death in that population.¹⁵

The study by Wells et al¹⁴ was the first trial to compare drugs within the LMWH class, and it also was the first study to treat patients with acute DVT and PE solely on an outpatient basis. The question of whether there is any significant clinical difference between these LMWH agents for the treatment of DVT or PE was only partially answered. The authors estimated that the projected sample size needed to detect any significant difference between dalteparin and tinzaparin would exceed 30,000 patients. Such a study is unlikely to be funded at the present time.

Once-Daily Versus Twice-Daily Enoxaparin

Van Dongen and colleagues¹⁶ as part of the Cochrane Database of Systemic Reviews performed a meta-analysis to specifically evaluate the safety and efficacy of once-daily versus twice-daily dosing of enoxaparin for treatment of DVT. The authors hypothesized that twice-daily dosing would be more effective and safer with fewer bleeding complications. Higher frequency of dosing would allow more stability in anticoagulation; therefore, they expected fewer complications with this group. Using strict criteria for exclusion, they compared 5 randomized controlled trials with a total of 1508 patients. These trials all involved patients treated for initial VTE. When the data was pooled, the actual incidence of VTE recurrence between the two groups was not statistically significant, complying with the predetermined equivalence criteria. In assessing discrepancies in thrombus size, no statistical difference was noted. A lower mortality was observed in the twice-daily group, while a lower incidence of hemorrhage was seen in the once-daily group, but again, neither of these differences was statistically significant. While admitting that the wide confidence interval led to decreased precision in these results, the authors concluded that once-daily dosing is as safe and efficacious as the standard twice-daily regimen.

Enoxaparin in the Morbidly Obese, in Renal Failure, in Pregnancy, and in Cancer

A number of questions have arisen about the use of enoxaparin in special patient populations such as those with renal insufficiency, those who are pregnant, and those who are morbidly obese. The article by Michota reviewed the efficacy, safety, and dosing of enoxaparin in DVT prophylaxis and in the treatment of VTE in special patient populations—the morbidly obese, pregnancy, renal insufficiency, and cancer.

Given the prevalence of obesity, a problem that afflicts one third of Americans today, Michota reviewed its effect on enoxaparin dosing. Morbid obesity was defined as body weight greater than 150 kg or a BMI greater than 50.¹⁷ The author noted that there is a paucity of morbidly obese patients represented in the major clinical trials evaluating the LMWH agents. The authors cited a British trial that demonstrated decreased anti-Xa activity with increased body weight when fixed as opposed to weight-based enoxaparin dosing was used. The relationship between intravascular volume, volume of distribution of the drug, and body weight is not linear. Therefore, there is concern that weight-based dosing in the morbidly obese patient population might lead to an excessive rate of bleeding complications. However, other studies have shown that no significant increase in anti-Xa activity occurs when weight-based dosing of LMWH is used. In a cardiovascular trial, no increase in bleeding rates between obese and nonobese patients was documented when full weight-based dosing was used.

In morbidly obese patients, the author concluded that, although the general consensus suggests that weight-based dosing without a cap is currently recommended, a paucity of data supports it. Therefore, the author concluded that it is not unreasonable to initiate therapy with full weight-based dosing and to monitor the anti-Xa levels.¹⁷ The therapeutic ranges for anti-Xa activity for the various LMWH compounds are listed in Table 2 (below). Anti-Xa levels are drawn 4 hours after a subcutaneous dose.

Enoxaparin dosing has also been poorly studied in patients with renal conditions. Higher peak anti-Xa levels as well as half-life prolongation correlate with decreasing creatinine clearance because LMWH is renally cleared. Patients with renal failure may be at increased risk for bleeding secondary to excessive anticoagulation. Several trials have substantiated increased bleeding rates with UFH and LMWH among patients with renal insufficiency (CrCl <30mL/min). Although UFH has a dual clearance mechanism and is less susceptible to drug accumulation in renal insufficiency than LMWH, its greater adverse effect on platelet function and capillary permeability leads to a similar rate of bleeding problems. A negative linear correlation exists between anti-Xa activity and CrCl. As a result, the FDA issued new dosing guidelines for enoxaparin of 1 mg/kg daily instead of twice a day. No revised dosing guidelines are available for the other LMWH agents. Michota also concluded that monitoring of anti-Xa levels is the safest approach in patients with chronic renal insufficiency.¹⁷

