Treatment of acute DVT

Two major advances in the treatment of DVT have been made in the last decade. First, is the introduction of low-molecular-weight hep-arin (LMWH) as a replacement for un-fractionated heparin (UFH) and, second, is the potential benefit from a longer duration of anticoagulant therapy. Large meta-analyses have shown that unmoni-tored, weight-adjusted subcutaneous LMWH is as safe and as effective as UFH administered by continuous infusion guided by the activated partial thromboplastin time (aPTT).146,147 As a result, subcutaneous LMWH is replacing intravenous UFH for the initial therapy of acute venous thromboembolism (VTE). Vitamin K antagonists are highly effective for long-term therapy, but they require laboratory monitoring and are problematic in some patients. Several new anti-coagulants with more convenient and potentially safer profiles are now undergoing clinical evaluation in randomised, controlled trials.

Initial anti-coagulant therapy

LMWH is the anti-coagulant of choice for initial therapy in the majority of patients with objectively confirmed DVT. The predictable pharmacokinetic properties enable LMWHs to be given as weight-adjusted subcutaneous injections without the need for laboratory monitoring.148 Although laboratory monitoring is not usually required for patients receiving LMWHs, checking the 4-hour anti-Xa level is recommended in the following patient groups: advanced renal disease, pregnancy, children, and obese. If necessary, the LMWH dose should be adjusted.148 In addition to their convenient dosing administration, LMWHs are more cost effective than UFH because the elimination of laboratory monitoring in most patients reduces the length of hospitalisation.149 Another advantage of LMWHs over UFH is a lower risk of heparin-induced thrombocytopenia.150 The majority of outpatients with newly diagnosed DVT are treated entirely at home.

This requires appropriate resources and infrastructure, including the ability to be able to teach all suitable patients or family members to administer subcutaneous injections, or arrange for the home support of a district nurse in those who are visually impaired or physically unable to inject themselves. Outpatient treatment requires an organised service with dedicated staff to provide patient support and education. Despite the disadvantages of UFH, it is often used in patients with extensive iliofemoral DVT with circulatory compromise and those who are haemodynamically unstable from associated major pulmonary embolism, because these groups were excluded in clinical trials that compared LMWHs with UFH. The usual intravenous regimen for UFH is a loading dose of 5000 U followed by a continuous infusion of around 1400 U hourly. The dose of UFH is adjusted according to the aPTT by following a validated standard nomogram to maintain a therapeutic heparin level.148 Alternatively, a weight adjusted loading dose and nomogram can be used.151 If subcutaneous UFH is used, it is given at a starting dose of 17,500 U twice daily, and the dose is adjusted to achieve a therapeutic aPTT at six hours after the initial injection.148 In patients requiring large doses of UFH (> 35,000 U/24 h), the heparin level should be monitored by anti-Xa assay. LMWH or UFH should be administered for a minimum of 5 days in patients with uncomplicated thrombosis and for 7 days or longer in patients who have extensive disease (e.g., iliofemoral DVT or massive pulmonary embolism). Oral anti-coagulant therapy can be started on the first day of treatment, and LMWH/UFH should not be stopped until the INR has been at least 2.0 for 2 consecutive days. A baseline platelet count and on days 5 to 7 should be done to check for heparin-induced thrombocytopenia if the patient is receiving UFH.

