Introduction

Acute pulmonary embolism (PE) is a prevalent condition,¹ affecting up to one out of every 1,000 to 2,000 Americans each year.^2,3 After acute PE, mortality surpasses 15% within the first three months,⁴ and up to 30% of patients will die without treatment. In this review, the authors describe their approach to the treatment of acute PE, which tailors therapy according to patient risk as determined by the hemodynamic significance of the PE (Table 1). In addition to summarizing the routine approach to the care of patients with PE, the authors will focus on emerging therapies in the treatment of "intermediate-risk" patients with PE (i.e., hemodynamically-stable patients with high-risk features, such as those listed in Table 1).

Table 1: Clinical Features of Low-, Intermediate-, and High-Risk Pulmonary Embolism

	Low-risk (“nonmassive”)	Intermediate-risk (“submassive”)	High-risk (“massive”)
Hemodynamic status*	Normal	Normal	Unstable
Hypoxia	May be present	Likely present	Present
Serum troponin^	Normal	Likely elevated	Usually elevated
Serum BNP%	Normal	Likely elevated	Usually elevated
RV dysfunction&	Normal	Likely present	Present
Abbreviations: PE = pulmonary embolism; BNP = bone natriuretic peptide; RV = right ventricle; LV = left ventricle; CT = computerized tomography * Systolic BP < 90 mm Hg or drop  ≥ 40 mm Hg from baseline, or need for pressors. ^ Troponin I > 0.9 ng/mL or troponin T > 0.1 ng/mL. % BNP > 90 pg/mL or pro-NT BNP > 500 pg/mL & See Table 2 for definition Modified from Piazza G, Goldhaber SZ. Management of submassive pulmonary embolism. Circulation 2010;122:1124-9.

Table 2: Definition of RV Dysfunction and Common Clinical Sequelae of Submassive PE

Diagnostic Criteria*	Criteria
RV dilation	Echocardiogram or CT: 1 – Apical 4-chmber RV diameter divided by LV diameter > 0.9; and/or 2 – RV systolic dysfunction
ECG changes	1 – New complete or incomplete right bundle-branch block; and/or 2 – Anteroseptal ST elevation or depression; and/or 3 – Anteroseptal T-wave inversion
Serum biomarkers	Elevations in BNP, pro-NT BNP and/or cardiac Troponin (as per Table 1)
Common Clinical Sequlae	Symptoms
Pulmonary hypertension / CTEPH	Chronic dyspnea (exertional or rest) Chest discomfort Fatigue Syncope
Rhythm disturbance	Right-bundle branch block Atrial arrhythmia (fibrillation or flutter)
RV failure^	Chronic dyspnea (exertional or rest) Ascites / congestive hepatopathy Peripheral edema, sacral edema Nocturia
* At least 1 of the following. Abbreviations: RV = right ventricle; LV = left ventricular; ECG = electrocardiogram; BNP = brain natriuretic peptide; CTEPH = chronic thromboembolic pulmonary hypertension References Piazza G, Goldhaber SZ. Management of submassive pulmonary embolism. Circulation 2010;122:1124-9. Jaff MR, McMurtry MS, Archer SL, et al. Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association. Circulation 2011;123:1788-830.

In the absence of contraindications, all patients with acute PE should be anticoagulated. Unfractionated heparin (UFH) is the most widely used anticoagulant for the initial treatment of PE. However, a meta-analysis from the Cochrane group suggests that treatment with fixed-dose, low-molecular weight heparin (i.e., enoxaparin) is more effective at reducing recurrent venous thromboembolism (VTE) and bleeding complications, and may improve mortality over an adjusted-dose UFH regimen.⁵ Once the patient has stabilized, options for outpatient anticoagulation include warfarin therapy, long-term enoxaparin, or a novel oral anticoagulant agent (such as dabigatran, rivaroxaban, or apixaban). Choosing the optimal outpatient anticoagulant for patients with pulmonary embolism will not be discussed here.

Risk-Stratification of Patients With Pulmonary Embolism

Patients with low-risk (or "nonmassive") PE include those without hemodynamic instability or evidence of right ventricular (RV) dysfunction. Consistent with the guidelines, we treat these low-risk patients with anticoagulation alone (in the absence of contraindications), and otherwise manage them supportively.^4,6-8 It is generally accepted that the risks of thrombolysis outweigh the benefits in patients with low-risk PE.

