Pulmonary Embolism Prevention and Treatment Update
July 1, 2016
July 31, 2018
Michelle Lamb, PharmD, CDE, BC-ACP
Comprehensive Pharmacy Services
FACULTY DISCLOSURE STATEMENTS:
Dr. Lamb has no actual or potential conflict of interest in relation to this activity.
Postgraduate Healthcare Education, LLC does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced, objective, and scientifically rigorous. Occasionally, authors express opinions that represent their own viewpoint. Conclusions drawn by participants should be derived from objective analysis of scientific data.
Postgraduate Healthcare Education, LLC is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.
Credits: 2.0 hours (0.20 ceu)
Type of Activity: Knowledge
This accredited activity is targeted to pharmacists. Estimated time to complete this activity is 120 minutes.
Exam processing and other inquiries to:
CE Customer Service: (800) 825-4696 or firstname.lastname@example.org
Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients' conditions and possible contraindications or dangers in use, review of any applicable manufacturer's product information, and comparison with recommendations of other authorities.
To provide pharmacists with an overview of the diagnostic tools and risk factors for pulmonary embolism (PE) as well as treatment options, the role of new anticoagulants, and the feasibility of an outpatient treatment approach.
After completing this activity, the participant should be able to:
- List diagnostic strategies for PE.
- Describe the risk factors for and patient presentation of PE.
- Outline treatment strategies for PE, including the role of nonvitamin K oral anticoagulants.
- Discuss the role of the pharmacist in counseling patients with PE.
ABSTRACT: Pulmonary embolism (PE) represents a life-threatening condition with a clinical presentation that includes chest pain, coughing up blood, or sudden death. Diagnostic strategies include use of plasma D-dimer measurement, imaging tests, and a variety of algorithms. Patients of all ages may be affected, with increased incidence in those with risks including clotting-factor deficiencies, smoking, obesity, surgery, trauma, and pregnancy. Pharmacists are in a unique position to help implement recommendations released in the new antithrombotic CHEST guidelines, particularly on the use of novel oral anticoagulant agents, as well as to counsel patients on medication use and risk reduction.
The development of a blood clot in a vein, known as a deep vein thrombosis (DVT), represents a potentially serious health problem for patients, particularly if the thrombus breaks off and travels through the blood stream (embolus) and lodges in the lungs, causing a pulmonary embolism (PE). The concept of thrombosis has historically been attributed to Rudolf Virchow, who is best known for Virchow’s triad, despite the fact that he did not necessarily include this exact triad of factors in his philosophy of circulatory problems. The three broad categories associated with this triad and thus the development of thrombosis include the following: alterations in blood flow; injury to the vascular epithelium; and hypercoagulability (changes in the composition of the blood).1,2
Blood-flow alterations are characterized by two key variables—shear rate and shear stress—and affect coagulation by altering the transport rate of platelets and plasma proteins to and from an injury site. Injury to the vascular epithelium results in the recruitment of leukocytes and platelets to the site of damage, causing a procoagulant effect, a tendency for hypercoagulability, and a surface for coagulation complexes to assemble. The third factor of the triad, blood composition, refers to the function of circulating blood cells and plasma proteins and may be the most well-studied component of the triad. Specific examples related to hypercoagulability of the blood include increased levels of procoagulant proteins (prothrombin, fibrinogen) or deficiencies in plasma factors associated with an increasing risk of bleeding, i.e., plasma factors VIII and IX, the lack of which is implicated in hemophilia A and B, respectively.1
The CDC estimates that up to 900,000 people (1-2 per 1,000) are affected by DVT/PE per year in the United States, and that approximately 60,000 to 100,000 Americans will die of complications associated with venous thromboembolism (VTE). Of the patients who succumb to death from thromboembolism, sudden death will occur in 25% of those with PE and 10% to 30% of these patients will expire within 1 month of diagnosis. In addition, patients who survive a diagnosis of DVT may experience long-term complications (postthrombotic syndrome), including pain, swelling, scaling, and discoloration in the affected limb.3 Treatment costs associated with abnormalities in blood coagulation are estimated to exceed $250 billion annually and are projected to triple to over $818 billion per year by 2030.1
Clinical Presentation and Diagnosis
The diagnosis of PE may be delayed in some patients due to the fact that the clinical signs and symptoms are somewhat nonspecific. In fact, PE has been termed the “great masquerader” because the signs and symptoms may be subtle and mimic other disease states. Diagnosis is further complicated because there is no single accepted and standardized algorithm, outcomes data and evaluation for newer therapies is still forthcoming, assessment of bleeding and other risks is complex, and long-term effects of PE are poorly understood.
