New Concepts in the Management of Pulmonary Embolus

Historical Background

Risk Stratification

Conventionally, patients with acute, symptomatic PE who present with shock or arterial hypotension warrant thrombolysis. However, in PE patients with preserved hemodynamic function, patient-risk stratification is paramount in dictating therapeutic options. Low thrombus burden, negative D-dimer, or complete lower limb ultrasound testing may identify patients at a lower risk of death when compared with patients with a higher risk. Unfortunately, test standardization and lack of generalizability limit the use of these biomarkers and imaging testing regarding outpatient PE therapy.

Identification of patients who are at a higher risk for complications is critical in determining whether escalation of PE therapy is necessary. Some evidence has suggested that high-risk normotensive patients with PE would benefit from thrombolytic therapy. However, markers such as BNP testing, indicating RV strain, or cardiac troponin T or I, indicating myocardial injury, lack positive predictive value for mortality specifically related to PE. No single test has a sufficient positive predictive value for PE-related mortality to direct an escalation of therapy. Studies have suggested that a combination of these prognostic indicators, including both elevated cardiac biomarkers and echocardiographic RV dysfunction, is sufficient to determine which patients are at higher risk for death. However, the combination of normal echocardiographic RV function and normal cardiac biomarkers did not more accurately identify low-risk patients with PE than each test individually. A meta-analysis of the prognostic value of elevated troponin levels for short-term death and adverse outcome events (overall mortality, mortality from shock, thrombolysis requirement, intubation, vasopressor infusion requirement, cardiopulmonary resuscitation, or recurrent PE), suggests that an elevated troponin had a positive predictive value of 43.6% (95% CI, 36.9–50.3). Lower limb venous compression ultrasound had a positive predictive value for 90-day morality related to PE of 6.6%. Only 9 out of 20 studies included in the analysis had information on the composite endpoint, however.

These data echo the need for reliable risk stratification methods. One such method is the PESI, which stratifies patients into five classes of increasing risk of mortality within 30 days of hospitalization. The PESI score uses 11 clinical parameters at the time of presentation: age, male sex, malignancy, heart failure, chronic lung disease, pulse greater than 110 beats per minute, systolic blood pressure lower than 100 mm Hg, respiratory rate 30 breaths or more per minute, temperature lower than 36°C, altered mental status, and oxyhemoglobin saturation lower than 90% ( Table 15.1 ). A simplified version of the PESI, or sPESI, which uses age (>80 years), history of malignancy, history of chronic obstructive pulmonary disease, heart rate greater than 110 beats per minute, systolic blood pressure lower than 100 mm Hg (see Table 15.1 and Table 15.2 ).

TABLE 15.1

PESI and sPESI Clinical Models Prognostic Factors and Weighting

PESI (Original and Simplified)
Parameter	Standard PESI	sPESI
Age	Age in years	1 point is age >80 years
Male sex	+ 10 points
Cancer	+ 30 points	1 point
Chronic heart failure	+ 10 points	1 point
Chronic pulmonary disease	+ 10 points	1 point
Pulse rate > 109 beats per minute	+ 20 points	1 point
Systolic blood pressure < 100 mm Hg	+ 30 points	1 point
Respiratory rate > 30 breaths per minute	+ 20 points
Temperature < 36°C	+ 20 points
Altered mental status	+ 60 points
Arterial oxyhemoglobin saturation < 90%	+ 20 points	1 point

PESI, Pulmonary Embolism Severity Index; sPESI, simplified Pulmonary Embolism Severity Index.

TABLE 15.2

Risk Evaluation by PESI and sPESI Clinical Models

PESI	Risk	sPESI	Risk
Class I ≤65 points	Very low 30-day mortality risk (0%–1.6%)	0 points	30-day mortality risk of 1.0%
Class II 66–85 points	Low mortality risk (1.7%–3.5%)		(95% CI, 0.0–2.1)
Class III 86–105 points	Moderate mortality risk (3.2%–7.1%)	>0 points	30-day mortality risk 10.9%
Class IV 106–125 points	High risk mortality risk (4.0%–11.4%)		(95% CI, 8.5–13.2)
Class V >125 points	Very high mortality risk (10.0%–24.5%)

PESI, Pulmonary Embolism Severity Index; sPESI, simplified Pulmonary Embolism Severity Index.

