Pulmonary Embolism (PE) results when there is blockage of pulmonary arterial system preventing both circulation and gas exchange in the lungs. PEs have a variety of causes including air, amniotic fluid, fat, foreign bodies, septic emboli, and, the most common, embolus of a thrombus originating in the venous circulation or the heart (Lange). Blockage may present in a variety of ways depending on the extent of arterial blockage. Small emboli can cause alveoli hemorrhage, called pulmonary infarction, which causes hemoptysis, pleuritic chest pain, and pleural effusions which are usually mild (uptodate and 3). If 30-50% of the total cross sectional area of the pulmonary arterial bed is obstructed, the pulmonary artery pressure increases which increases the right ventricular afterload. This issue is further potentiated with the release of thromboxane A2 and serotonin which causes vasoconstriction making the blockage more extensive. The increase in pressure in the right ventricle causes stress which dilates the heart which decreases its contractile strength via the Frank Starling law of the heart. This stretch also increases the time that it takes for the right ventricular to contract which causes the intraventricular septum to shift into the left ventricle. This combined with the fact that the right ventricle is not functioning properly leads to a decrease in the left ventricular preload which decreases the systemic perfusion which is a big reason you may see a decrease in the blood pressure in patients with PE who are hemodynamically unstable (3).
The development of a pulmonary embolism (PE) is relatively common, seen in anywhere from 20.8 to 65.8 cases per 100,000 (21), and it is due to an interaction between a wide variety of patient-related factors and situational factors that come together and put someone at increased risk of developing PE. PE is closely associated with deep vein thrombosis as they are two manifestations of the same disease. The risk factors involve defects in the venous circulation. Virchow’s triad describes the combination of variables that contribute to thrombus formation: venous stasis, hypercoagulability, and injury to the vessel wall. Any time one of these factors is compromised a person is at increased risk of developing a PE. Hyperviscosity, from polycythemia, increased central venous pressure, from pregnancy, and immobility, from surgery or obesity, are all things cause venous stasis which puts a person at risk for thrombus formation (lange). Hypercoagulability can be caused by medications (oral contraceptives and erythropoiesis stimulating agents), malignancy (particularly hematological malignancies, pancreatic cancer, gastrointestinal cancer, lung cancer, and brain cancer), anticoagulation protein deficiency, such as deficiencies in protein C and S, and genetic disorders, such as factor V Leiden (present in ~3% of American men and 20-40% of patients with idiopathic venous thrombosis) (Lange and 3). Lastly, vessels may be damaged due to trauma, lower limb fracture, surgery, or prior thrombosis (Lange). Another disease process that causes stasis of blood is a patient who is in atrial fibrillation. Because of the altered electrical system in the heart, the muscle contraction is uncoordinated and ineffective causing blood flow to be altered over time causing thrombogenesis and, if it breaks free, a pulmonary embolism or stroke (7). Other factors that indirectly contribute to the development of PE include cardiovascular disease, cigarette smoking, obesity, hypercholesterinemia, and diabetes mellitus.
HM has many major risk factors for developing pulmonary embolisms. First, and perhaps most significantly, he is a paraplegic and his legs have been rendered immobile. Blood is then able to pool which puts him at high risk for developing a clot. He also mentioned his extensive hospital and surgical history. He said that he has had 32 procedures which may have resulted in damaged vasculature. This injury to the vasculature is an area of the vessel that could form a thrombus that could rupture. The multiple surgeries and hospitalizations for the recurrent UTIs also increase his immobility as discussed earlier. He is also moderately obese which is a factor that increases his risk for thrombus formation as well. Trauma is also a major risk factor for developing a PE and he was involved in a motor vehicle accident which resulted in his spinal injury. He did not specify if he had any familial blood condition which would affect clotting. A more detailed family history would be necessary to assess his risk of a clotting disorder.
