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CHAPTER 39: Pulmonary Embolic Disorders: Thrombus, Air, and Fat 329

been extensively studied in prospective comparison to heparin or LMWH Vena Caval Interruption: Occasionally patients have compelling rea-
in treatment of pulmonary embolism. sons which preclude anticoagulation, or continue to embolize despite
Argatroban represents a different class of direct thrombin inhibi- adequate anticoagulation. As most thromboemboli originate in the
tors, in addition to melagatran and the now discontinued oral agent legs, pelvis, or inferior vena cava (IVC), inferior vena caval inter-
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ximelagatran. Argatroban is an effective anticoagulant in patients with ruption (VCI) has the potential to prevent subsequent embolization.
heparin-induced thrombocytopenia, and has been licensed for use in Conventional indications for the use of VCI in patients with venous
this capacity. Like the hirudins, argatroban has not been studied in any thromboembolism have included contraindications to anticoagulation,
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randomized trials in PE, but it appears to be as safe as or safer than hep- hemorrhage following anticoagulation, failure of anticoagulation to
arin when given to patients with myocardial infarction. It is cleared prevent recurrent embolization, and prophylaxis of extremely high-
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principally by the biliary system and the dose needs no adjustment for risk patients. Only one randomized prospective trial has evaluated
renal failure. Monitoring of both the aPTT and the prothrombin time using VCI to prevent PE. This trial randomized 400 patients with
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(PT) is recommended. Newer oral direct thrombin inhibitors have been proximal DVT who were at risk for PE to receive a vena caval filter or
developed but withdrawn from the market due to excessive bleeding, standard anticoagulation. Over the first 12 days, the vena caval filter
though more may appear in the future. 111 group had significantly fewer cases of PE (1.1% vs 4.8%, P <0.03).
Among the newest of antithrombotic agents approved in the prophy- However, over the subsequent 2 years, during which all patients were
laxis of deep venous thrombosis and pulmonary embolus is fondaparinux, anticoagulated for at least three months, the rates of PE, major bleed-
a novel synthetic drug inhibiting factor Xa. By binding to antithrombin ing, and death were similar in both groups. Moreover, the vena caval
with tight affinity and inducing a conformational change, fondaparinux filter group actually had a significantly higher rate of recurrent deep-
facilitates the binding of antithrombin with factor Xa, thus blocking the vein thrombosis, with a nearly twofold increase in odds ratio for DVT
common pathway of coagulation. It has been approved by the FDA as a compared to the no-filter group. Thus VCI appeared to be a successful
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subcutaneous injection of 2.5 mg once daily for use in DVT and PE pro- short-term strategy to prevent PE, but came at the expense of increased
phylaxis in patients undergoing orthopedic surgery for hip fracture, hip long-term DVT and a trend toward increased thromboembolic disease.
replacement, or knee replacement, after several randomized controlled This landmark study prompted widespread discussion on two fronts:
trials found superior reduction of DVT for fondaparinux compared to whether anticoagulation should be considered for all patients receiving
enoxaparin. The Matisse PE study comparing fondaparinux and heparin a vena caval filter, and whether a temporary, or retrievable filter might
for pulmonary embolism found the new agent to be as effective and be more successful. Unfortunately, no prospective trial evaluates
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safe as heparin, with a nonsignificant trend toward fewer recurrences of either question. Progress has been made in the technology of retriev-
venous thromboembolism in the fondaparinux group. Bleeding events able filters, and small case series of several different types of temporary
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were similar, and no difference in mortality was detected. Heparin- filters have been published. 119,120 Whereas initially, temporary filters had
induced thrombocytopenia has not been observed with fondaparinux to be removed within a 2-week period in order to minimize the risk
use. A number of additional anti-factor Xa agents are in development, but of endothelialization, newer filters have been retrieved up to 134 days
have not yet been widely tested in humans. Fondaparinux is now recom- without complication. 119
mended as an appropriate short-term initial therapy for PE. Limitations As VCI devices have evolved, they have become smaller and more
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to the use of fondaparinux are similar to those for LMWH, in that for easily placed. As physicians have become more experienced with them,
unstable patients or patients at high risk for bleeding, the long half-life and they have become safer as well, although published complication rates
lack of a readily available antidote may favor the use of heparin. have varied widely, from 2% to 19%. Patients who survive sublethal
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For most patients with PE, warfarin anticoagulation should be insti- embolism but remain hemodynamically compromised may benefit from
tuted on the first treatment day (5 mg PO qhs for the first 2 days, then VCI since recurrent embolism, while unlikely, will be fatal. Nevertheless,
adjust the dose to achieve an INR between 2.0 and 3.0) and continued there are few data to inform management in these sickest patients.