In pregnant patients with VTE, LMWH has clear advantages over UFH including better bioavailability, lower incidence of heparin-induced thrombocytopenia and osteoporosis, and reduced monitoring requirements. Throughout pregnancy, the volume of distribution of LMWH is larger. Drug clearance is higher in early pregnancy and trends toward normal at delivery. Therefore, monitoring of anti-Xa levels is important. Drug therapy should be initiated at the same dose as for nonpregnant patients, but the dose may have to be increased if anti-Xa levels fall below the therapeutic ranges outlined in Table 2. Therapy should be held during delivery but then restarted postpartum and continued while the patient is crossed over to a vitamin K antagonist.

Table 2. Therapeutic Peak Anti-Xa levels With Low-Molecular-Weight Heparins for Treatment of Venous Thromboembolism

Open table in new window

*VIa chromogenic: Anti-Xa assay drawn 4 hours after subcutaneous dose.

Patients with cancer have a particularly higher rate of DVT recurrence than noncancer patients. Long-term therapy for DVT is strongly recommended. Recent studies have shown a lower rate of VTE recurrence without increasing the risk of bleeding with LMWH therapy. Reports also describe that the LMWH compounds may decrease the all-cause mortality rate. The author recommends LMWH therapy alone without crossover to warfarin (Coumadin) if the patient's insurance will cover it.¹⁷

Fondaparinux, a Direct Factor Xa Inhibitor in Acute DVT

Currently, enoxaparin and other LMWH agents are recommended for the treatment of DVT. However, the data on once-daily or twice-daily dosing of enoxaparin is not clear. Secondly, the practical issues that surround the administration of a weight-based 1 mg/kg dose from fixed-volume syringes of enoxaparin may be an issue for some patients. Thirdly, the incidence of heparin-induced thrombocytopenia, although reduced with enoxaparin, is not completely eliminated. Fondaparinux, a direct selective inhibitor of factor Xa, overcomes many of these disadvantages. Pharmacokinetic studies of fondaparinux reveal that only a single-daily subcutaneous dose is required. Furthermore, a single dose of 7.5 mg is effective over a wide range of patient weights between 50 and 100 kg. Daily doses of 5 mg or 10 mg are appropriate for patients who weigh less or more than that weight range. Heparin-induced thrombocytopenia has not been reported. Therapeutic monitoring of laboratory parameters such as the prothrombin time or partial thromboplastin time is also not required.

Buller and his coauthors on behalf of the Matisse Investigators conducted a randomized double-blind international study of fondaparinux versus enoxaparin on 2205 patients with objectively confirmed acute DVT.¹¹ The efficacy and safety of fondaparinux was compared with enoxaparin. Patients were randomly assigned to receive fondaparinux or enoxaparin therapy. Fondaparinux was administered as a single 7.5-mg subcutaneous daily dose, with adjustments made for those patients weighing less than 50 kg (5 mg) or greater than 100 kg (10 mg). Enoxaparin was given 1 mg/kg subcutaneously twice daily. Both agents were bridged with a vitamin K antagonist until a therapeutic INR was achieved. Anticoagulation with a vitamin K antagonist was continued for 3 months. Efficacy was measured by the rate of recurrent VTE in the 3-month follow-up period after enrollment. Safety was assessed by the incidence of major bleeding and mortality over the same interval.