Long-term anti-coagulant therapy

After an initial course of LMWH or UFH, continuing anti-coagulant therapy with oral vitamin-K antagonists is required to prevent recurrence. Warfarin is the most common agent used in UK. The use of a loading dose is discouraged because it may be associated with a transient period of excessive anti-coagulation, without a corresponding anti-thrombotic effect.152 The INR is measured after the first 2 or 3 doses of warfarin, and subsequent doses are adjusted to maintain the INR within the target range. As the therapeutic window for oral anti-coagulant therapy is narrow, frequent monitoring of the INR is essential to reduce the risks of recurrent thrombosis and anti-coagulant-related haemorrhage (ARH). Appropriate adjustments in the dose of warfarin usually require twice-weekly monitoring for the first 1 to 2 weeks, followed by weekly monitoring for the next 4 weeks, then once every 2 weeks for a month and, finally, every 4 weeks if the INRs have remained in the therapeutic range on a stable warfarin dose and the patient has not experienced any adverse effects. It is wise to monitor the INR at 4-week interval even in patients who have maintained a stable warfarin dose because of the potential interactions of warfarin with food or drugs. If there are changes in the patient's medications, more frequent monitoring is needed until a stable dose response is achieved.153 Because oral anti-coagulant therapy is inconvenient, LMWH is being evaluated as an alternative for long-term treatment of VTE. LMWH has a number of advantages over warfarin. First, because LMWH does not require INR monitoring, it can be used when laboratory monitoring is problematic (e.g., difficult venous access). Second, LMWH has a more rapid onset and offset of action than warfarin. Therefore, it is more convenient to use in patients who require dental or surgical procedures while anti-coagulated. Third, there is a clinical impression that LMWH is more effective than warfarin in patients with thrombosis and cancer and in those who develop recurrent thrombosis despite therapeutic warfarin therapy. Despite these advantages, however, the routine use of LMWH is not practical or economical because LMWH requires administration by subcutaneous injection and is more expensive than warfarin. LMWHs may be difficult to reverse completely in the event of life-threatening haemorrhage. Randomised controlled trials comparing LMWH with oral anti-coagulant therapy have shown that the rates of recurrent thrombosis and major bleeding between the two treatment groups are similar.154,155

Duration of anti-coagulant therapy

The duration of anti-coagulant therapy is influenced by balancing the risks of recurrence of thrombosis and of anti-coagulant related haemorrhage (ARH), and by the patient preference. The risk of bleeding during the initial period of anti-coagulation with UFH or LMWHs is 2 to 5%, while the estimated risk of major bleeding with oral anti-coagulant therapy is about 3% annually.156 As 20% of major bleeds are fatal, the annual case fatality rate from ARH is about 0.6%. The risk of bleeding is increased by patient-specific factors, such as, age (65 years or older) and co-morbidity (renal failure, liver disease, diabetes, peptic ulcer disease, cerebrovascular disease, malignancy) and by the concomitant use of anti-platelet agents.157,158 Evidence also indicates that the risk of bleeding on anti-coagulant therapy is reduced over time, so the long-term fatality rate is likely to be lower in patients who have tolerated months or years of anti-coagulant treatment without bleeding. On the other hand, the case fatality rate from recurrent VTE is about 5%, with the rate being higher within the first 3 months of an episode of pulmonary embolism. Therefore, at an annual recurrence rate of 12%, the risk of death from recurrent thrombosis is balanced by the risk of death from ARH. In general, patients should be treated with anti-coagulant therapy for a minimum of 3 months. Patients with a reversible risk factor have a low risk of recurrence after 3 months of anti-coagulant therapy. In contrast, patients with idiopathic or unprovoked DVT who are treated for only 3 months have 10 to 27% risk of recurrence in the year after anti-coagulants are discontinued.159--161 Recent evidence suggests that extending therapy beyond 6 months in patients with idiopathic thrombosis does not reduce the risk of recurrent thrombosis to less than 10% in the year after discontinuing anti-coagulant therapy. Continuing warfarin after this period protects the patient against future recurrence, but also exposes the patient to the risk of ARH. Based on the results of prospective studies and extrapolation from studies on the risk of recurrence after a first episode of venous thrombosis, patients can be stratified into low, moderate, high, and very high-risk groups for recurrence when anti-coagulants are discontinued. Low-risk patients are those who had an important risk factor for thrombosis (e.g., major surgery, pelvic or leg trauma, or major medical illness) from which they have fully recovered. Their risk of recurrence when anti-coagulants are discontinued at 3 months is estimated to be less than 5% in the next year and somewhat lesser in subsequent years. These patients should be encouraged to have prophylactic anti-coagulants if exposed to a high-risk state and, in general, should be encouraged to seek alternatives to oestrogens for contraception or post-menopausal use. Moderate-risk patients are those without inherited or acquired thrombophilia who had a thromboembolic event in association with a minor risk factor, such as, oestrogen use or long distance travel. Their risk of recurrent thrombosis after 6 months of anti-coagulants is likely to be less than 10% in the year after stopping anti-coagulants, provided that the precipitating risk factor is avoided; they should be treated with anti-coagulants for 6 months. If, however, the precipitating factor cannot be avoided (e.g., oestrogens) they should be given the option of remaining on anti-coagulants during the period of exposure. High-risk patients are those who have an unprovoked venous thromboembolic event and who either have no demonstrable throm-bophilia or are heterozygous for factor V Leiden or the prothrombin G20210A mutation. Their risk of recurrence after 6 months of anticoagulant therapy is likely to be about 10% per annum. In general, anti-coagulant therapy can be stopped after 6 months in these high-risk patients. If, however, the bleeding risk is low, the INR monitoring is smooth and convenient, and the patient prefers to remain on anticoagulant therapy, treatment can be continued and the treatment duration reviewed on an annual basis. Very high-risk patients are those with more than one unprovoked thromboembolic event; patients with inherited deficiencies of anti-thrombin, protein C, or protein S; those with anti-phospholipid antibody syndrome or advanced malignancy; and those who are homozygous for factor V Leiden or prothrom-bin gene mutation or double heterozygotes. The risk of recurrence after a 6-month course of anti-coagulants is likely to be more than 12% annually and, in general, these patients should remain on anticoagulants indefinitely. Firm evidence for this last recommendation is not available, but because the listed thrombophilic states are strong risk factors for a first episode of VTE, they are also likely to increase the risk of recurrent VTE.

