A 51-year-old woman with dyspnea
Classified as massive, submassive, or low-risk
Pulmonary embolism is often stratified as massive, submassive, or low-risk, reflecting the severity and the degree of cardiovascular collapse. The treatment depends on the classification.
Pulmonary embolism is classified as massive if the patient has a cardiac arrest or a systolic blood pressure lower than 90 mm Hg for more than 15 minutes.23 Nearly half of patients in this category die.24
Pulmonary embolism is submassive if the patient has systolic pressure greater than 90 mm Hg but has right ventricular dysfunction, as evidenced by physical examination, elevated cardiac biomarkers, electrocardiography, transthoracic echocardiography, or computed tomography. The death rate is as high as 15%.24
Pulmonary embolism in a normotensive patient with no right ventricular dysfunction is defined as low-risk.
Our patient so far
Our patient has bilateral pulmonary emboli, most likely originating from a deep vein thrombosis in her right lower leg. Her pulmonary embolism would be classified as submassive, as her systolic pressure is greater than 90 mm Hg and right ventricular dysfunction—significant right ventricular strain—was noted on both transthoracic echocardiography and computed tomography. Also, cardiac biomarkers are elevated, and the physical examination revealed a prominent P2 sound and right parasternal heave, also suggestive of right ventricular dysfunction.
Now, 6 hours have passed, and even though she has been receiving intravenous heparin during this time, her shock index remains greater than 1, indicating hemodynamic instability. Her pulse rate is still markedly high—over 160 bpm—and she still appears quite anxious and uncomfortable.
HOW SHOULD THIS PATIENT BE TREATED?
3. Which of the following is the most appropriate treatment for this patient?
- Start warfarin immediately while bridging with unfractionated heparin, low-molecular-weight heparin, or fondaparinux
- Start fibrinolysis with alteplase
- Give metoprolol intravenously to control her heart rate
- Start dabigatran immediately while bridging with unfractionated heparin
- Place an inferior vena cava filter
- Consult cardiothoracic surgery for emergency pulmonary embolectomy
All patients with confirmed pulmonary embolism and no contraindications to anticoagulation should begin treatment with low-molecular-weight heparin, unfractionated heparin, or fondaparinux.23 In addition, this therapy should be started empirically while the patient is still undergoing diagnostic testing if the pretest probability of pulmonary embolism is intermediate or high.23
Warfarin is indicated for all patients with pulmonary embolism who do not have contraindications to it (Table 3). If unfractionated heparin, low-molecular-weight heparin, or fondaparinux has not already been started, it should be started at the same time as warfarin and should be continued until the international normalized ratio (INR) is within the therapeutic range.
Fibrinolysis. Treatment with a fibrinolytic agent in addition to heparin results in faster improvement of right ventricular function and pulmonary perfusion than with heparin alone.25 It may also decrease the incidence of pulmonary hypertension secondary to chronic thromboembolic disease.26 It should be considered in patients with massive pulmonary embolism.23
Whether fibrinolysis is appropriate for all patients with submassive pulmonary embolism remains controversial. Currently, it is not recommended for minor right ventricular dysfunction or myocardial necrosis if the patient has no signs of overt clinical decline.23 The Pulmonary Embolism Thrombolysis trial27 is an ongoing prospective randomized comparison of tenecteplase in a single bolus plus heparin vs heparin alone in normotensive patients with submassive pulmonary embolism, such as our patient. This trial may elucidate the benefit of fibrinolytic therapy in patients with submassive pulmonary embolism.
Patients at low risk are generally treated with heparin and warfarin anticoagulation alone. Fibrinolysis is not recommended in these patients, as the risk of bleeding outweighs the potential benefits.23
Metoprolol may not be advisable for our patient, as her tachycardia is likely compensatory, and beta-blocker therapy could blunt this compensatory response, leading to inadequate systemic perfusion.
Dabigatran is an oral direct thrombin inhibitor that does not require laboratory monitoring. It is currently approved for the prevention of stroke in patients with atrial fibrillation. It has been shown to be as effective as warfarin in the treatment of acute venous thromboembolism28 and may be a viable option in the future, but as of this writing it has not yet been approved in the United States for this indication. Furthermore, dabigatran inhibits thrombin immediately, so continued heparin bridging would not be necessary.