The recurrence rate showed a nonsignificant trend in favor of fondaparinux (3.9%) compared with enoxaparin (4.1%) (absolute difference = 0.15%; 95% CI, 1.8% to -1.5%). The conservative noninferiority margin was attained, and fondaparinux was determined to be equally as effective as enoxaparin for the treatment of DVT. Major bleeding rates were essentially identical, and mortality rates were also comparable. In a subgroup analysis, the authors also evaluated the relationship between the recurrence rate, the bleeding risks, and the patients' body weight. In general, the safety and efficacy of fondaparinux were independent of body weight. However, patients with mild renal insufficiency and a low creatinine clearance had the same risk of bleeding in both the LMWH and fondaparinux groups. Overall, the authors concluded that once-daily fondaparinux was as effective and as safe as twice-daily, weight-adjusted enoxaparin.¹¹

The Matisse-DVT trial confirmed that fondaparinux and enoxaparin have similar safety and efficacy for the initial treatment of DVT. Only one fixed-dosage regimen for fondaparinux is required for patients who weigh between 50 kg and 100 kg, and only one subcutaneous dose per day is required. This greatly simplifies the treatment of DVT and facilitates outpatient therapy. In the original study, about one third of the patients were treated partially or entirely as outpatients without any increased risk when compared with those treated as inpatients.

In renal insufficiency with a creatinine clearance less than 30 mL/min, major bleeding occurred in 2 of 25 patients (8%) on fondaparinux versus 1 of 18 patients (5.6%) treated with enoxaparin (P=NS). Because of the small sample size and the higher risk of bleeding, fondaparinux is contraindicated in patients with renal insufficiency and a creatinine clearance less than 30 mL/min.

In the event of a major bleed, protamine sulfate partially reverses the anticoagulant effect of enoxaparin. However, no specific antidote to fondaparinux is available. A recent study revealed that a bolus dose of 90 mcg/kg of recombinant factor VIIa reversed the anticoagulant effect of fondaparinux, at least in healthy volunteers given a larger 10-mg dose.¹⁸

In some regions, the cost of therapy with fondaparinux is less than enoxaparin when it is being used to bridge therapy to a vitamin K antagonist.

Isolated Calf Vein DVT

Despite the lower (but not zero) risk of PE and mortality associated with calf vein DVT, current guidelines recommend short-term anticoagulation for 3 months in symptomatic patients albeit with a relatively low Grade 2B recommendation. Asymptomatic patients with isolated calf vein DVT do not require anticoagulation, and surveillance ultrasound studies over 10-14 days to detect proximal extension is recommended instead.¹¹

Thrombolytic Therapy for DVT

Thrombolytic therapy offers significant advantages over conventional anticoagulant therapy including the prompt resolution of symptoms, the prevention of PE, the restoration of normal venous circulation, the preservation of venous valvular function, and the prevention of postphlebitic syndrome. Thrombolytic therapy does not prevent clot propagation, rethrombosis, or subsequent embolization. Heparin therapy and oral anticoagulant therapy must always follow a course of thrombolysis.

Unfortunately, most patients with DVT have absolute contraindications to thrombolytic therapy. Thrombolytic therapy is also not effective once the thrombus is adherent and begins to organize. Venous thrombi in the legs are often large and associated with complete venous occlusion. The thrombolytic agent that acts on the surface of the clot may not be able to penetrate and lyse the entire thrombus.

Nevertheless, the data from many published studies indicate that thrombolytic therapy is more effective than heparin in achieving vein patency. The unproven assumption is that the degree of lysis observed on posttreatment venography is predictive of future venous valvular insufficiency and late (5-10 y) development of postphlebitic syndrome. Preliminary evidence suggests that thrombolytic therapy reduces but unfortunately does not entirely eliminate the incidence of postphlebitic syndrome at 3 years.

The hemorrhagic complications of thrombolytic therapy are formidable (~3 times higher) and include the small but potentially fatal risk of intracerebral hemorrhage. The uncertainty regarding thrombolytic therapy is likely to continue. Currently, the American College of Chest Physicians (ACCP) consensus guidelines recommend thrombolytic therapy only for patients with massive ileofemoral vein thrombosis associated with limb ischemia or vascular compromise.