PPS and its prevention

Following an episode of DVT, one-fifth of patients may experience PPS.162 Leg pain and swelling exacerbated by standing and physical activity and reduced with elevation of the affected leg are typical features. In severe cases, venous ulceration can develop. PPS occurs as a result of venous hypertension, most commonly caused by venous valvular incompetence and less frequently by persistent venous obstruction. Not all patients with valvular incompetence develop the clinical features of PPS.163 Two approaches have been proposed to prevent and treat PPS, thrombolytic therapy to reduce the damage to venous valves and graduated compression stockings to counter venous hypertension. Results from clinical trials have, however, not clearly shown beneficial effects with either method.162,164,165 The development of PPS is more likely after recurrent episodes of DVT. Therefore, every effort should be made to reduce the likelihood of recurrent thrombosis by using an appropriate course of anti-coagulant therapy for the initial episode and anti-coagulant prophylaxis in subsequent high-risk situations.

Treatment of DVT in pregnancy

UFH was the standard treatment for DVT in pregnant women prior to the introduction of LMWHs. Warfarin is generally avoided because of the risk of warfarin embryopathy and other potential teratogenic effects. UFH has a number of limitations, including heparin-induced osteoporosis, the need for twice-daily subcutaneous injections, and the necessity for aPTT monitoring. These disadvantages are virtually eliminated with LMWH. Although there have been no randomised controlled trials comparing UFH with LMWH in pregnancy, there is no reason to expect that the advantages of LMWH in the non-pregnant population would not apply to pregnant women.166 In addition to the convenience of once-daily injection without the need for frequent laboratory monitoring, like UFH, LMWH does not cross the placenta. Therefore, it is not teratogenic and is not excreted into breast milk. Pregnant women are treated throughout their pregnancy with LMWH and arrange for a planned induction of labour in consultation with the obstetrician. The controlled delivery date enables discontinuation of LMWH 24 hours prior to induction, reducing the risk of bleeding during delivery.

Screening for thrombophilia

The indications for screening patients, who present with a first episode of venous thrombosis to identify underlying thrombophilia, are controversial. From a practical viewpoint, screening would be indicated if the results influenced the duration of anti-coagulant therapy or the need for family counseling. The duration of anti-coagulant therapy is influenced by finding deficiencies in anti-thrombin, protein C, or protein S, homozygous factor V Leiden, homozygous prothrombin gene mutation double heterozygosity, and persistently elevated anti-phospholipid antibodies. Family counselling is particularly important for female carriers who are contemplating oestrogen use. Based on these considerations, we think that it is reasonable to perform screening for thrombophilia in the following groups: first episode of idiopathic thrombosis at age 50 or younger; history of two or more episodes of recurrent thrombosis, especially if the events were unprovoked; thrombosis in an unusual site (e.g., cerebral, mesenteric, retinal); positive family history with two or more first-degree relatives with documented venous thrombosis; women who develop pregnancy associated thrombosis or in the setting of a hormonal agent; and women who have unexplained recurrent pregnancy loss. This latter group requires special consideration because anti-coagulant and anti-platelet therapy may improve future pregnancy outcomes if underlying thrombophilia is documented.167 A standard screening panel includes functional assays for anti-thrombin and protein C, free protein S level, activated protein C resistance assay with DNA testing for factor V Leiden, molecular assay for prothrombin G20210A mutation, a phospholipid-based clotting test for lupus anti-coagulant, ELISAs for anti-cardiolipin antibodies, and a fasting homocysteine level.168