Characteristics of patients who present to the emergency room with suspected PE include the following: dyspnea, pleuritic chest or back pain (usually worsening with deep breathing or cough), cough, substernal chest pain, fever, hemoptysis (coughing up blood), progressive fatigue, syncope, or sudden death. Other symptoms may include fast or irregular heartbeat, very low blood pressure, or those associated with DVT (unilateral leg pain or extremity swelling).4-6
Diagnostic tools include plasma D-dimer measurement (especially prevalent in symptomatic patients), imaging tests (CT angiography, echocardiography), and a variety of diagnostic algorithms.4,7 The formation of D-dimer occurs when cross-linked fibrin is lysed by plasmin, and these concentrations are increased in patients with PE. D-dimer levels are not specific to PE and may be increased by other factors, such as bleeding, trauma, surgery, or necrosis; however, the absence of elevated D-dimer concentrations can help exclude the diagnosis of PE.7 The options for D-dimer testing with the highest specificity include quantitative enzyme-linked immunosorbent assay (ELISA) or ELISA-derived assays (diagnostic sensitivity of 95%). Less sensitive tests include quantitative latex-derived assays, whole-blood agglutination assay, and point-of-care testing—all with diagnostic sensitivity of <95%, also termed moderate specificity. Other patient factors that may complicate interpretation of D-dimer concentrations include age (specificity decreases in the elderly), and D-dimer concentrations may be increased in patients who are hospitalized, pregnant, or have cancer.4
Pharmacists practicing in the community setting may encounter patients who are most familiar with the link between long-distance travel and VTE, whether by car, bus, or train. The World Health Organization (WHO) performed a study entitled “WHO Research Into Global Hazards of Travel” (WRIGHT) and found the risk of VTE is increased two to threefold after flights of greater than a 4-hour duration, or “long-haul” travel. In addition, the risk of VTE increases with multiple flights within a short period of time. In absolute terms, approximately 1 passenger in 6,000 who participates in a long-haul flight will experience VTE, although these clots may be small and asymptomatic as the body is able to break down the clot with no long-term effects. The thrombotic symptoms associated with travel may occur hours or days after initial formation of the clot.8
Other causes of increased risk of thromboembolism include large anterior myocardial infarction, significant heart failure, intracardiac thrombus (i.e., visible on transthoracic echo), atrial fibrillation, and history of prior thromboembolic event.9 Oral contraception is the most common risk factor in women who are of child-bearing age, and the elevated risk during pregnancy is a major cause of maternal mortality. Unfortunately, the highest level of risk occurs during the third trimester, and the risk of VTE during the time period of 3 months after delivery is up to 60 times higher compared with the risk level of nonpregnant women.4
Research into other unique environmental risk factors for DVT is ongoing and includes a seasonal effect (increased admissions during colder seasons) as well as higher amounts of ambient air pollution (NO2, O3).10 Refer to TABLE 1 for a detailed list of risk factors for VTE and PE.