Catheter-directed intrathrombus thrombolysis (CDT) is an image-guided therapy where a thrombolytic agent is administered directly into the thrombus and enhances thrombus removal. A variety of specialized catheters and mechanical devices are used to optimally deliver the drug and mechanically remove the clot. Secondly, balloon angioplasty and stents may be used at the same time to treat any underlying venous obstruction that predisposes the patient to recurrent DVT. Direct intrathrombus delivery of the thrombolytic agent achieves higher drug concentration at the site of thrombosis with a lower total dose than would be used by systemic intravenous thrombolytic therapy. This is the suggested mechanism for the lower incidence of systemic and in particular intracranial hemorrhagic complications with CDT.

The Society of Interventional Radiology (SIR) has published a position paper that supports the adjunctive use of CDT in addition to anticoagulant therapy for carefully selected patients with acute ileofemoral deep vein thrombosis. The authors evaluated this therapeutic option in the context of the major therapeutic goals for the treatment of DVT: (1) provision of early symptom relief, (2) prevention of the postthrombotic syndrome (PTS), and (3) prevention of PE.¹⁹

The authors of the position statement cited a number of comparative studies that support the use of CDT to prevent PTS and provide rapid symptom relief. They explained that the natural history of ileofemoral vein DVT is different than isolated femoral-popliteal DVT. In the latter group, recanalization and collateral venous blood flow limit the degree of PTS. However, in the iliac veins, adequate recanalization is unlikely and collateral venous blood flow is minimal. This leads to persistent venous outflow obstruction and an increased risk of PTS. Long-term studies of patients with ileofemoral DVT reported a 44% incidence of venous claudication at 5-year follow-up with standard anticoagulant therapy alone. Furthermore, the rate of recurrence of DVT is twice as high in patients with an ileofemoral DVT than in those with more distal, femoral-popliteal DVT. The authors referenced a meta-analysis that demonstrated a 90% success rate with CDT for thrombus removal as well as a case-control study that reported a decreased incidence of PTS compared with anticoagulant therapy alone.

SIR recognized that the main risk of adjunctive CDT is bleeding. Their pooled review of 19 published studies reported an 8% incidence of major bleeding (mostly at the catheter insertion site) and an intracranial bleeding rate of only 0.2%, which is less than that reported for systemic thrombolytic therapy. However, the range of major bleeding risk in the studies reviewed was actually 0-24%. The incidence of PE was 1%, which is also less than the incidence of PE complicating standard anticoagulant therapy. However, they conceded that no prospective randomized study has yet been conducted to evaluate CDT compared with standard anticoagulant therapy for ileofemoral DVT. In conclusion, the SIR affirmed that the available evidence defended a clinical benefit of CDT in the specific subgroup of patients with ileofemoral DVT, limb-threatening disease, and low bleeding risk.¹⁹

Filters for DVT

The idea of placing a barrier in the inferior vena cava to prevent PE from DVT was first suggested by Trousseau in 1868. In the mid 1900s before the adoption of anticoagulant therapy, DVT and PE were generally managed by laparotomy and vena caval ligation. Mortality rates were high. The next evolutionary step was the introduction of vena caval clips that were applied during laparotomy. These were meant to decrease the luminal diameter of the IVC but were also associated with poor results. The concept of inferior vena cava filters arose from the recognition of these late complications of surgical ligation of the inferior vena cava as first proposed by Homans in 1934. These permanent filters were inserted transvenously under simple local anesthesia. The current benchmark standard is the Greenfield filter. More than 20 years of long-term follow-up experience with this filter is available. Its design incorporates all the features of an ideal filter—maintain caval patency, trap emboli, preserve prograde caval blood flow, avoid stasis, and enhance thrombolysis of trapped emboli. The Greenfield filter achieves a long-term patency rate of 98% with only a 4% incidence of recurrent PE.

Generally accepted indications for filter placement are (1) severe hemorrhagic complications on anticoagulant therapy or other absolute contraindications to anticoagulation and (2) failure of anticoagulant therapy, such as new or recurrent venous thrombosis or PE, despite adequate anticoagulation.