At the next stratum are approximately 30% of patients who present with intermediate-risk (or "submassive") PE. By definition, these patients are hemodynamically stable (i.e., systolic blood pressure [SBP] ≥ 90 mm Hg), but have other features predictive of adverse outcomes including either RV dysfunction or myocardial necrosis (Tables 1 and 2).⁷ As RV dysfunction may signify impending hemodynamic compromise, this is a particularly concerning finding and has been associated with worsened prognosis, including increased short- and long-term mortality up to one year after submassive PE.^4,7

Given the paucity of data on how to optimally manage patients with intermediate-risk PE, practice varies widely, with most clinicians favoring conservative management (i.e., anticoagulation alone) due to the perceived risks of systemic thrombolysis.⁹ While controversial, this paradigm is beginning to change with the introduction of targeted therapies that may have less bleeding risk compared with systemic thrombolysis (further described in the next section).

Finally, high-risk (or "massive") PE is defined as hemodynamic instability marked by sustained hypotension (SBP <90 mm Hg, a decrease in SBP by ≥40 mm Hg from baseline, and/or the requirement for inopressors) or cardiac arrest (Table 1). Patients with high-risk PE and hemodynamic collapse due to RV pressure overload often require aggressive intravenous fluid administration, pressor agents, and, in the most extreme cases, may benefit from mechanical circulatory support including extracorporeal membrane oxygenation (ECMO). There is consensus across professional societies that patients with high-risk PE be considered for urgent thrombolysis (in the absence of contraindications, listed in Table 3) or surgical embolectomy.^6,10

Table 3: Summary of Common Contraindications to Systemic and Local Fibrinolysis

Major Contraindications	Relative Contraindications
Evidence of active bleeding	Age >75 years
Bleeding disorder	Low body weight (<60 kg)
History of intracranial bleeding	Traumatic CPR (e.g., prolonged chest compressions)
Ischemic stroke within 3 months	Systolic Blood Pressure >180 mm Hg
Recent brain or spine surgery	Diastolic Blood Pressure >110 mm Hg
	Current anticoagulation
	Pregnancy
	Pericarditis
	Recent surgery or invasive procedure
	Recent major non-intracranial bleeding
Abbreviations: CPR = cardiopulmonary resuscitation Modified from Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e419S-94S.

Emerging Therapies for Treatment of Intermediate Risk Pulmonary Embolism

The recently published Pulmonary Embolism Thrombolysis (PEITHO) trial randomized 1,006 patients with intermediate-risk PE to either systemic thrombolysis with tenecteplase or to placebo, on a background of weight-based heparin.¹¹ In PEITHO, the primary composite endpoint of all-cause mortality or hemodyamic decompensation (defined as SBP <90 mm Hg or SBP fall ≥40 mm Hg with evidence of hypoperfsuion or need for pressors) occurred in 2.6% of patients given tenecteplase versus 5.6% of patients in the placebo group (Odds Ratio [OR], 0.44; 95% CI, 0.23-0.87; p = 0.02). This benefit was driven mostly by a decreased occurrence of hemodynamic instability (i.e., 30-day mortality alone did not differ between the groups); however, the trial was not powered for this endpoint. Further, in the tenecteplase group, there was an increased risk of extracranial bleeding (6.3% vs. 1.2%, respectively; p <0.001) and increased intracererebral hemorrhage (2.4% vs. 0.2%, respectively; p = 0.003),¹¹ but all of these events occurred in those over the age of 65 years. Critics of the trial argue that prevention of morbidity (e.g., freedom from chronic thromboembolic pulmonary hypertension) is a more relevant endpoint, an outcome not captured by PEITHO. Regardless, PEITHO suggests that systemic thrombolysis may help prevent hemodynamic decompensation in patients at low-risk for bleeding.

A meta-analysis by Chatterjee et al. builds on the evidence from PEITHO. In pooled data from eight trials containing 1,775 patients with intermediate-risk PE, thrombolysis was associated with lower all-cause mortality (OR 0.48; 95% CI, 0.25-0.92), but significantly more bleeding events (OR, 3.19; 95% CI, 2.07-4.92). Interestingly, when including patients with both high- or intermediate-risk PE, major bleeding was not significantly increased in patients 65 years of age or younger, which affirms that patients with a lower bleeding risk profile may benefit the most from lytic therapy.¹²

As opposed to the narrow therapeutic index of systemic thrombolysis, catheter-directed therapies (such as local thrombolysis or catheter thrombectomy) are conceptually attractive in patients with intermediate-risk PE. Supporting this, the Ultrasound Accelerated Thrombolysis of Pulmonary Embolism (ULTIMA) trial randomized 59 patients with submassive PE (defined as echocardiographic right ventricular to left ventricular dimension [RV/LV] ≥1.0) to heparin alone or to selective ultrasound-assisted catheter-directed thrombolysis with tissue plasminogen activator using the Ekos catheter.¹³ In the ultrasound assisted thrombolysis (USAT) group, the mean RV/LV ratio was reduced approximately 22% over 24 hours (1.28 vs. 0.99; p <0.001), compared to no significant change in the heparin alone group (1.20 vs. 1.18; p = 0.31). Further, there were no significant bleeding episodes in either treatment group, though there were few events and the trial may have been underpowered to detect a difference. Regardless, ULTIMA suggests USAT for intermediate-risk PE may be a useful therapy to prevent prolonged RV dysfunction, although larger studies should be done to confirm these findings and determine whether USAT improves more meaningful clinical endpoints.¹⁴