New anti-thrombotic agents

Several new anti-thrombotic agents that target selectively single molecules in the coagulation cascade are under development. Parenteral direct inhibitors of thrombin; hirudin and argatroban have been approved for the treatment of HIT. Danaparoid, a heparnoid can be also used for HIT. The synthetic pentasaccharide, fondaparinux (Arixtra) and the oral direct thrombin inhibitor ximelagatran (Mela-gatran) are two potential additional agents.

Synthetic pentasaccharide is administered as a once-daily subcutaneous injection and is being compared with UFH for initial treatment of DVT and pulmonary embolism. This new agent has the advantage of a longer half-life than LMWH and is unlikely to produce heparin-induced thrombocytopenia. A newer form of synthetic pentasaccha-ride with a longer half-life that enables once-weekly subcutaneous injection is also being evaluated for the out-of-hospital longer-term treatment of patients with VTE. Large randomized controlled trials have shown that pentasaccharide is superior to enoxaparin in thromboprophylaxis after major orthopaedic surgery.167,170 Ximelagatran is administered orally and is being compared against standard anticoagulants for thromboprophylaxis in orthopaedic surgery, atrial fibrillation, as well as initial and long-term treatment of VTE.171,172

Thrombolytic therapy for DVT

The role of thrombolysis in DVT treatment remains ill-defined. Veno-graphic studies, thrombolytic agents can produce rapid lysis of venous thromboemboli and restore venous flow. Consequently, thrombolytic therapy has the potential to provide prompt symptomatic relief and reduce the risk of the PPS.173,174 Despite documented improvements on radiologic imaging, however, appropriate studies have not been performed to demonstrate improvements over standard anticoagulant therapy alone, using clinically relevant outcomes. Throm-bolytic therapy increases the risk of major bleeding about 3-fold over that observed with UFH alone, and the observed rate of intracra-nial haemorrhage is approximately 2%.175 There is no agreement on whether systemic or catheter-directed thrombolysis is the preferred method of delivery. A recent randomised, controlled trial comparing UFH alone with four regimens of systemic or regional throm-bolysis showed greater venographic improvement at 12 months with systemic thrombolytic therapy, but at a cost of substantially higher rates of major bleeding and pulmonary embolism compared with

UFH.176 Therefore, even if thrombolysis is effective in reducing the risk of recurrent thrombosis or PPS, the cost, the bleeding risk, and the technical expertise required for this aggressive therapy are major obstacles to its routine use. Most clinicians limit thrombolytic therapy to younger patients with massive iliofemoral vein thrombosis, who have limb-threatening circulatory compromise.

Vena caval interruption

In the presence of a contraindication to anti-coagulant therapy, an inferior vena caval filter is placed in patients with iliofemoral DVT. These circumstances include active bleeding, risk of serious bleeding, and failure of therapeutic anti-coagulant therapy. The use of filters remains controversial in other clinical situations, for example, for preventing embolisation of ''free-floating'' thrombi in iliofemoral territory and as the first-line treatment (alone) in patients with central nervous system malignancy and acute DVT.177 Only one randomised, controlled trial has evaluated the use of vena caval filters in patients with proximal DVT, all of whom also received anti-coagulant therapy.178 There was a significant initial reduction in the incidence of pulmonary embolism in the filter group, but this advantage was lost with longer follow-up. In addition, patients with a filter had a higher risk of recurrent DVT and there was no difference in the overall mortality at 2 years following the study. Similar results are reported by a population-based analysis in more than 3600 patients in whom a filter was inserted for DVT.179 Other potential situations where caval interruption may be indicated include: patients with a newly diagnosed proximal DVT or pulmonary embolism who have to undergo urgent surgery; who have severe thrombocytopenia; or have active and potentially life-threatening bleeding. In all cases, anti-coagulant therapy is restarted when normal haemostasis is achieved.

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