Revised Antithrombotic Guidelines The American College of Chest Physicians (CHEST) released a newly revised and highly anticipated set of antithrombotic guidelines in February 2016 containing a total of 53 updated recommendations for patients with VTE. The culmination of these guidelines represents the 10th edition in a series of documents that have spanned 30 years. The therapeutic options for treatment of thrombotic disorders have greatly increased since the first set of guidelines was released in the 1970s, when options were limited to unfractionated heparin, streptokinase, warfarin, and aspirin. The authors of the new guidelines state that this version has “cornered” the market of antithrombotic guidelines claiming innovations such as the inclusion of patient-physician discussions in relation to duration of warfarin therapy in treatment of idiopathic DVT.11 Lead author Clive Kearon, MD, McMaster University, said, “This guideline article, another from CHEST living guidelines, provides the most up-to-date treatment options for patients with VTE. The guideline presents stronger recommendations and weaker suggestions for treatment based on the best available evidence, and identifies gaps in our knowledge and areas for future research.”12
From a pharmacist perspective, the most important change to these guidelines is the greatly expanded role of nonvitamin K oral anticoagulants.11 These agents, also known as novel oral anticoagulants (NOACs), have several pharmacokinetic and pharmacodynamic advantages over traditional vitamin K antagonists (VKA) (i.e., warfarin). The 10th edition of the CHEST guidelines recommends use of NOACs over warfarin for initial and long-term therapy for patients with VTE who do not have cancer. New studies published since the 9th edition present evidence that NOACs work as well as VKAs with few risks of bleeding and are more convenient for patients and healthcare providers.12
Although warfarin is inexpensive, use of this agent requires close monitoring by clinicians due to its narrow therapeutic index, numerous food and drug interactions, genetic heterogeneity in patient response, and requirements for regularly scheduled international normalized ratio monitoring.9 However, warfarin therapy may still be preferred in patients where medication cost is a consideration, adherence is poor, or in patients with mechanical heart valves. Low molecular weight heparin (LMWH) remains a very reasonable choice in patients who are unable to tolerate oral therapy (i.e., vomiting due to chemotherapy).13
In comparison to warfarin, use of NOAC agents does not require regular monitoring due to more predictable pharmacodynamic and pharmacokinetic properties, and these agents are associated with fewer drug, herbal, and dietary interactions. However, NOACs do require dosage adjustment in renal impairment and are contraindicated in severe hepatic impairment, have more frequent dosing, have no specific antidotes in situations of overanticoagulation, and are significantly more expensive than warfarin.9
Nonvitamin K oral anticoagulants include dabigatran (Pradaxa), rivaroxaban (Xarelto), apixaban (Eliquis), and edoxaban (Savaysa). Each of these new agents are “direct and specific inhibitors of a single coagulation factor” and have the following characteristics in common: rapid onset of action (peak plasma levels in 2-4 hours); relatively short half-lives (8-12 hours); lack of significant food interactions (although food may increase absorption in some agents); and fewer drug interactions compared with traditional VKAs.14
In addition, the risk of bleeding (especially intracranial bleeds) appears to be less with NOAC therapy compared with VKA therapy.13 Should overanticoagulation occur with warfarin, treatment options include vitamin K, fresh frozen plasma, and/or activated factor VII.9 In October 2015, the FDA granted approval of an antidote for dabigatran. Idarucizumab (Praxbind) is an IV solution that binds to a drug compound, thus neutralizing the anticoagulant effect, which received accelerated approval for use.15 This antidote should be reserved for emergency surgery/urgent procedures or in life-threatening or uncontrolled bleeding and is administered in a 5-g dose (two separate vials each containing 2.5 g/50 mL idarucizumab). The most common adverse effects associated with idarucizumab in patients are hypokalemia, delirium, constipation, pyrexia, and pneumonia.16
Of the four available NOAC options, apixaban and rivaroxaban have the advantage of not requiring pre-treatment with LMWH (enoxaparin, etc).13 Please refer to TABLE 2 for a more detailed comparison of these new treatment options.
