TREATMENT Pulmonary Embolism RISK STRATIFICATION
Hemodynamic instability, RV dysfunction on echocardiography, RV enlargement on chest CT, or elevation of the troponin level due to RV microinfarction portend a high risk of an adverse clinical outcome despite anticoagulation. When RV function remains normal in a hemodynamically stable patient, a good clinical outcome is highly likely with anticoagulation alone (Fig. 273-7). ANTICOAGULATION
Effective anticoagulation is the foundation for successful treatment of DVT and PE. There are three major strategies: (1) the classical but waning strategy of parenteral anticoagulation with unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), or fondaparinux “bridged” to warfarin, (2) parenteral therapy switched after 5 days to a novel oral anticoagulant such as dabigatran (a direct thrombin inhibitor) or edoxaban (an anti-Xa agent), or (3) oral anticoagulation monotherapy with rivaroxaban or apixaban (both are anti-Xa agents) with a 3-week or 1-week loading dose, respectively, followed by a maintenance dose without parenteral anticoagulation. For patients with VTE in the setting of suspected or proven heparin-induced thrombocytopenia, one can choose between two parenteral direct thrombin inhibitors: argatroban and bivalirudin (Table 273-3). Unfractionated Heparin
UFH anticoagulates by binding to and accelerating the activity of antithrombin, thus preventing additional thrombus formation. UFH is dosed to achieve a target activated partial thromboplastin time (aPTT) of 60–80 s. The most popular nomogram uses an initial bolus of 80 U/kg, followed by an initial infusion rate of 18 U/kg per h in patients with normal liver function. The major advantage of UFH is its short half-life, which is especially useful in patients in whom hour-to-hour control of the intensity of anticoagulation is desired. Heparin also has pleiotropic effects that may decrease systemic and local inflammation. Low-Molecular-Weight Heparins
These fragments of UFH exhibit less binding to plasma proteins and endothelial cells and consequently have greater bioavailability, a more predictable dose response, and a longer half-life than does UFH. No monitoring or dose adjustment is needed unless the patient is markedly obese or has chronic kidney disease. Fondaparinux
Fondaparinux, an anti-Xa pentasaccharide, is administered as a weight-based once-daily subcutaneous injection in a prefilled syringe. No laboratory monitoring is required. Fondaparinux is synthesized in a laboratory and, unlike LMWH or UFH, is not derived from animal products. It does not cause heparin-induced thrombocytopenia. The dose must be adjusted downward for patients with renal dysfunction. Warfarin
This vitamin K antagonist prevents carboxylation activation of coagulation factors II, VII, IX, and X. The full effect of warfarin requires at least 5 days, even if the prothrombin time, used for monitoring, becomes elevated more rapidly. If warfarin is initiated as monotherapy during an acute thrombotic illness, a paradoxical exacerbation of hypercoagulability increases the likelihood of thrombosis. Overlapping UFH, LMWH, fondaparinux, or parenteral direct thrombin inhibitors with warfarin for at least 5 days will nullify the early procoagulant effect of warfarin. Warfarin dosing
In an average-size adult, warfarin is often initiated in a dose of 5 mg. The prothrombin time is standardized by calculating the international normalized ratio (INR), which assesses the anticoagulant effect of warfarin (Chap. 61). The target INR is usually 2.5, with a range of 2.0–3.0.
The warfarin dose is usually titrated empirically to achieve the target INR. Proper dosing is difficult because hundreds of drug-drug and drug-food interactions affect warfarin metabolism. Increasing age and systemic illness reduce the required warfarin dose. Pharmacogenomics may provide more precise initial dosing of warfarin. CYP2C9 variant alleles impair the hydroxylation of S-warfarin, thereby lowering the dose requirement. Variants in the gene encoding the vitamin K epoxide reductase complex 1 (VKORC1) can predict whether patients require low, moderate, or high warfarin doses. However, genetic testing is not used clinically to dose patients with warfarin.
Centralized anticoagulation clinics have improved the efficacy and safety of warfarin dosing. Patients can self-monitor their INR with a home point-of-care fingerstick machine and can occasionally be taught to self-dose their warfarin.