An inferior vena cava filter may prevent recurrent pulmonary embolism for patients who have absolute contraindications to anticoagulation, most significantly in the short term, ie, in the first few weeks after placement. However, these devices have not yet been shown to improve long-term mortality rates.
Embolectomy, percutaneous or surgical, is also an option. For patients in whom thrombolytic therapy is not effective, “rescue” surgical embolectomy has been associated with better outcomes compared with secondary thrombolysis and so should be considered.29
Back to our patient
An intravenous infusion of alteplase is started, and the patient’s tachycardia improves. Her oxygen requirements normalize, and she is transferred to the general medical floor the next day. She receives subcutaneous dalteparin as a bridge therapy, and warfarin is titrated to a goal INR of 2.0 to 3.0. Because of the acute deep vein thrombosis in her right lower leg, she is instructed to wear knee-high fitted compression hose for primary prevention of postphlebitic syndrome.
HOW LONG TO TREAT? IS GENETIC TESTING INDICATED?
Patients with a first episode of unprovoked venous thromboembolism should receive oral anticoagulants for 6 months, while those with recurrent unprovoked venous thromboembolism require lifelong oral anticoagulation.23
Whether to test for inherited thrombophilia after a first episode of venous thromboembolism to guide the duration of anticoagulation is controversial.30 Indiscriminate testing has not been recommended in these patients,31 but the American College of Medical Genetics recommends genetic screening for factor V Leiden in patients who have an unprovoked incident of venous thromboembolism before age 50.32
No randomized controlled trial has assessed whether thrombophilia testing decreases the recurrence rate of venous thromboembolism.33 One uncontrolled study suggested that testing for inherited thrombophilias in patients with a first episode does not affect the risk of recurrence.34 Testing is costly and may cause psychological distress for patients and family members.
Our patient is discharged home on warfarin for 6 months with subsequent follow-up evaluation in the thrombophilia clinic.
WHEN SHOULD WARFARIN BE RESTARTED?
4. If our patient were to discontinue oral anticoagulation in 6 months, which of the following, if present 1 month afterwards, would be a reason to restart oral anticoagulation?
- Elevated serum cotinine
- Positive pregnancy test
- Elevated follicle-stimulating hormone and luteinizing hormone and low estradiol levels
- Elevated D-dimer
Cotinine is a nicotine metabolite, and serum levels are elevated in smokers. Smoking and pregnancy both increase the risk of venous thromboembolism. However, smoking or pregnancy alone would not be a reason to increase the duration of anticoagulation.
Warfarin is contraindicated in pregnancy because of its teratogenic effects, particularly in the first trimester. Follicle-stimulating hormone and luteinizing hormone levels increase in response to decreased estradiol at menopause. Postmenopausal women are not at increased risk of venous thromboembolism unless they are taking oral estrogen hormone replacement therapy.
An elevated D-dimer level 1 month after stopping of oral anticoagulation has been associated with a higher rate of recurrence of venous thromboembolism, which is reduced by a resumption of anticoagulation.35 Therefore, consideration should be given to resuming anticoagulation in patients who have an elevated D-dimer level.
TAKE-HOME POINTS
It is important to distinguish between massive, submassive, and low-risk pulmonary embolism, since each type has a different treatment and prognosis.
Fibrinolytic therapy is indicated in patients with massive pulmonary embolism when no contraindication is present, whereas it is not indicated in those with low-risk pulmonary embolism.
Management of submassive pulmonary embolism continues to be an area of considerable debate. Current American Heart Association guidelines recommend consideration of fibrinolysis initially in patients with submassive acute pulmonary embolism if there is concurrent clinical evidence of adverse prognosis—eg, new hemodynamic instability, worsening respiratory insufficiency, severe right ventricular dysfunction, or major myocardial necrosis.23 On the other hand, the American College of Chest Physicians recommends against initial systemic fibrinolysis in submassive acute pulmonary embolism based on biomarkers or findings on ECG, transthoracic echocardiography, or CT, recommending it only in therapeutically anticoagulated patients deemed to be at high risk of hypotension.36
Since the optimal treatment of submassive pulmonary embolism is still not known, it is important that clinicians remain up to date on the evidence and guidelines.
