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Keywords:

  • deep vein thrombosis;
  • embolectomy;
  • pulmonary embolism;
  • risk stratification;
  • thrombolysis

Abstract

  1. Top of page
  2. Abstract
  3. Disease burden
  4. Team approach
  5. Risk stratification
  6. Advanced treatment options
  7. Conclusions
  8. Disclosure of Conflict of Interests
  9. References

Summary.  The optimal treatment strategy for acute pulmonary embolism relies upon a multidisciplinary team that rapidly assesses available data, performs additional testing if necessary, weighs treatment options, and recommends an appropriate therapeutic plan to the patient and family. Round-the-clock availability is imperative. Centers that specialize in pulmonary embolism management offer a wide range of therapeutic options. Hospitals with more limited facilities should establish pulmonary embolism patient referral and transfer contingency plans that can be activated at a moment’s notice. Management options include anticoagulation alone, thrombolysis plus anticoagulation, insertion of an inferior vena caval filter, catheter embolectomy, or surgical embolectomy. The decision-making process requires accurate risk stratification, which is comprised of several crucial components: clinical evaluation that includes history and physical examination, biomarker measurement especially of troponin, as well as assessment of right ventricular size and function based upon chest CT scanning and echocardiography. The ‘old school’ approach of declaring a benign prognosis based solely upon the presence of normal systemic arterial pressure can delay advanced therapy until after the onset of irreversible cardiogenic shock. We have now formulated a more contemporary, comprehensive, and multifaceted strategy to prognosticate. Our ‘new approach’ uses advanced treatment strategies in addition to anticoagulation for those pulmonary embolism patients deemed to be at high risk for a poor outcome.

Pulmonary embolism (PE) afflicts millions of individuals worldwide and accounts for at least 100 000 deaths annually in the United States alone. The case–fatality rate for PE, approximately 15%, exceeds the mortality rate for acute myocardial infarction [1].

Disease burden

  1. Top of page
  2. Abstract
  3. Disease burden
  4. Team approach
  5. Risk stratification
  6. Advanced treatment options
  7. Conclusions
  8. Disclosure of Conflict of Interests
  9. References

The US Surgeon General’s Call To Action to Prevent PE and Deep Vein Thrombosis in 2008 constituted a landmark of progress by focusing the attention of government, health care professionals, and the public on PE [http://www.surgeongeneral.gov/topics/deepvein/calltoaction/call-to-action-on-dvt-2008.pdf]. Venous thromboembolism (VTE) is the most preventable cardiovascular illness among hospitalized patients. However, prophylaxis against VTE is underutilized and is not completely effective. Therefore, we will always require an evidence-based treatment strategy to manage acute PE. Each hospital should develop its own PE treatment protocol that fits the particular strengths of the institution. This commitment to advanced planning will expedite decision-making and resolution of any potential disagreements about patient management that may arise when an acute PE patient presents and requires advanced therapy.

Although most individuals survive an initial episode of acute PE, this disease impairs quality of life by increasing the likelihood of developing chronic thromboembolic pulmonary hypertension [2] and chronic venous insufficiency. Thoughtful treatment plans are crafted to minimize the likelihood of these complications. Underemphasized is that for many individuals, immense anxiety surrounds the diagnosis of PE and extracts a psychological burden on patients who wonder whether they will suffer a recurrent event, whether PE will affect their family members, and whether PE will lower their quality of life and shorten their lifespan. Therefore, optimal treatment incorporates appropriate emotional support and provides educational resources for patients, families, and friends (http://www.NATFonline.org).

The major questions to address after diagnosis of PE are: (i) Will anticoagulation alone suffice? (ii) Will the patient benefit from thrombolysis [3], catheter embolectomy [4], surgical embolectomy [5], or placement of an inferior vena caval filter [6]? (iii) Is triage to an Intensive Care Unit bed appropriate?

Team approach

  1. Top of page
  2. Abstract
  3. Disease burden
  4. Team approach
  5. Risk stratification
  6. Advanced treatment options
  7. Conclusions
  8. Disclosure of Conflict of Interests
  9. References

At Brigham and Women’s Hospital, we use the ‘trauma center model’ to manage advanced PE therapy with a multidisciplinary team. We have found three prerequisites for success: (i) around-the-clock availability with readiness to accept patients transferred from other institutions with minimal delay and inconvenience, (ii) affability and mutual respect among team members, who comprise the disciplines of diagnostic radiology, interventional cardiology and radiology, cardiac surgery, and medical subspecialties including pulmonary, hematology, cardiology, and vascular medicine, and (iii) ability to work under pressure and make logical and, whenever possible, evidence-based decisions, after individualized discussions with patients and family members.