Clinical Findings in the History and Physical of Pulmonary Embolism:
When evaluating a patient for a PE, it is notoriously difficult because the common signs and symptoms are highly variable and nonspecific for PE. The most common symptom in patients presenting with PE is dyspnea with pleuritic chest pain (uptodate). The Prospective Investigation of PE Diagnosis study looked specifically at common presenting signs and symptoms in patients with acute PE. They included dyspnea (73%), inspiratory chest pain (66%), cough (37%), leg pain (26%), hemoptysis (13%), palpitations (10%), wheezing (9%), angina pain (4%), respiratory rate >20 (70%), crackles (51%), heart rate >100 (30%), fourth heart sound (S4) (24%), accentuated P2 heart sound (23%), temperature >38.5C (7%), Homans sign (4%), pleural friction rub (3%), third heart sound (3%), cyanosis (1%) (lange). In the study, 97% of patients had at least one of these three findings: dyspnea, chest pain with breathing, or tachypnea (lange). However, as seen in the wide variety of signs and symptoms, the clinical picture that the patient presents with could be vastly dissimilar. Because of this, clinical decision tools have been formulated to use information that the patient can provide to make a more educated assessment of the likelihood that the patient is having an acute PE. Some of these tools are discussed below. Shock and arterial hypotension are two clinical findings that are rare but extremely important to identify as they indicate a central PE and a lack of hemodynamic reserve (3).
An electrocardiogram (ECG) is a tool that can be used in the work up of a patient who is experiencing acute chest pain that may result from a PE. While there are no signs that are diagnostic of acute PE, it is useful in ruling out other causes of chest pain such as myocardial infarction or pericarditis. Having said that, 70% of ECG results in patients experiencing acute PEs are abnormal but most are nonspecific (lange). The most common abnormality seen is sinus tachycardia (lange) but another common finding is T-wave inversion in leads V1-V4 which is most commonly associated with the severity of the PE (13). Other classic findings associated with PE include S1Q3T3 (S wave in lead I, Q wave in lead III, and inverted T wave in lead III) and right bundle branch block both indicating right ventricular strain.
Chest x-ray is another test that is commonly done to rule out other causes of the presenting symptoms. There is nothing that is diagnostic of PE on chest x-ray, but there are some signs that are suggestive of the diagnosis. The three signs are Westermark sign, Fleishner sign, and Hampton hump. The Westermark sign is a sharp cut off in the pulmonary vasculature that results from dilation of the pulmonary artery proximal to the embolism and a collapse of the vasculature distal to the embolism. Fleishner sign (also called the knuckle sign) is an enlargement in the pulmonary artery proximal to the embolism. The Hampton hump is a wedge-shaped opacity in the lung that is secondary to infracting tissue due to a PE. While these signs are characteristic of acute PE, they are not commonly seen.
HM was breathing comfortably and had normal breath sounds with no crackles or wheezes and had a normal respiratory rate. He has no chest pain or cough which are common presenting symptoms of PE.
Work up:
The provider must have a high index of suspicion of PE and respond accordingly. One meta-analysis found that the clinical impression alone provided a sensitivity and specificity of 85% and 51% respectively (10). The first step in the assessment of the patient who is presenting with signs and symptoms characteristic of a PE is to determine the hemodynamic stability of the patient. Hemodynamic instability is that which results in hypotension which is defined as systolic blood pressure <90 mmHg or a drop > 40 mmHg from baseline for more than 15 minutes or hypotension demanding vasopressors or inotropic support that is not explained by other sources. Hemodynamically stable patients are those that do not fit the definition of hemodynamically unstable patients. The stability of the patient does not necessarily dictate the size of the PE although there is an association between the size of the emboli and the hemodynamic status of the patient (i.e. larger emboli are more likely to result in a hemodynamically unstable patient). However, a small embolus in a patient who has multiple comorbidities can result in a hemodynamically unstable patient. This hemodynamic distinction is important because the patients who are hemodynamically unstable are more likely to die from obstructive shock due to right ventricular failure within two hours from onset of symptoms (uptodate). Hemodynamically unstable patients also have been seen to have a 90-day mortality rate of 52.4% despite treatment. It was once thought that saddle PEs (3-6% of all PEs), which is an embolus that lodges at the bifurcation of the main pulmonary artery which often extends into the left and right main pulmonary arteries, was a significant cause of hemodynamic instability and mortality. However, studies have shown that only 22% of saddle emboli result in patients who are hemodynamically unstable and some studies have shown that rapid embolectomy is not necessary and they can be treated more conservatively using thrombolytic therapy or even standard anticoagulate therapy (8). Most PEs bypass the left and right pulmonary artery bifurcation and flow distally into the main lobar, segmental, or sub-segmental branches of the pulmonary artery (lange). A clot in transit is a mobile echogenic mass in the right atrium that, in the patient with acute PE, is a residual thrombus that has the propensity to embolize into the lung and is often associated with malignancy or infection. Therapy is urgent in these patients as mortality is high (27 to 45%), with nearly all deaths occurring in the first 24 hours (9).