A Role for Inferior Vena Cava Filters

While the efficacy of inferior vena cava (IVC) filters is debated, it has been the authors' practice that IVC filter placement is reasonable in patients with acute PE and contraindications for anticoagulation or failed anticoagulation.⁶ Further, IVC filters may be considered when the hemodynamic or respiratory insult from another PE may be lethal.⁶ We reserve IVC filter placement for individuals with these indications and aim to remove the IVC filter if and when contraindications for oral anticoagulation resolve.

Conclusions

Our current generation of practitioners is fortunate to have a number of options for treatment of pulmonary embolism. While treatment of low- and high-risk PE is relatively straightforward (anticoagulation alone and anticoagulation with or without lysis, respectively), there is growing evidence to support a specific strategy to treat patients with intermediate-risk PE. Overall, treatment of intermediate PE is complex and requires a multidisciplinary team of specialist areas, including pulmonary, cardiology, cardiothoracic surgery, and interventions.

References

1. Beckman MG, Hooper WC, Critchley SE, Ortel TL. Venous thromboembolism: a public health concern. Am J Prev Med 2010;38:S495-501.
2. Wiener RS, Schwartz LM, Woloshin S. Time trends in pulmonary embolism in the United States: evidence of overdiagnosis. Arch Intern Med 2011;171:831-7.
3. White RH. The epidemiology of venous thromboembolism. Circulation 2003;107:I4-8.
4. Piazza G, Goldhaber SZ. Management of submassive pulmonary embolism. Circulation 2010;122:1124-9.
5. Erkens PM, Prins MH. Fixed dose subcutaneous low molecular weight heparins versus adjusted dose unfractionated heparin for venous thromboembolism. Cochrane Database Syst Rev 2010;4:CD001100.
6. Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e419S-94S.
7. Jaff MR, McMurtry MS, Archer SL, et al. Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association. Circulation 2011;123:1788-830.
8. Chatterjee S, Chakraborty A, Weinberg I, et al. Thrombolysis for pulmonary embolism and risk of all-cause mortality, major bleeding, and intracranial hemorrhage: a meta-analysis. JAMA 2014;311:2414-21.
9. Goldhaber SZ. Pulmonary embolism. Lancet 2004;363:1295-305.
10. Konstantinides S, Goldhaber SZ. Pulmonary embolism: risk assessment and management. Eur Heart J 2012;33:3014-22.
11. Meyer G, Vicaut E, Danays T, et al. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med 2014;370:1402-11.
12. Weinberg I, Jaff MR. Treating large pulmonary emboli: do the guidelines guide us? Curr Opin Pulm Med 2013;19:413-21.
13. Kucher N, Boekstegers P, Muller OJ, et al. Randomized, controlled trial of ultrasound-assisted catheter-directed thrombolysis for acute intermediate-risk pulmonary embolism. Circulation 2014;129:479-86.
14. Weinberg I, Jaff MR. Accelerated thrombolysis for pulmonary embolism: will clinical benefit be ULTIMAtely realized? Circulation 2014;129:420-1.

Keywords: American Heart Association, Anticoagulants, Arrhythmias, Cardiac, Ascites, Benzimidazoles, Biomarkers, Blood Pressure, Body Weight, Brain, Bundle-Branch Block, Cardiopulmonary Resuscitation, Consensus, Depression, Dyspnea, Edema, Electrocardiography, Embolectomy, Enoxaparin, Extracorporeal Membrane Oxygenation, Female, Fibrinolysis, Fibrinolytic Agents, Freedom, Heart Arrest, Heart Conduction System, Heart Ventricles, Heparin, Heparin, Low-Molecular-Weight, Humans, Hypertension, Pulmonary, Hypotension, Molecular Weight, Morpholines, Natriuretic Peptide, Brain, Nocturia, Odds Ratio, Outpatients, Peptide Fragments, Pericarditis, Pregnancy, Prognosis, Pulmonary Embolism, Pyrazoles, Pyridones, Stroke, Syncope, Thiophenes, Thrombectomy, Tissue Plasminogen Activator, Tomography, Troponin, Troponin I, Troponin T, Vena Cava Filters, Vena Cava, Inferior, Venous Thromboembolism, Venous Thrombosis, Warfarin, beta-Alanine, Vascular Diseases

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