As soon as a DVT or PE is suspected, it is crucial to promptly assess the patient to optimize management, which usually includes initiating anticoagulant therapy in those with established DVT or PE and as an interim measure until definitive diagnostic testing is performed. Treatment should start before the diagnosis of DVT or PE has been confirmed in two common scenarios. The first is the patient arriving at the emergency room with symptoms suggestive of DVT and in whom lower limb venous ultrasound is not available and has to be deferred until the next morning. If a standardized clinical prediction rule (see Chapter 83) shows that DVT is likely and the patient has a low risk of bleeding, a dose of low molecular weight heparin (LMWH) should be given while awaiting definitive diagnostic testing.¹ If the bleeding risk is high, it is acceptable to defer therapy until the diagnosis of DVT has been verified; in such patients, best efforts should be made to establish a definitive diagnosis on the day of presentation.

The second scenario occurs in the patient with likely PE according to a clinical prediction rule, in whom it is unacceptable to defer anticoagulant therapy until the diagnosis of PE is confirmed.¹

In two randomized controlled trials (RCTs), in which 254 patients with DVT were treated with heparin or placebo and had 3 to 24 weeks of follow-up observation, the risk for disease recurrence was 7% and 21% in the treated and untreated groups, respectively, calculated to a convincing number-needed-to-treat of only seven patients to prevent one recurrent thrombosis.^2,3 However, the need to treat isolated calf DVT has been questioned, based on observational data showing low risk of progression or recurrence without anticoagulation.⁴ A comparison of nadroparin versus placebo (CACTUS trial) in patients with isolated calf DVT is ongoing and may resolve this uncertainty (ClinicalTrials.gov NCT00421538). In the meantime, for patients with isolated calf DVT and minimal or no symptoms, it may be reasonable to withhold anticoagulation, perform repeat venous ultrasound testing for 2 weeks, and initiate anticoagulation only if there is thrombus progression into proximal veins. An increasingly prevalent patient group is one with asymptomatic, incidentally identified PE, typically detected by contrast-enhanced computed tomography pulmonary angiography (CTPA) while assessing another disease. On one hand, anticoagulant-treated patients with cancer and incidental PE have similar high risks of recurrent VTE, bleeding, and death as patients with symptomatic PE.⁵ On the other hand, the introduction of multiple-detector CTPA has doubled the rate of diagnosis of subsegmental PE compared with single-detector CTPA (9.4% vs. 4.7%) without any change in the 3-month risk of symptomatic VTE.⁶ It therefore seems reasonable to withhold anticoagulant treatment of incidental subsegmental PE, particularly if the patient has no active cancer.

Intravenous unfractionated heparin (UFH), which was the initial treatment standard until 10 to 15 years ago, is currently mainly used for special patient groups summarized in Table 87.2. It is usually recommended to initiate UFH treatment with a bolus dose of 80 IU/kg followed by an infusion of 18 U/kg/h.¹ This UFH regimen is based on three RCTs totaling 292 patients,
which compared this or a similar regimen with fixed initial dosing.^11,12,13 The dose is then adjusted according to the results of an activated partial thromboplastin time (aPTT) performed 4 to 6 hours after initiation of UFH to keep the aPTT in a therapeutic range. aPTT reagents vary in their sensitivities to UFH so that an aPTT range that corresponds to an anti-factor Xa heparin level of 0.3 to 0.7 IU/mL should be targeted.¹ Subcutaneous injection of UFH versus intravenous therapy, both adjusted according to the aPTT, was compared in a meta-analysis of six trials totaling 783 patients¹⁴ and demonstrated favorable results with subcutaneous UFH for recurrent VTE (relative risk [RR], 0.62; 95% CI, 0.39 to 98) and major bleeding (RR, 0.79; 95% CI, 0.42 to 1.48). A subcutaneous, weight-adjusted, unmonitored UFH regimen (250 IU/kg twice-daily dosing after a 333 U/kg initial dose) was compared with LMWH therapy in an RCT (FIDO) of almost 700 patients with DVT or PE.¹⁵ There was no statistically significant difference in the incidence of recurrent VTE (3.8% vs. 3.4%) or major hemorrhage during the first 10 days (1.1% vs. 1.4%) with fixed-dose, unmonitored UFH and LMWH. This is the only UFH regimen that allows for convenient outpatient therapy, which actually was achieved entirely for 72% of the patients in this treatment group in the study.