Warfarin can cause major hemorrhage, including intracranial hemorrhage, even when the INR remains within the desired therapeutic range. Warfarin can cause “off target” side effects such as alopecia or arterial vascular calcification. Some patients complain that warfarin makes them feel cold or fatigued. Novel Oral Anticoagulants
Novel oral anticoagulants (NOACs) are administered in a fixed dose, establish effective anticoagulation within hours of ingestion, require no laboratory coagulation monitoring, and have few of the drug-drug or drug-food interactions. Betrixaban, a direct factor Xa inhibitor, was approved by the FDA in 2017 for VTE prophylaxis in acutely ill medical patients during hospitalization and continuing for a total duration of 5 to 6 weeks. Rivaroxaban and apixaban, direct factor Xa inhibitors, are approved as monotherapy for acute and extended treatment of DVT and PE, without a parenteral “bridging” anticoagulant. Dabigatran, a direct thrombin inhibitor, and edoxaban, a factor Xa inhibitor, are approved for treatment of VTE after an initial 5-day course of parenteral anticoagulation. Complications of Anticoagulants
The most serious adverse effect of anticoagulation is hemorrhage. For life-threatening or intracranial hemorrhage due to heparin or LMWH, protamine sulfate can be administered. There is no specific reversal agent for bleeding caused by fondaparinux or factor Xa inhibitors. However, the dabigatran antibody, idarucizumab, is an effective and rapidly acting antidote for dabigatran that is now licensed for use. Andexanet is a universal anti-Xa antidote for betrixaban, rivaroxaban, apixaban, and edoxaban that is undergoing review by the FDA.
Major bleeding from warfarin is best managed with prothrombin complex concentrate. With less serious bleeding, fresh-frozen plasma or intravenous vitamin K can be used. Oral vitamin K is effective for managing minor bleeding or an excessively high INR in the absence of bleeding. Duration of Anticoagulation
For DVT isolated to an upper extremity or calf that has been provoked by surgery, trauma, estrogen, or an indwelling central venous catheter or pacemaker, 3 months of anticoagulation usually suffice. For an initial episode of provoked proximal leg DVT or PE, 3–6 months of anticoagulation used to be the classic teaching. However, the EINSTEIN CHOICE study found that patients with provoked VTE derived as great a risk reduction in recurrent VTE with extended duration anticoagulation as patients with unprovoked VTE. For patients with cancer and VTE, prescribe LMWH as monotherapy without warfarin and continue anticoagulation indefinitely unless the patient is rendered cancer-free.
Among patients with idiopathic, unprovoked VTE, the recurrence rate is high after cessation of anticoagulation. VTE that occurs during long-haul air travel is considered unprovoked. Unprovoked VTE may be caused by an exacerbation of an underlying inflammatory state and can be conceptualized as a chronic illness, with latent periods between flares of recurrent episodes. American College of Chest Physicians (ACCP) guidelines recommend considering anticoagulation for an indefinite duration with a target INR between 2 and 3 for patients with idiopathic VTE and a low bleeding risk. An alternative approach after the first 6 months of anticoagulation is to reduce the intensity of anticoagulation and to lower the target INR range to between 1.5 and 2. Another approach for patients at lower risk of recurrence, especially if there is an important reason to avoid long-term anticoagulation, is to consider low-dose aspirin after completing the initial period of standard anticoagulation.
Counterintuitively, the presence of genetic mutations such as heterozygous factor V Leiden and prothrombin gene mutation does not appear to increase the risk of recurrent VTE. However, patients with antiphospholipid antibody syndrome may warrant indefinite-duration anticoagulation, even if the initial VTE was provoked by trauma or surgery. INFERIOR VENA CAVA FILTERS
The two principal indications for insertion of an IVC filter are (1) active bleeding that precludes anticoagulation and (2) recurrent venous thrombosis despite intensive anticoagulation. Prevention of recurrent PE in patients with right heart failure who are not candidates for fibrinolysis and prophylaxis of extremely high-risk patients are “softer” indications for filter placement. The filter itself may fail by permitting the passage of small- to medium-size clots. Large thrombi may embolize to the pulmonary arteries via collateral veins that develop.
Paradoxically, by providing a nidus for clot formation, filters increase the DVT rate, even though they usually prevent PE. Therefore, a common complication is recurrent DVT or caval thrombosis with marked leg swelling. Retrievable filters can now be placed for patients with an anticipated temporary bleeding disorder or for patients at temporary high risk of PE, such as individuals undergoing bariatric surgery who have a prior history of perioperative PE. The filters can be retrieved for months after insertion, unless thrombus forms and is trapped within the filter. The retrievable filter becomes permanent if it remains in place or if, for technical reasons such as rapid endothelialization, it cannot be removed. MANAGEMENT OF MASSIVE PE
For patients with massive PE and hypotension, replete volume with 500 mL of normal saline. Additional fluid should be infused with extreme caution because excessive fluid administration exacerbates RV wall stress, causes more profound RV ischemia, and worsens LV compliance and filling by causing further interventricular septal shift toward the LV. Dopamine and dobutamine are first-line inotropic agents for treatment of PE-related shock. Maintain a low threshold for initiating these pressors. Often, a “trial-and-error” approach works best; other agents that may be effective include norepinephrine, vasopressin, or phenylephrine. FIBRINOLYSIS
Successful fibrinolytic therapy rapidly reverses right heart failure and may result in a lower rate of death and recurrent PE by (1) dissolving much of the anatomically obstructing pulmonary arterial thrombus, (2) preventing the continued release of serotonin and other neurohumoral factors that exacerbate pulmonary hypertension, and (3) lysing much of the source of the thrombus in the pelvic or deep leg veins, thereby decreasing the likelihood of recurrent PE.