The multidisciplinary PE team rapidly assesses available data, performs additional testing if necessary, weighs treatment options, and recommends therapy to the patient and family. The menu of choices ranges from conservative management with anticoagulation alone to emergency catheter or surgical embolectomy.

The immediate foundation of PE therapy is anticoagulation. Options include unfractionated heparin (usually administered with a bolus and then continuous intravenous infusion targeted to twice the upper limit of normal of the activated partial thromboplastin time), low-molecular weight heparin (dosed by weight and adjusted to account for chronic kidney disease), and fondaparinux (also dosed by weight and adjusted downward for kidney disease). These anticoagulants exert an immediate therapeutic effect and are continued during a ‘bridging’ process to the oral anticoagulant, warfarin, which requires 5–7 days of administration to become fully effective. Three oral anticoagulants with immediate anticoagulant effect will probably become available within the next several years – two direct anti-Xa agents (rivaroxaban and apixaban) and an antithrombin agent – dabigatran [7].

Low-risk patients generally warrant low-molecular weight heparin [8] or fondaparinux [9] as a ‘bridge’ to warfarin (or other vitamin K antagonist). Neither low-molecular weight heparin nor fondaparinux requires dose titration with laboratory coagulation studies. In contrast, high-risk patients, whose clinical status may become unstable over the initial days of hospitalization, are best managed initially with short-acting intravenous unfractionated heparin.

Risk stratification

  1. Top of page
  2. Abstract
  3. Disease burden
  4. Team approach
  5. Risk stratification
  6. Advanced treatment options
  7. Conclusions
  8. Disclosure of Conflict of Interests
  9. References

To devise an appropriate treatment strategy, accurate and rapid risk stratification and prognostication are required. This assessment will clarify whether patients will benefit from advanced therapy in addition to anticoagulation and whether use of an Intensive Care Unit bed is appropriate. The three key components for risk stratification are: (i) clinical evaluation, (ii) determination of cardiac biomarkers levels such as troponin, and (iii) estimation of right ventricular size and/or function by CT scan and/or echocardiography.

Pathophysiology

The extent of pulmonary arterial thrombosis and underlying cardiopulmonary status help determine whether right ventricular dysfunction ensues [10]. As pulmonary arterial obstruction increases, pulmonary artery pressure and pulmonary vascular resistance rise. Pulmonary hypertension is exacerbated by secretion of vasoconstricting compounds such as serotonin, reflex pulmonary artery vasoconstriction, and hypoxemia. The injured right ventricle [11] releases cardiac biomarkers, including pro-brain natriuretic peptide, brain natriuretic peptide, and troponin, which predict an adverse clinical outcome [12]. As the right ventricle dilates, the interventricular septum shifts toward the left, resulting in left ventricular underfilling and decreased left ventricular diastolic distensibility. Consequently, systemic cardiac output and systolic arterial pressure decline, thereby impairing coronary perfusion and causing myocardial ischemia. Elevated right ventricular wall tension reduces right coronary artery blood flow, increases right ventricular myocardial oxygen demand, and causes coronary arterial ischemia [13]. Ultimately, right ventricular infarction, circulatory collapse, and death may ensue.

Clinical assessment

The initial risk assessment relies upon clinical risk factors for fatal PE. These include the presence of an anatomically massive PE, immobilization, age >75 years, or cancer [14]. A multicenter prospective cohort study of 1338 PE patients suggests that the two most important risk factors for predicting short-term mortality during the first week after diagnosis are systemic arterial hypotension and immobilization, each of which tripled the risk of death [15].

Semi-quantitative risk stratification can be undertaken with the Pulmonary Embolism Severity Index (PESI). There are 11 clinical parameters with four different severity weights used to stratify patients into five risk classes. The three most heavily weighted variables are altered mental status, history of cancer, and hypotension [16].

The history and physical examination play an important and often overlooked role. Syncope or breathlessness without chest pain are ominous symptoms suggesting massive PE. Cyanosis, even if transient, is an unequivocal sign of massive PE. However, the absence of systemic arterial hypotension is not necessarily reassuring, because patients are often critically ill from PE but ‘defend’ their blood pressure and maintain normotension until shortly before they succumb. Tachycardia and tachypnea suggest a poor prognosis but, like blood pressure, may not be apparent in previously healthy patients until the clinical situation has deteriorated markedly.