Surprisingly, only one randomized controlled study on venocaval filters has been performed. The study was by Decousus et al and was published in 1998. This trial randomized 400 patients with proximal DVT to filter or no filter groups. Both groups were anticoagulated with UFH. This study design excluded patients with contraindications to anticoagulation, which is one of the major indications for a veno-caval filter. After 12 days, a statistically significant reduction occurred in PE in the filter group (1.1% vs 4.8%, P= 0.03), but this disappeared at 2 years to become 3.4% versus 6.3%, P= 0.16. Significantly, the incidence of later DVT was much higher in the filter group (21% vs 12%, P=0.02).²⁰

The Decousus study propelled the development and introduction of temporary/optionally retrievable filters that provide temporary prophylaxis for PE yet avoid the longer-term risk of later DVT. Unfortunately, randomized prospective studies evaluating the use of these retrievable filters, despite their ever-increasing use, are lacking. Today, more than 10 different retrievable vena cava filters are available. This begs the question: who gets what filter? Rectenwald in his review article points out that, despite the fact that these new filters are supposed to be removed or repositioned within 2-6 weeks, less than 50% are actually removed.²¹ This review questions the rationale for placing a temporary filter for permanent use without long-term studies when more than 20 years of experience is available with the permanent Greenfield filter.

The major indications for vena caval filters are primarily for patients with a contraindication to anticoagulation or for patients with major complications while anticoagulated (hemorrhage or heparin-induced thrombocytopenia). The use of vena caval filters has expanded to include primary venous thromboembolism (VTE) prophylaxis in special patient populations such as major trauma patients, major surgery patients, advanced malignancy, and neurological or neurosurgical patients with paralysis or prolonged immobilization. These special patient populations are generally characterized by contraindications to anticoagulation, ineffective anticoagulant prophylaxis, hypercoagulable states, or other exceedingly high risks of PE.

Currently, the newer filters are placed under ultrasonographic guidance either by transabdominal or by intravascular ultrasonography. The advantage of ultrasonography is that the filters may be placed at the bedside in the ICU or the ED, thereby avoiding the pitfalls and difficulties of transporting the patient to the angiography suite. Transabdominal ultrasonography machines are generally more readily available, do not require a separate femoral venous puncture, and there is more experience with their use. However, the patient's body habitus must provide adequate acoustic windows to permit the transabdominal technique.

There is a need for more study and more data on which filter to use. The temporary optionally retrievable filters have the ultimate advantage but currently are removed less than half the time and no proven long-term results are available.

Surgery for DVT

Surgical therapy for DVT may be indicated when anticoagulant therapy is ineffective, unsafe, or contraindicated. The major surgical procedures for DVT are clot removal and partial interruption of the inferior vena cava to prevent PE.

The rationale for thrombectomy is to restore venous patency and valvular function. Thrombectomy alone is not indicated because rethrombosis is frequent. Heparin therapy is a necessary adjunct. Thrombectomy is reserved for patients with massive ileofemoral vein thrombosis (phlegmasia cerulea dolens) with vascular compromise when thrombolysis is absolutely contraindicated.

Compression stockings (routinely recommended)

The postthrombotic syndrome affects approximately 50% of patients with DVT after 2 years. Elderly patients and patients with recurrent ipsilateral DVT have the highest risk. Below-the-knee elastic stockings assist the calf muscle pump and reduce venous hypertension and venous valvular reflux. This reduces leg edema, aids the microcirculation, and prevents venous ischemia.

Prandoni and colleagues conducted a randomized controlled study in an Italian university setting involving 180 patients who presented with a first episode of symptomatic proximal DVT. They sought to evaluate the efficacy of graduated below-the-knee elastic compression stockings (ECS) in the prevention of the postthrombotic syndrome (PTS). After conventional anticoagulation with heparin, patients were discharged on therapeutic warfarin for 3-6 months and randomly assigned to the control (no ECS) or the ECS group. Graduated compression stockings with ankle pressures of 30-40 mm Hg were given to the participants, who were required to wear them daily on the affected leg or legs over 2 years. Ninety percent of trial participants were compliant (wore the stockings for at least 80% of daytime hours), and 5-year cumulative data was evaluated to compare the incidence of PTS between the groups.²²