Duration of therapy can be divided into two subcategories: long-term (3 months) or extended (no stop date). A key component of patient history when assessing DVT or PE is to determine risk factors, such as thrombosis provoked by surgery. For patients with their first VTE in the form of a PE, extended anticoagulant therapy (no scheduled stop date) is recommended over 3 months of therapy. After 3 months of therapy, however, patients with an unprovoked PE should be evaluated for the risk-to-benefit ratio associated with extended therapy (i.e., patients with a high bleeding risk). For patients that experience a second unprovoked VTE and have low or moderate bleeding risk, guidelines recommend extended anticoagulant therapy (no stop date) compared with 3 months of treatment. Patients with a second unprovoked VTE and high bleeding risk may limit treatment duration to 3 months of anticoagulant therapy (i.e., a stop date is scheduled).13
The recommended duration of treatment for patients who experience a DVT of the leg or a PE provoked by surgery (or nonsurgical transient risk factors) is 3 months. In patients who received extended therapy, there is no compelling indication to change the initial anticoagulant except due to patient circumstances or preferences.13
Treatment and Management
For patients with proximal DVT of the leg or PE who do not have cancer, long-term therapy (3 months) should be initiated over no such therapy. The following recommendations apply regarding the choice of initial therapy: A nonvitamin K oral anticoagulant is considered first line and recommended over a VKA; if a nonvitamin K oral anticoagulant is not used, the VKA therapy is recommended over LMWH.13
Please refer to TABLE 3 for a summary of factors that may influence selection of anticoagulant choice (adapted from CHEST, Table 6).13 Please refer to TABLE 4 for detailed dosing instructions of direct oral anticoagulation in clinical practice.
Some patients may experience recurrent VTE despite VKA therapy (in therapeutic range) or compliance with one of the four nonvitamin K oral anticoagulants. These patients should be converted to treatment with LMWH, at least on a temporary basis. In this scenario, providers should consider accuracy of the recurrent VTE diagnosis, evaluation of therapy compliance, and rule out underlying malignancy. If this subset of patients is found to be in full compliance and truly have recurrent VTE, the dosage of LMWH should be increased by one-quarter to one-third. Dosing of direct or anti-coagulant agents for VTE prevention are shown in TABLE 4.
Aspirin is less effective at preventing recurrent VTE compared with all other anticoagulants, but may be considered an alternative for patients who have chosen to stop anticoagulant therapy. However, the clinician should make a decision to balance the risk-versus-benefit ratio of using aspirin in these patients and determine whether aspirin was stopped on initiation of anticoagulants. For example, risk of bleeding is increased in patients of older age, history of previous bleed, cancer, renal or hepatic failure, diabetes, anemia, and in those who take nonsteroidal anti-inflammatory drugs or abuse alcohol.13
Patients who experience DVT of the leg or PE and cancer are considered to have cancer-associated throm bosis.13 This type of thrombosis is the second-leading cause of death in patients with cancer, and such patients have worse VTE outcomes compared with patients without cancer.17
The first-line therapy consists of LMWH over VKA therapy or use of nonvitamin K oral anticoagulants due to greater risk reduction for recurrent VTE and potential greater efficacy. These patients should receive extended anticoagulant therapy (no stop date) over 3 months of therapy regardless of bleeding risk (low, moderate, or high).13 However, full-dose anticoagulation may be considered unsafe in patients with cancer who have a platelet count of <50,000/L. Prophylactic thrombotic prevention may be considered in high-risk ambulatory patients such as those with a diagnosis of multiple myeloma who are receiving thalidomide-based therapy.17
Inferior Vena Cava Filter
Some patients may be unable to receive anticoagulation and may benefit from an inferior vena cava (IVC) filter, which is essentially a device used to help catch emboli that break loose from DVT. Examples of risk factors for bleeding that would be major contraindications for thrombotic therapy include patients with structural intracranial disease, previous intracranial hemorrhage, ischemic stroke within 3 months, active bleeding, recent brain or spinal surgery, or recent head trauma.13 One study compared the use of retrievable (temporary) IVCs plus anticoagulation versus anticoagulation alone in patients with a history of PE and a high risk of recurrence. This study, entitled the “Prevention du Risque d’Embolie Pulmonary Par Interruption Cave 2” (Prevention of Recurrent Embolism by Vena Cava Interrupt 2 or PRECIP2), included 399 patients randomized over a period of 6 years (200 in the filter group and 199 in the control group). All patients received full-dose anticoagulation for at least 6 months, and patients in the filter group were inserted with a retrievable IVC. Filter retrieval was planned at 3 months from placement. This study concluded that among patients who were hospitalized with severe acute PE, insertion of such a filter compared plus anticoagulation compared with anticoagulation alone did not reduce risk of symptomatic PE at 3 months. If an IVC filter is needed, it should be removed when anticoagulation becomes an option.18