Another stratification method, known as the Geneva Score, uses six parameters at time of presentation: malignancy, heart failure, previous deep venous thrombosis (DVT), systolic blood pressure lower than 100 mm Hg, partial pressure of oxygen (PaO ₂ ) less than 8 kPa, and the presence of DVT on ultrasound. The Geneva Score is based on adverse outcomes that include death, recurrent thromboembolism, and major bleeding in a 3-month follow-up period (see Table 15.1 ).

Treatment Guidelines

Guidelines for the management of acute PE have been published by several societies, including the American College of Cardiology (ACC), the AHA, and the European Society of Cardiology (ESC). The ESC suggests that intravenous anticoagulation should be administered to patients with a high or intermediate clinical probability of PE awaiting results of diagnostic tests. Appropriate anticoagulation includes intravenous unfractionated heparin (UFH), subcutaneous low-molecular-weight heparin (LMWH), or subcutaneous fondaparinux. For patients with high-risk PE or with hemodynamic compromise, intravenous anticoagulation with UFH should be initiated immediately. In this same cohort of patients, LMWH or fondaparinux have not been adequately studied. Normotensive patients classified as PESI class III, or sPESI of 1, and who demonstrate either negative RV dysfunction and negative cardiac troponins are classified as intermediate-low risk. For these patients, parenteral anticoagulation followed by a vitamin K antagonist or nonvitamin K antagonist oral anticoagulants can be offered. Low-risk patients, such as those satisfying criteria for PESI class I or II, may be considered for early discharge and outpatient treatment, according to the ESC. The American College of Clinical Pharmacy (ACCP) states that at-home treatment with LMWH of acute-PE in these low-risk patients is adequate. The goal of anticoagulation in patients with PE is to prevent recurrence of venous thromboembolism (VTE). General consensus is to treat patients for at least 3 months. However, the decision to continue treatment beyond this time is based on individual clinical assessment.

In patients with high-risk PE, primary reperfusion treatment, particularly systemic fibrinolysis, is the treatment of choice. This method can rapidly reduce thrombus burden, RV dysfunction, and pulmonary vascular resistance. In a meta-analysis of 1061 patients treated with fibrinolytic therapy and 1054 patients treated only with anticoagulation, fibrinolytic therapy reduced total mortality (adjusted OR, 0.53; 95% CI, 0.32–0.88) and recurrent PE (adjusted OR, 0.40; 95% CI, 0.22–0.74). Consequently, patients with massive PE and associated hemodynamic instability receive a clear mortality benefit from systemic fibrinolysis compared with anticoagulation alone. For those with submassive PE and major myocardial necrosis or severe RV dysfunction, patients must be considered on a case-by-case basis. Although systemic fibrinolysis in massive PE has been found to decrease mortality compared with anticoagulation alone, it also carries a high morbidity risk. There is a 20% risk of major hemorrhage and a 3% to 5% risk of intracranial hemorrhage. This is primarily caused by the large recombinant tissue plasminogen activator (r-tPA) dosage of up to 100 mg over 2 hours. Conversely, anticoagulation is not without its own risks and has been associated with a 15% chance of minor hemorrhage and a 1% to 5% risk of major bleeding complications. Surgical pulmonary embolectomy has been used in patients with large, centrally-located thromboemboli. This procedure requires a median sternotomy and cardiopulmonary bypass. In patients with submassive PE, surgical embolectomy can be considered when systemic fibrinolysis is contraindicated or has failed, when patients have thrombi in the right atrium or ventricle, or when patients are ineligible for catheter directed therapy.