The preferred systemically administered fibrinolytic regimen is 100 mg of recombinant tissue plasminogen activator (tPA) prescribed as a continuous peripheral intravenous infusion over 2 h. The sooner thrombolysis is administered, the more effective it is. However, this approach can be used for at least 14 days after the PE has occurred. A popular off-label dosing regimen is 50 mg of TPA administered over 2 h. This lower dose is widely perceived to be associated with fewer bleeding complications.
Contraindications to fibrinolysis include intracranial disease, recent surgery, and trauma. The overall major bleeding rate is about 10%, including a 2–3% risk of intracranial hemorrhage. Careful screening of patients for contraindications to fibrinolytic therapy (Chap. 269) is the best way to minimize bleeding risk.
The only Food and Drug Administration–approved indication for PE fibrinolysis is massive PE. For patients with submassive PE, who have preserved systolic blood pressure but moderate or severe RV dysfunction, use of fibrinolysis remains controversial. Results of a 1006-patient European multicentered randomized trial of submassive PE, using the thrombolytic agent tenecteplase versus heparin alone, showed that death or hemodynamic collapse within 7 days of randomization was reduced by 56% in the tenecteplase group. However, hemorrhagic stroke occurred in 2% of tenecteplase patients versus 0.2% in patients who only received heparin. PHARMACOMECHANICAL CATHETER-DIRECTED THERAPY
Many patients have relative contraindications to full-dose thrombolysis. Pharmacomechanical catheter-directed therapy usually combines physical fragmentation or pulverization of thrombus with catheter-directed low-dose thrombolysis. Mechanical techniques include catheter maceration and intentional embolization of clot more distally, suction thrombectomy, rheolytic hydrolysis, and low-energy ultrasound-facilitated thrombolysis. The dose of alteplase can be markedly reduced, usually to a range of 20–25 mg, instead of the peripheral intravenous systemic dose of 100 mg. In 2014, the FDA approved ultrasound-facilitated catheter-directed thrombolysis for acute massive and submassive PE. Using a total tPA dose of 24 mg, this approach decreased RV dilation, reduced pulmonary hypertension, decreased anatomic thrombus burden, and minimized intracranial hemorrhage. Lower doses and durations of TPA are currently being studied. PULMONARY EMBOLECTOMY
The risk of major hemorrhage with systemically administered fibrinolysis has prompted a renaissance of interest in surgical embolectomy, an operation that had almost become extinct. More rapid referral before the onset of irreversible multisystem organ failure and improved surgical technique have resulted in a high survival rate. PULMONARY THROMBOENDARTERECTOMY
Chronic thromboembolic pulmonary hypertension develops in 2–4% of acute PE patients. Therefore, PE patients who have initial pulmonary hypertension (usually diagnosed with Doppler echocardiography) should be followed up at about 6 weeks with a repeat echocardiogram to determine whether pulmonary arterial pressure has normalized. Patients impaired by dyspnea due to chronic thromboembolic pulmonary hypertension should be considered for pulmonary thromboendarterectomy, which, when successful, can markedly reduce, and sometimes even cure, pulmonary hypertension (Chap. 277). The operation requires median sternotomy, cardiopulmonary bypass, deep hypothermia, and periods of hypothermic circulatory arrest. The mortality rate at experienced centers is ~5%. Inoperable patients should be managed with pulmonary vasodilator therapy and balloon angioplasty of pulmonary arterial webs. EMOTIONAL SUPPORT
Patients with VTE may feel overwhelmed when they learn that they are suffering from PE or DVT. Some have never previously encountered serious cardiovascular illness. They fear they will not be able to adapt to the new limitations imposed by anticoagulation. They worry about the health of their families and the genetic implications of their illness. Those who are advised to discontinue anticoagulation may feel especially vulnerable about the potential for suffering recurrent VTE. At Brigham and Women’s Hospital, a physician-nurse–facilitated PE support group was initiated to address these concerns and has met monthly for >25 years. The nonprofit organization, North American Thrombosis Forum (www.NATFonline.org), has initiated other online support groups which garner worldwide participation.