Some patients with low-risk PE and adequate home circumstances may be eligible for treatment at home. This approach entails treatment at home (or early discharge) compared with a standard 5-day hospital stay. New guidelines also recommend that patients who are diagnosed with subsegmental PE (SSPE) who do not have DVT may be cared for with clinical surveillance over anticoagulation with a low risk of recurrent DVT, i.e., appropriately selected patients may be treated in their homes rather than under hospitalization. More specifically, patients must meet the following criteria to be considered suitable for treatment of acute PE at home: clinically stable with good cardiac reserve; no contraindications (i.e., recent bleeding episode), severe hepatic or renal disease, or severe thrombocytopenia (i.e., <70,000/mm3); expectation of treatment compliance; and patient feels well enough to be treated at home.13
Additional Changes to Antithrombotic Guidelines
The authors of the 10th edition of CHEST antithrombotic guidelines no longer recommend routine use of compression stockings to prevent postthrombotic syndrome in acute DVT. This syndrome is a chronic condition of the leg with symptoms of swelling, pain, skin discoloration, and ulcers. The previous edition of these guidelines included the suggestion of compression stockings as a routine preventative measure in these patients.12,13
The 10th edition also elaborates on previous treatment recommendations, including suggestions regarding which patients diagnosed with isolated SSPE should, and should not, receive anticoagulant therapy.12,13
Education and Lifestyle Modifications
Pharmacists have an important role in teaching patients how to prevent DVT and PE. For example, patients should resume movement as soon as possible after bed rest such as due to surgery, illness, or injury. Some patients at high risk for DVT may also benefit from graduated compression stockings (medical compression stockings).
Travel is a known risk factor for DVT and PE, as discussed earlier. Patients who sit for long periods of time (i.e., travel longer than 4 hours) should be counseled to stretch and walk every 2 to 3 hours as well as exercise their legs in the following ways: raising and lowering heels while keeping toes on the floor; raising and lowering toes while keeping heels on the floor; and tightening and releasing leg muscles.19
Role of the Pharmacist
Pharmacists must be knowledgeable about presentation and management in order to help prevent morbidity and mortality associated with this condition, as well as to improve adherence to medication therapy. For example, patients should be counseled to not remove the hydroxypropyl methylcellulose shell that surrounds dabigatran capsules because this action may lead to significantly increased bioavailability. In addition, patients should be counseled that higher doses of rivaroxaban should be taken with food.9 Pharmacists should also be prepared to counsel patients on how to address missed doses of NOACs. If a patient misses a once-daily dose, the medication should be taken on the same day if possible and a morning regimen resumed the next day. If a patient misses a dose of a once-daily drug, it should not be taken on the next day in addition to usual therapy (i.e., double dosing). If a patient misses a dose of NOACs that is dosed twice daily, he or she should be counseled to postpone the missed dose at least 6 hours before the next scheduled dose. Finally, patients should be counseled on the increased risk of bleeding if NOACs are combined with antiplatelet agents such as aspirin or clopidogrel.14 Please refer to TABLE 5 for additional detail regarding drug interactions with oral anticoagulant agents.
Pharmacists must also stay vigilant as further clinical updates are made in the treatment of antithrombotic disease. For example, the authors of the revised CHEST guidelines intend to publish frequent updates in the form of a “Living Guidelines Model” (an online serial publication) as well as employ new processes such as mobile applications and E-learning approaches.11 Perhaps most important, pharmacists should be diligent in teaching patients about the signs and symptoms of DVT (swelling, pain, tenderness, redness of the skin) and the importance of rapid treatment.19
PE is a life-threatening condition that affects patients across the spectrum of age and health status, independent of fitness and/or health literacy levels. NOACs represent a major addition to the armamentarium of oral agents used to treat PE and a cornerstone of the updated 10th edition of the CHEST antithrombotic guidelines, but long-term outcomes data are lacking. Data do not support routine use of IVC filters in patients who are able to receive anticoagulation or use of compression stockings to prevent recurrent VTE. With the addition of NOACs in the updated CHEST antithrombotic guidelines, pharmacists are in a unique position to assist with care coordination and decision-making for patients who are receiving drug therapy for PE.