The only way of definitively diagnosing a PE is through imaging studies of which the computed tomography pulmonary angiography (CTPA) is the most commonly used. However, the use of these tests is only necessary in a subset of patients as there are many situations where the risks outweigh the benefits that a CTPA provides. A practitioner must consider the elevating healthcare costs associated with the test, radiation exposure, as well as further risks associated with the contrast materials used in the scan. Thus, there have been a wide variety of efforts to create algorithms that sufficiently evaluate the likelihood that a patient is having a PE. These start with a clinical decision rule (CDR) which assesses the pretest probability that a patient is having a PE, which is followed by a D-dimer blood test, and if necessary a CTPA (A). Two of these CDRs that have been adequately validated include the Wells Rule and the Revised Geneva score and they are shown below (3). They work by classifying patients as either likely or unlikely. Patients who are likely having a PE, according to the scores, are immediately imaged using CTPA to definitively diagnose the PE. CTPA provides the benefit of visualizing the pulmonary artery to the point of the segmental level and has a sensitivity and specificity of 83% and 96% (3).
Wells Rule
Original version
Simplified version
Revised Geneva score
Original version
Simplified version
Previous PE or DVT
1.5
1
Previous PE or DVT
3
1
Heart Rate >100 bpm
1.5
1
Heart Rate 75-94 bpm
3
1
Immobilization (>3 days) or Surgery within 4 weeks
1.5
1
Heart Rate > 95 bpm
5
2
Hemoptysis
1
1
Surgery or fracture within 1 month
2
1
Active Malignancy
1
1
Hemoptysis
2
1
Clinical signs of DVT
3
1
Active Malignancy
2
1
Alternative diagnosis less likely than PE
3
1
Unilateral lower limb pain
3
1
Pain on lower limb deep vein palpation and unilateral edema
4
1
Age > 65 years
1
1
Modified Wells Clinical Probability Categories
Clinical Probability Categories
PE likely (37-43%)
> 4
> 1
PE likely (37-43%)
> 5
>2
PE unlikely (12-17%)
< 4
< 1
PE unlikely (12-17%)
< 5
< 2 (A uptodate) There is a two and three category classification system for the Wells criteria. The two category system is listed above and the three category includes patients were scored high (>6), moderate (2-6), or low (<2) and given a percent probability of developing a PE (3.4%, 20-28%, and 60-78% respectively) (uptodate). One thing that is extremely important when considering the use of these scores is the proper use of the evaluations. Improperly implementing these tools could lead to inappropriate use of imaging modalities as well as an elevated 3 month VTE incidence in whom anticoagulant therapy is withheld (A). This is a big reason that the scores were simplified from the original version: to provide a more clinician friendly test so that they would more accurately implemented. This was done without significantly changing their diagnostic sensitivity and specificity from the original model (A).
The fibrin D-dimer serum marker is a blood test that is an index of intravascular thrombogenesis. As cross-linked fibrin assembles during intravascular thrombin formation, the serum levels of D-dimer rise making this a useful tool in the evaluation in patients with PEs as the sensitivity for a negative test (<500 ng/mL) is 90% making it an excellent test when trying to rule out PE in a patient (4,2). Many providers are hesitant to order a D-dimer because it has a very low specificity (40-68%). A big reason for this low specificity is the fact that a wide variety of factors may contribute to elevating the serum D-dimer such as cancer, surgery, pregnancy, necrosis, bleeding, or trauma (3). However, a quantitative D-dimer can be a good way of detecting PE when a patient presents with vague signs and symptoms and PE is on the differential.
Pulmonary Embolism Rule-out Criteria
Age < 50 years
Heart Rate < 100 bpm Oxygen Saturation > 94%
No unilateral leg swelling
No hemoptysis
No surgery or trauma within 4 weeks
No history of venous thromboembolism
No estrogen use
The pulmonary embolism rule-out criteria (PERC) is a tool that is used in patients who are clinically considered low risk to rule out PE and prevent unnecessary imaging in patients who are low risk. The clinician will apply each of these criteria to the patient. If they meet any of the criteria they are considered PERC negative and must continue further work up for PE. If patients are negative for the PERC then it reduces the probability that the patient is experiencing a PE to less than 2% (6).