A standardized validated scale was used to assess symptoms, severity, and/or progression of PTS. The postthrombotic syndrome occurred in 26% of patients who wore ECS compared with 49% of patients without ECS. All patients with PTS except one developed manifestations of the syndrome within the first 2 years after the initial diagnosis of DVT. The number of patients who need to be treated with ECS was estimated at 4.3 to prevent one case of PTS. The adjusted hazard ratio was 0.49 (CI 0.29-0.84, p=0.011) in favor of ECS.²² Almost 50% of their patients with proximal DVT developed PTS within 2 years. The regular use of graduated elastic compression stockings reduced the incidence of the syndrome by 50%. The authors also noted that the benefit conferred by ECS was not related to the rate of recurrent DVT, which was identical in both groups. The authors strongly recommended the early use and widespread implementation of graduated elastic stockings with adequate anticoagulant therapy for symptomatic proximal DVT to prevent the development of the PTS.

The Eighth ACCP Conference on Antithrombotic and Thrombolytic Therapy observed that PTS occurs in 20-50% of patients with objectively confirmed DVT and assigned a grade 1A recommendation for the use of graduated elastic compression stockings for 2 years after the onset of proximal DVT. With the adoption of outpatient therapy for proximal DVT, the initial management of DVT increasingly becomes the responsibility of the emergency physician. It therefore behooves us to prescribe graduated elastic compression stockings to all our DVT patients at discharge.

Ambulation

Controversy exists regarding the role of ambulation in the therapy of DVT. The study by Partsch reviews the myths surrounding immediate ambulation and compression in the patient with newly diagnosed DVT. It is well recognized from the older literature that almost 50% of patients with acute proximal DVT have evidence, based on V/Q pulmonary scanning, of asymptomatic PE at baseline. Analyzing the effect of ambulation and compression in this patient cohort focused on the development of a new PE, the relief of pain and swelling, and the reduction in the incidence and severity of PTS. The authors cite 2 small previous studies that demonstrated that the incidence of a new PE after initiation of anticoagulant therapy with a LMWH did not increase significantly in patients treated with early ambulation and compression. They had previously reported their own prospective cohort study of 1289 patients with acute DVT treated as outpatients with LMWH, early ambulation, and compression. Partsch et al reported that only 77 of 1289 patients (5.9%) developed a new PE, only 6 of 1289 patients (0.4%) of these were symptomatic, and only 3 deaths (0.23%) were attributed to the PE. This was not significantly different than historical controls. The authors concluded that early ambulation and compression is not associated with any significant risk of PE.²³

A systematic review by Kahn et al found that in patients with acute DVT, early walking exercise is safe and may help to reduce acute symptoms and that in patients with previous DVT, exercise training does not increase leg symptoms acutely and may help to prevent or improve the postthrombotic syndrome.²⁴

In Europe, early ambulation and compression has been the mainstay of adjunctive treatment for DVT. In North America, the unsubstantiated fear of dislodging clots by ambulation led clinicians to recommend bed rest and leg elevation to their patients. The authors explained that bed rest promotes venous stasis, which is a major risk factor for DVT and, therefore, may actually enhance thrombus propagation and the risk of subsequent PE.

The authors also cited a number of other studies that revealed a significant decrease in leg swelling (using leg circumference measures) and pain (analog pain scales and quality of life scores) with early ambulation and compression. They also recognized the limited data that are available to assess the effect of early ambulation and compression on the subsequent development of PTS. In their own small trial, they reported a trend toward a lower incidence of PTS. They conceded that a larger, long-term study would be required. Nevertheless, they strongly recommended early ambulation for their patients in addition to elastic compression stockings.

The ACCP Consensus Conference on Antithrombotic and Thrombolytic Therapy for VTE also recommends ambulation as tolerated for patients with DVT. Therefore, early ambulation on day 2 after initiation of outpatient anticoagulant therapy in addition to effective compression is strongly recommended. Early ambulation without compression stockings is not recommended. The fear of dislodging clots and precipitating a fatal PE is unfounded.