- Wolberg AS, Aleman MM, Leiderman K, et al. Procoagulant activity in hemostasis and thrombosis: Virchow’s triad revisited. Anesth Analg. 2012;114(2):275-285.
- The Free Library By Farlex. Virchow’s Triad Revisited. www.thefreelibrary. com/Virchow%27s+triad+revisited.(Letters+to+the+Editor) (Letter+to+the...-a0114134751. Accessed April 17, 2016.
- Centers for Disease Control and Prevention. Venous Thromboembolism (Blood Clots). Data and Statistics. www.cdc.gov/ncbddd/dvt/data.html. Accessed April 17, 2016.
- Konstantinides S, Torbicki A, Agnelli G. 2014 ESC Guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J. doi:10.1093/eurheartj/ehu283.
- Streiff MB, Agnelli G, Connors JM. Guidance for the treatment of deep vein thrombosis and pulmonary embolism. J Thromb Thrombolysis. 2016;41:32-67.
- Centers for Disease Control and Prevention. Venous Thromboembolism (Blood Clots). Facts. www.cdc.gov/ncbddd/dvt/facts.html. Accessed April 17, 2016.
- Kearon C. Diagnosis of pulmonary embolism. Can Med Assoc J. 2003:168(2):183-194.
- World Health Organization. International Travel and Health. Immobility, circulatory problems and deep vein thrombosis. www.who.int/ith/mode_of_ travel/DVT/en/. Accessed April 12, 2016.
- Wang Y, Bajorek B. New oral anticoagulants in practice: pharmacological and practical considerations. Am J Cardiovasc Drugs. 2014;14:175-189.
- Miguel-Díez J, Jiménez-García R, de Andrés AL, et al. Analysis of environmental risk factors for pulmonary embolism: A case-crossover study (2001–2013). Eur J Intern Med (2016), http://dx.doi.org/10.1016/j. ejim.2016.03.001. (Article in press)
- Heffner J. Update of antithrombotic guidelines. Chest. 2016;149(2):293-294.
- American College of Physicians. Press Release. CHEST issues new antithrombotic guideline update for treatment of VTE disease. www.chestnet. org/News/Press-Releases/2016/01/AT10-VTE. Accessed April 26, 2016.
- Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest. 2016;149(2):315-352.
- Fontana P, et al. Direct oral anticoagulants: a guide for daily practice. Swiss Med Wkly. 2016;146:w14286.
- U.S. Food and Drug Administration. FDA News Release. FDA approves Praxbind, the first reversal agent for the anticoagulant Pradaxa. www.fda.gov/ NewsEvents/Newsroom/PressAnnouncements/ucm467300.htm. Accessed June 7, 2016.
- Product information for Praxbind. Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877. October 2015.
- Deng A, Galanis T, Graham MG. Venous thromboembolism in cancer patients. Hosp Pract. 2014;42(5):24-33.
- Mismetti P, Laporte S, Pellerin O, et al. Effect of a retrievable inferior vena cava filter plus anticoagulation vs anticoagulation alone on risk of recurrent pulmonary embolism: a randomized clinical trial. JAMA. 2015;313(16):1627-1635.
- Centers for Disease Control and Prevention. Deep Vein Thrombosis (Blood Clots). www.cdc.gov/features/deep-vein-thrombosis/index.html. Accessed April 17, 2016.
- Product information for Eliquis. Bristol-Myers Squibb Company. Princeton, NJ 08543. September 2015.
- Product information for Pradaxa. Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877. November 2015.
- Product information for Xarelto. Janssen Pharmaceuticals, Inc. Titusville, NJ 08560. September 2015.
- Product information for Savaysa. Daiichi Sankyo, Inc. Parsippany, NJ 07054. September 2015.