If we apply the PERC to HM, he fits none of the criteria so PE can safely be ruled out in him with less than a 2% probability. If we were to get a quantitative D-dimer on this patient it may come back elevated. Since he experienced the trauma plus has had so many procedures, this could have elevated the value. CTPA is unnecessary due to the fact that there is little chance that he is experiencing a PE. If he were to develop symptoms, a CTPA may be necessary.
Treatment:
Anticoagulation therapy in patients with acute PE is need for two reasons: to limit the extend of the damage caused by the PE as well as prevent any recurrent PEs. The standard initial treatment for a PE is low molecular weight heparin (LMWH) (A). Unfractionated heparin is an option that is to be used in patients who have a creatinine clearance < 20-30 mL/min with severe renal impairment (A). Fondaparinux is also another option that can be used in place of LMWH in patients who have a history of heparin induced thrombocytopenia (A). The benefits of LMWH and fondaparinux over unfractionated heparin include a longer half, better bioavailability and a more predictable anticoagulation response with sub-cutaneous injection (11). All patients who have an acute PE from all causes must be treated with anticoagulated therapy for at least 3 months. Those suffering from an acute PE resulting from malignancy, antiphospholipid syndrome, or a recurrent PE should automatically receive 6 months of anticoagulant therapy. Traditionally, this is done using a vitamin K antagonist, such as warfarin, for extended treatment with the additional use of a parenterally administered direct-onset anticoagulated drug until the international normalized ration reaches a range of 2-3 in two consecutive days. The major advantage to these drugs are that they provide a safe and reliable means of providing anticoagulated therapy while maintaining a low risk of hemorrhage (1-2% in 3 months) (A). The downside is that labs must be monitored closely to assure that the patient is receiving proper treatment. Another downside is that there are a wide variety of food interactions that can both increase and decrease the effectiveness of the drug in the body which can either lead to hemorrhagic events or thromboembolic events. Recently, several additional drugs have been proposed as long term treatment options for anticoagulation for patients who experienced an acute PE. They are referred to as the new oral anticoagulants (NOAC) and they include rivaroxaban, apixaban, dabigatran and edoxaban. They have been shown to have a comparable effectiveness at preventing recurrent PEs with the added benefit of having a shorter half-life, decreased incidence of bleeding complications, and not having to monitor blood levels which is a major quality of life factor. The main concern with these new agents is the lack of antidotes that could offset their actions in the case of a hemorrhagic event. Clinically this isn’t as big of an issue because of the shorter half-life as well as the fact that there is a lower incidence of hemorrhagic events in the patients that take the NOACs. The newer agents should not be recommended in patients with cancer associated PEs (A). Once patients complete the 3-month course of anticoagulation therapy, it must be determined whether therapy will be continued further. The major concern with extended long term anticoagulant therapy is the risk of bleeding complications that goes along with it. So, the risks of continuing the anticoagulant agent must be weighed with the benefits of preventing a recurrent PE. In patients who have a transient provoking factor such as surgery, prolonged immobility, or pregnancy, a recurrence risk of 2.5% in a year is sufficient to stop anticoagulant therapy. One of the ways that this risk is being assessed is by using the Vienna prediction model which considers variables such as sex, location of the VTE, and D-dimer tests to produce a risk for recurrence. Traditionally vitamin K antagonists (VKA) have been used for this long-term therapy, however, with the advent of the NOACs they have proven to be as effective as the VKAs while providing a lower risk of hemorrhage. For patients who are unable to tolerate any of these oral anticoagulants, aspirin may be used as it has been shown to provide some ability to lower the risk of recurrent PEs. However, this is nowhere to the degree of the other oral anticoagulants. Aspiration vs open surgical thromboectomy 9 Prognosis: Pulmonary Embolism Severity Index Score Parameter Orignal Version Simplified Version Age Age in years 1 point if age > 80 years
Male Sex
+10 points
Cancer
+30 points
1 point
Chronic Heart Failure
+10 points
1 point
Chronic Pulmonary Disease
+10 points
Heart Rate > 110 bpm
+20 points
1 point
Systolic BP < 100 mmHg +30 points 1 point Respiratory Rate > 30 breaths per min
+20 points
Temperature < 30C
+20 points
Alerted Mental Status
+60 points
Oxygen Saturation < 90%
+20 points
1 point
Risk Stratification:
• Original Version
o Class I: < 65 points; very low mortality risk: 30-day mortality risk 0 – 1.6% o Class II: 66 – 85 points; low mortality risk: 1.7 – 3.5% o Class III: 86 – 105 points; moderate mortality risk: 3.2 – 7.1% o Class IV: 106 – 125 points; high mortality risk: 4.0 – 11.4% o Class V: > 125 points; very high mortality risk: 10.0 – 24.5%
• Simplified Version
o 0 points: 30-day mortality risk 0 – 2.1%
o > 1 point(s): 30-day mortality risk 8.5 – 13.2%
Right ventricular (RV) function has a significant impact on mortality in the patient with an acute PE. The RV can also be assessed using echocardiography as well as the CTPA. Changes in the RV include, “RV dilation, increased RV/left ventricular diameter ratio, hypokinesia of the free RV wall, increased tricuspid regurgitation jet velocity or decreased tricuspid annulus plane systolic excursion” (A). As many as 25% of patients who present with an acute PE will have some signs of RV dysfunction. Abnormalities present in the RV on echocardiography and CTPA are associated with an increased short-term mortality in patients who are hemodynamically stable (OR of 2.4 and 1.8 respectively).