Consultations

• Hematologist
• Vascular surgeon
• Radiologist
• Interventional radiologist

Medication

The goals of pharmacotherapy in venous thrombosis are to reduce morbidity, to prevent the postphlebitic syndrome, and to prevent PE, all with minimal adverse effects and cost.

Anticoagulants

These agents prevent recurrent or ongoing thrombolytic occlusion of the vertebrobasilar circulation.

Fondaparinux sodium (Arixtra)

Synthetic anticoagulant, which works by inhibiting factor Xa, a key component involved in blood clotting. Provides highly predictable response. Bioavailability is 100%, has a rapid onset of action, and a half-life of 14-16 h, allowing for sustained antithrombotic activity over 24-h period. Does not affect PT or aPTT, and it does not affect platelet function or aggregation.
Prevent DVT, which may lead to PE, in patients undergoing orthopedic surgery who are at risk for thromboembolic complications.

Heparin

Augments activity of antithrombin III and prevents conversion of fibrinogen to fibrin. Does not actively lyse but is able to inhibit further thrombogenesis. Prevents reaccumulation of a clot after a spontaneous fibrinolysis.

Dalteparin (Fragmin)

Enhances inhibition of factor Xa and thrombin by increasing antithrombin III activity. In addition, preferentially increases inhibition of factor Xa.
Except in overdoses, no utility exists in checking PT or aPTT because aPTT does not correlate with anticoagulant effect of fractionated LMWH. Average duration of treatment is 7-14 d.

Warfarin (Coumadin)

Interferes with hepatic synthesis of vitamin K–dependent coagulation factors. Used for prophylaxis and treatment of venous thrombosis, PE, and thromboembolic disorders.
Dose must be individualized and adjusted to maintain INR at 2-3.

Enoxaparin (Lovenox)

LMWH used in treatment of DVT and PE as well as DVT prophylaxis.
Enhances inhibition of factor Xa and thrombin by increasing antithrombin III activity. Slightly affects thrombin and clotting time and preferentially increases inhibition of factor Xa.
Average duration of treatment is 7-14 d.

Tinzaparin (Innohep)

Enhances inhibition of factor Xa and thrombin by increasing antithrombin III activity. In addition, preferentially increases inhibition of factor Xa.
Average duration of treatment is 7-14 d.

Thrombolytics

These agents are used to dissolve a pathologic intraluminal thrombus or embolus that has not been dissolved by the endogenous fibrinolytic system. Also used for the prevention of recurrent thrombus formation and rapid restoration of hemodynamic disturbances.

Tenecteplase (TKNase)

Modified version of alteplase (tPA) made by substituting 3 amino acids of alteplase. Has longer half-life and, thus, can be given as single bolus over 5 sec infusion instead of 90 min with alteplase. Appears to cause less non-intracranial bleeding but has similar risk of intracranial bleeding and stroke as alteplase. Base the dose using patient weight. Initiate treatment as soon as possible after onset of AMI symptoms. Because tenecteplase contains no antibacterial preservatives, reconstitute immediately before use.

Urokinase (Abbokinase)

Direct plasminogen activator isolated from human fetal kidney cells grown in culture. Acts on endogenous fibrinolytic system and converts plasminogen to enzyme plasmin. Plasmin degrades fibrin clots, fibrinogen, and other plasma proteins. It is nonantigenic but more expensive than streptokinase, which limits its use. When used for purely local fibrinolysis, it is administered as local infusion directly into area of thrombus and with no bolus.
Adjust dose to achieve clot lysis or patency of affected vessel.

Streptokinase (Kabikinase, Streptase)

Acts with plasminogen to convert plasminogen to plasmin. Plasmin degrades fibrin clots as well as fibrinogen and other plasma proteins. An increase in fibrinolytic activity that degrades fibrinogen levels for 24-36 h takes place with IV infusion of streptokinase.

Alteplase, tPA (Activase)

Thrombolytic agent for DVT or PE. A tissue plasminogen activator (tPA) produced by recombinant DNA and used in the management of acute myocardial infarction, acute ischemic stroke, and PE.
Safety and efficacy of this regimen with coadministration of heparin and aspirin during the first 24 h after symptom onset have not been investigated.

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