Over the past 10 to 15 years, the initial treatment of DVT with LMWH has become standard therapy due to its convenience of once-daily subcutaneous dosing, and no requirement for laboratory monitoring. For patients with PE, a twice-daily LMWH regimen is usually recommended (Table 87.1). Several meta-analyses have compared the efficacy and safety of LMWH with UFH. The results of the systematic review by van Dongen¹⁶ are summarized in Table 87.3, showing that in addition to the convenience of administration and the compelling data on the safety without laboratory monitoring, LMWH also has a lower potential for heparin-induced thrombocytopenia (HIT) than UFH. As for individual LMWH regimens, a meta-analysis of five trials totaling 1,508 patients compared once- versus twice-daily LMWH regimens and showed no significant difference in recurrent VTE (OR, 0.82; 95% CI, 0.49 to 1.39), major hemorrhage (OR, 0.77; 95% CI, 0.40 to 1.45), or death (OR, 1.14; 95% CI, 0.62 to 2.08).¹⁷

Fondaparinux is an indirect inhibitor of factor Xa that is produced synthetically, with a lower risk for allergic reactions and a negligible risk for HIT. However, its elimination half-life is longer than that for LMWH (17 hours vs. 4 to 5 hours), which may be a drawback in cases of bleeding or perioperative management. The treatment dose of fondaparinux is 7.5 mg once daily (5 mg for body weight <50 kg; 10 mg for weight >100 kg). This dose regimen was compared in the MATISSE trials against LMWH (enoxaparin 1 mg/kg twice daily) in approximately 2,200 patients with DVT and against intravenous UFH in 2,200 patients with PE.^18,19 The efficacy (recurrent VTE) and safety (major bleeding) were similar for fondaparinux and LMWH (or UFH) in these trials. Fondaparinux is currently the preferred initial anticoagulant in patients with recent HIT, occurring within the preceding 100 days. Rivaroxaban, a direct factor Xa inhibitor, is so far the only available oral anticoagulant shown to be effective for the initial treatment of VTE, although at the time of writing it has not been approved for this indication. In the phase III trial (EINSTEIN DVT), rivaroxaban was given at a dose of 15 mg twice daily for 3 weeks, followed
by a dose of 20 mg once daily, whereas standard therapy with enoxaparin was given for 5 to 10 days followed by a VKA.²⁰ Rivaroxaban was noninferior to standard therapy for recurrent VTE during the entire study period (how long was the study period?) (2.1% vs. 3.0%; hazard ratio [HR], 0.68; 95% CI, 0.44 to 1.04); moreover, there was no excess in recurrent VTE events during the initial treatment period. Clinically relevant bleeding was seen in 8.1% of patients in each group.

A similar treatment strategy is used in the ongoing phase III trial with the oral factor Xa inhibitor apixaban in the treatment of VTE (AMPLIFY; ClinicalTrials.gov NCT00643201). Apixaban is given at a dose of 10 mg twice daily for the first week, followed by 5 mg twice daily and compared with standard therapy of an LMWH and a VKA.

Studies with the oral factor Xa inhibitor, edoxaban tosylate (NCT00986154), and the oral direct thrombin inhibitor, dabigatran etexilate (RE-COVER trial),²¹ assessed treatment only after an initial 5 to 10 days of treatment with an LMWH (or UFH).

In the large majority (>80%) of patients with DVT, anticoagulant therapy can be done out-of-hospital by subcutaneous LMWH, which can be self-administered by the patient or with assistance from a family member or a health professional. Most trials supporting outpatient management are designed in a way that makes interpretation of the results difficult since the comparator group was in-hospital treatment with UFH.¹ One study directly compared outpatient versus inpatient treatment with LMWH in 201 patients with VTE and found no difference in clinical outcomes but a 56% cost reduction with outpatient therapy.²² For patients with PE, a clinical prediction rule for risk stratification such as the Pulmonary Embolism Severity Index (PESI)²³ may be used to assess the safety of outpatient management (see Chapter 83). Several retrospective cohort studies have assessed out-of-hospital management of patients with hemodynamically stable PE who did not require oxygen or narcotic analgesics and were at low risk for bleeding.^24,25 After 3 months of follow-up, there were no cases of fatal PE. A recently published RCT compared inpatient and outpatient treatment for 344 patients with PE at low risk of death, defined as PESI class I or II.²⁶ The mean stay in hospital was 3.9 and 0.5 days, respectively. During the 90-day follow-up, there was one death but no recurrent VTE or major bleeding among those treated as inpatients compared to one death, one recurrent VTE, and two major bleeding events (within 14 days) among those randomized to outpatient therapy, fulfilling the preset noninferiority criteria. Taken together, these studies suggest that most patients with DVT and at least 40% of patients with PE²³—after careful risk stratification and documentation—can be treated entirely as outpatients.