High levels brain-type natriuretic peptides (BNPs) or the N-terminal of the prohormone of BNP (NT-proBNP) in PEs associated with right ventricular pressure are strongly associated with mortality in acute PE comparted to low levels which have a marked less mortality rate (A33). Additionally, high troponin I or troponin T in hemodynamically stable patients are associated with increased short-term mortality (A34).
Hestia Decision Rule
Hemodynamically instable?
Thrombolysis or embolectomy necessary?
High risk of bleeding?
Oxygen supply to maintain oxygen saturation >90% for more than 24h?
Pulmonary embolism diagnosed during anticoagulant treatment?
IV pain medication for more than 24h?
Medical or social reason for treatment in hospital for more than 24h?
Creatinine clearance <30 mL/min? Severe liver impairment? Pregnant? Documented history of heparin-induced thrombocytopenia? Interpretation: if the answer to at least one of the above questions is ‘YES,’ the patient cannot be treated as an outpatient Clinical Questions: 1. Clinical Findings In patients diagnosed with a deep vein thrombosis (DVT), is imaging looking for pulmonary embolism in the absence of symptoms compared to not looking for PEs in the absence of symptoms increase survival? 2. Differential Diagnosis In patients presenting with chest pain, is a quantitative D-dimer compared to an electrocardiogram (ECG) a more specific test to differentiate between myocardial infarction (MI) and PEs? The diagnosis of chest pain can be ominous because there are many very serious etiologies that demand a rapid diagnosis for the well-being of the patient. A D-dimer test and ECGs are similar in the sense that they can be rapidly obtained but also by the fact that their results are nonspecific and can be misleading. One study by Sakamoto et al looked at implementing the D-dimer test to differentiate between PE and MI upon admission to the hospital when both of those items were on the differential. They found that by implementing a cut-off value for the D-dimer of 5.0 μg/ml they had a sensitivity and specificity of 68.4% and 90.3% for PE. They found that they could raise the sensitivity to 88% if they lowered the cut off value to 2.0 μg/ml lowering the specificity to 75%. They demonstrated the effectiveness of this strategy by applying it to a case in a patient who presented with chest pain and non-specific ECG changes. A quantitative D-dimer revealed a value of 70 μg/ml and went straight to CT to get diagnosed as opposed to coronary angiography for the workup of MI. This serves as an example in patients where rapid diagnosis is urgent. While there are no studies that compare the two tests directly, the D-dimer provides information in that differentiates the two diagnoses in a valuable way (19). 3. Clinical Epidemiology In pregnant women, does a prior history of DVT compared to no prior history of DVT put a patient at increased risk for developing PE in pregnancy? 4. Etiology In patients who are having an acute pulmonary embolism, do patients who are diagnosed with saddle PE compared to all other types of PE (lobar, segmental, and sub-segmental) have a higher mortality rate? In the past, saddle PEs have been diagnosed during autopsy and was regarded as the most catastrophic forms of PE. With the increased use of CT scan over the years the diagnosis of PE, specifically saddle PEs, have gone up. Little is known about the best treatment for saddle PEs and how it differs from standard treatment for PE. It has been thought that urgent surgical treatment is necessary. However, others suggest that more conservative therapy may be successful as well. One study compared the progression of patients with saddle PEs with those who had at least lobar PEs. Both cases were treated with anticoagulation and, when necessary (based of patient status according to attending physician), thrombolysis. Thrombolytics were given more often in the saddle PE group (29% compared to 16%); however, this was not found to be statistically significant (p=0.1). Interestingly, mortality was found to be higher in the non-saddle PE group compared to the saddle PE group (20% compared to 5.8%) though it was not found to be statistically significant (16). Another study by Sardi et al looked at 680 patients with pulmonary embolisms, 37 of which were saddle embolisms. They showed that most patients with the saddle embolism are not hemodynamically unstable and can be treated with standard unfractionated heparin depending on the hemodynamic status of the patient. In this study, two of the 37 patients (5.4%) with the saddle embolisms died from complications associated with the embolism. The study did not specify how many other patients with acute PEs died but indicated that treatment should not be any different for those with saddle embolisms unless hemodynamically unstable. Thus, based off these two research articles saddle PEs are not more deadly than other types of PEs but more research needs to be done as to the best management for patients with saddle embolisms. 