to overlap with short-term therapy for at least 5 days. However, if Complications include filter fracture (occasionally with embolization
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the patient is clinically unstable or likely to require ongoing invasive of fragments), improper placement of the filter, venous thrombosis at
procedures, heparin or a rapidly adjustable agent such as lepirudin or the insertion site (seen in 8%-25%), caval occlusion (which is now
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argatroban should be used preferentially, to facilitate rapid adjustment far less common than when the Mobin-Uddin “umbrella” filters were
of anticoagulation if necessary. in use), inadvertent dislodgment by guidewires during central venous
In 2012, the US Food and Drug Administration approved the oral catheterization, and erosion or perforation of the caval wall and other
factor Xa inhibitor rivaroxaban for the acute and long-term treatment of viscera. A final point about VCI is that while it prevents most recurrent
PE. In an open-label noninferiority trial, investigators randomized almost emboli, it does not treat the (presumed) leg source. Therefore, when
5000 subjects with confirmed acute PE to either oral fixed dose rivaroxa- these devices are used, concomitant anticoagulation is necessary (unless
ban or beginning within 48 hours of PE diagnosis or enoxaparin plus war- the indication for VCI is contraindication to anticoagulation). The sig-
farin, titrated to international normalized ratio. Rivaroxaban was dosed nificance of upper extremity sources of thromboemboli in ICU patients,
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at 15 mg twice daily for the first 3 weeks, followed by 20 mg daily for 3, 6, who often have central catheters, is unknown but probably small.
or 12 months. Warfarin was continued for the same duration, and the ran- Nevertheless, inferior VCI would clearly be ineffective so that when
domization protocol accounted for planned treatment duration at study the clinical presentation suggests an upper source, due consideration
initiation. Fifty subjects in the rivaroxaban group (2.1%) and 44 in the should precede placement of this device. Filters have been placed in the
conventional treatment group (1.8%) experienced recurrent thromboem- superior vena cava and in the suprarenal IVC with apparent safety, but
bolism, consistent with noninferiority of rivaroxaban. Overall bleeding the experience is limited.
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rates were similar between the two treatment arms, but the rivaroxaban
arm had approximately half the rate of major bleeding compared to enoxa- Thrombolytic Therapy
parin/warfarin. Rivaroxaban can be used as both acute and long-term Massive PE With Shock It has been clear for more than three decades
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therapy for PE and does not require bridging with heparin or LMWH. It that thrombolytic therapy more rapidly lyses pulmonary emboli and
also appears that prothrombin complex concentrate can reverse the INR improves hemodynamics. However, 7 days after therapy, patients
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elevation caused by rivaroxaban, as can dialysis. There is limited data on given thrombolytic therapy cannot be distinguished from those treated
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rivaroxaban in pregnancy, and pregnant women were excluded from the only with heparin on the basis of clinical findings or lung perfusion.
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EINSTEIN-PE trial. In addition, patients with an estimated creatinine Combined with the clearly increased risk and cost of thrombolytic agents,
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clearance below 30 mL/min should not receive rivaroxaban, and the drug this has led to a general skepticism about the value of thrombolytic
has not been tested in patients with shock due to PE. 113,115 therapy for the treatment of PE. In a survey of pulmonary physicians,

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