5. Diagnostic Tests: In patients who are being worked up for having a pulmonary embolism, is a CT angiogram more sensitive compared to the gold standard pulmonary angiogram in detecting PEs? For decades, the gold standard in the diagnosis of PE is pulmonary angiography. However, since the introduction of the multi-detector computed tomographic pulmonary angiography (CTPA), pulmonary angiography has been widely replaced being mostly performed to guide percutaneous catheter mediated direct treatment. There are many reasons why the CTPA is more widely used; it allows for rapid and accurate assessment of the area under examination in a way that pulmonary angiography was never able to do due to the speed and ease of use. However, the reason that pulmonary angiography is still considered the gold standard is because it is accurate allowing for direct visualization of the vasculature. In a study by Remi et al, they compared CTPA with pulmonary angiography in patients with acute PE and found that CT provided images that were either excellent or good based off direct visualization of the clot. With CTPA, the findings of 112 emboli (8 main, 28 lobar, and 76 segmental) matched the results of the pulmonary angiography. There were nine instances where obstruction by lymph nodes were misinterpreted as filling defects and a case where a normal CTPA was misinterpreted as a PE (18). Another study found that CTPA was inconclusive anywhere between 0.9-4.6% of the time (3). Thus, the CTPA has comparable accuracy at diagnosing acute PEs relative to pulmonary angiography with the added benefits of being faster and more convenient in the emergency room setting. 6. Prognosis In patients who are experiencing a PE, does an elevated D-dimer level compared to a lower D-dimer level increase the 30-day mortality? The use of quantitative D-dimer in the work up of patients with pulmonary embolism is controversial as there are many things that can falsely elevate the value resulting in unnecessary imaging. However, the test is useful as it has a high sensitivity for detecting PEs. One thing that is not discussed often is the use of the quantitative D-dimer test as a means of a prognostic tool in patients. A study by Dr. Grau looked at 588 patients who were experiencing symptomatic PEs and got a quantitative D-dimer measurement on admission and were followed for 3 months. They were then put into three categories based off the initial D-dimer value: 500-2499 ng/mL, 2500-4999 ng/mL, > 5000ng/mL. The results of the study showed that patients with D-dimer levels > 5000ng/mL showed higher risk of death from fatal pulmonary embolism (odds ratio of 4.4) as well as associated with more significant disease. The study showed evidence to recommend the D-dimer as a useful biomarker and helpful in the determination of initial therapies (17).
7. Therapy
In patients who have had an acute pulmonary embolism, does the use of NOACs for long term anticoagulation therapy compared to vitamin K antagonists provide a significant decrease in hemorrhagic events?
Once patients have been treated for a PE, with heparin or thrombolytics, and are past the acute phase of treatment, they must receive prophylaxis for a period of time to prevent the reoccurrence of the PE. Traditionally this has been done with vitamin K antagonists such as warfarin. However, a lot of research is considering whether newer agents, such as rivaroxaban, idraparinux (both Factor Xa inhibitor) and dabigatran (thrombin inhibitor), are as effective at preventing recurrent thromboembolic events while providing additional benefits such as not having to monitor INR, no dietary restrictions, and less incidence of significant bleeding. In a noninferior study by Büller et al. involving 4832 patients comparing standard vitamin K prophylaxis and prophylaxis using rivaroxaban, rivaroxaban was shown to be noninferiority to the standard therapy at preventing recurrent thromboemboli while providing additional benefits such as reducing the incidence of hemorrhagic events that took place while on the medication. In another double-blind, noninferiority study, Eriksson et al. looked at oral dabigatran in total knee replacement patients against subcutaneous enoxaparin and found that it was as effective and had a similar safety profile (12). Another study looked at the effectiveness of idraparinux compared to standard therapy and found that it was as effective at preventing recurrent deep vein thrombosis (DVT) but not as effective at preventing PEs (3.4% compared to 1.5%). It was, however, more effective at preventing hemorrhagic events. In the study, the researchers noted that most of the recurrent PEs occurred early in the treatment suggesting sub-therapeutic anticoagulation. In their conclusion, they recommended that further research be done to investigate if higher doses early in treatment would make a difference (11). Dosing was an issue in the rivaroxaban study as well and patients receiving the drug had to go through an additional dose confirmation period (appraisal article).
These oral anticoagulant drugs provide a lot of promise in the treatment of PE as they provide a lot of benefits. However, research needs to look at more specific dosing for these drugs in providing the most effective anticoaguability without compromising hemorrhagic potential. Also, another significant issue with the new oral anticoagulant (NOAC) drugs is a lack of an antidote to reverse the effect of the drug. More research needs to consider the development of such an agent to use in the case of major bleeding or overdose. Based off the evidence, I would recommend the use of NOAC drugs as an alternative to warfarin in patients who may not be able to take warfarin (11).
8. Prevention
In patients who are at risk for developing a PE, does low dose aspirin compared to no treatment decrease the incidence of developing a PE? (article about this)
There are many acute events that put a person at risk for developing a PE. These risk factors include surgery, major trauma, fractures, spinal injuries, and joint replacement procedures. A big effort has gone into looking to reduce the incidence of PE in this population in order to reduce the morbidity and mortality associated with these events and cut down on hospital stay and medical costs that are increased as a result of the complications. Leg compression is a proven means of lowering rates of thromboembolic events that is commonly used in hospitals. Another potential option is the use of aspirin in these patients. One study published in The Lancet compared the use of 160 mg of aspirin daily to a placebo for 35 days in patients who had undergone elective arthroplasty or had a hip-fracture. They found that in the aspirin group, a third less patients experienced thromboembolic events and recommended the use in this population of patients as well as those who have prolonged immobilization (14). Another study looked at prolonging anticoagulation with aspirin after the use of oral anticoagulants and found a 30-35% reduction in the risk of developing a thromboembolic event (2014 euro). Thus, aspirin can be used as a prophylaxis in patients who are at risk for developing thromboembolic events as well as once oral anticoagulation is no longer needed to reduce the risk of developing an unprovoked PE.
9. Experience and Meaning
Do patients who are experiencing acute pulmonary embolisms experience depression and anxiety?
Little is known regarding the impact that PE has on a person’s psychological distress during the process of being worked up for PE and the factors that influence this. One study looked at this in 60 patients with acute PE using the Becks Depression Inventory and the State-Trait anxiety inventory. They stratified patients as either low, intermediate, and high risk and found that all patients experienced higher rates of depression and anxiety compared to controls. Both anxiety and depression were highly correlated particularly in patients who were high risk. Another thing that they found was an inverse correlation between arterial blood oxygenation pressure and both anxiety and depression (20).
10. Self-Improvement
How might I use this information to more rapidly diagnosis patients with PE who present with vague respiratory complaints?
Pulmonary embolism is a difficult diagnosis because the common signs and symptoms are nonspecific and suggestive of a variety of conditions. One must have a high index of suspicion for PE and based off the clinical findings respond accordingly. This is done by painting a clinical picture that looks for information in the history and physical exam that points to the diagnosis. Clinical impression alone has a sensitivity of 85% for ruling in PE (10). However, painting the clinical picture is challenging when the presentation is atypical and the common signs and symptoms are not present. Another situation that creates a difficulty for diagnosis is when the patient is presenting with shock or hypotension and is in critical condition. In this situation, rapid diagnosis is important and so knowing that the best test to do in this situation is a rapid transthoracic echocardiogram is important for morbidity and mortality (3). In a study looking at some of the reasons that the diagnosis of pulmonary embolism is missed, it was found that errors were most commonly made due to failing to order, report, or follow-up on lab results (44%) followed by errors by the clinician to properly assess the persons condition (32%) (15). Learning from these common mistakes by health care workers can prevent errors like this in the future leading to better patient outcomes.
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