Important physical findings suggesting high risk are those that indicate pulmonary hypertension, right ventricular strain, or right ventricular failure. They include a left parasternal lift, tricuspid regurgitation murmur (best heard at the left lower sternal border), a ‘palpable P2’ at the left upper sternal border, and jugular vein distension.

Biomarkers

Elevation of cardiac troponins indicates right ventricular microinfarction and increases the likelihood of an adverse outcome. A meta-analysis of troponin levels in 1985 PE patients from 20 studies showed that even troponin ‘leaks’ indicate poor prognosis. Among PE patients with elevated troponin levels, 20% of 618 (20%) patients died, compared with a 3.7% death rate among 1387 PE patients with normal troponin levels. Among hemodynamically stable PE patients, elevated troponin levels were associated with a 6-fold increased mortality [17].

Right ventricular pressure overload causes elevations of pro-BNP [18] and BNP [19] indicating myocardial stretch. Patients with abnormally high pro-BNP or BNP levels are at increased risk of respiratory failure requiring mechanical ventilation, hypotension requiring vasopressors, and death.

Right ventricular size and function

Echocardiography, with an emphasis on right ventricular size and wall motion, is suitable to determine right ventricular function. Pulmonary artery systolic pressure can also be estimated with Doppler. However, there are two potential problems with echocardiography. First, availability is limited, especially during non-daytime non-weekday hours. Second, accurate imaging of the right ventricular free wall can be technically challenging and at times impossible in a dyspneic patient, especially if there is concomitant obesity or chronic lung disease. An enlarged right ventricle, usually defined as a right ventricular to left ventricular end diastolic diameter ratio >0.9, is associated in acute PE patients with a more than doubling of in-hospital mortality [20] as well as an increased risk of recurrent and often fatal PE [21].

Right ventricular enlargement can be conveniently determined on the same chest CT scan used to diagnosis acute PE. As with echocardiography, the most widely accepted definition of right ventricular enlargement is a right ventricular diameter that is 90% or greater the size of the left ventricular diameter. On multivariable analysis, right ventricular enlargement emerges as an independent risk factor for death and nonfatal clinical complications [22,23]. While chest CT is virtually universally available around-the-clock, it provides only limited information on right ventricular wall motion and cannot estimate pulmonary artery pressure.

Advanced treatment options

  1. Top of page
  2. Abstract
  3. Disease burden
  4. Team approach
  5. Risk stratification
  6. Advanced treatment options
  7. Conclusions
  8. Disclosure of Conflict of Interests
  9. References

The 2008 consensus guidelines from the American College of Chest Physicians and the 2008 European Society of Cardiology Task Force guidelines are remarkably similar (Table 1). Both endorse risk stratification and employ similar criteria and recommendations for the use of advanced PE therapy such as thrombolysis, embolectomy, and inferior vena caval filter placement.

Table 1.   Guidelines for advanced therapy in acute pulmonary embolism
VariableESC guidelinesACCP guidelines
  1. Adapted from: Guidelines on the diagnosis and management of acute pulmonary embolism. The Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). Eur Heart J 2008; 29: 2276-315.

  2. Kearon C, Kahn SR, Agnelli G, Goldhaber SZ, Raskob GE, Comerota AJ. Antithrombotic therapy for venous thromboembolic disease. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest 2008; 133: 454S-545S.

Risk stratificationRisk stratification based on the presence of shock and hypotension, as well as further stratification based upon imaging or biochemical markers of right ventricular dysfunction and myocardial injuryAll should undergo rapid risk stratification
ThrombolysisFirst-line treatment for cardiogenic shock or persistent arterial hypotension. Consider in selected intermediate-risk patients after assessing bleeding riskUse if hemodynamic compromise, unless contraindications. If high-risk without hypotension, use depends on clinician’s assessment of PE severity, prognosis, and bleeding risk
Catheter embolectomyConsider as an alternative to surgical treatment in high-risk patients when thrombolysis is absolutely contraindicatedSelected highly compromised patients with too high bleeding risk for thrombolysis or insufficient time for systemic thrombolysis to be effective
Surgical embolectomyValuable therapeutic option in patients with high-risk PE in whom thrombolysis is absolutely contraindicated or has failedSelected highly compromised patients with too high bleeding risk for thrombolysis or insufficient time for systemic thrombolysis to be effective
Vena caval filterUse when there are absolute contraindications to anticoagulation and a high risk of PE recurrence. Remove retrievable filters as soon as it is safe to use anticoagulantsPlace if anticoagulation is not possible because of the risk of bleeding. If the bleeding risk resolves, administer a conventional course of anticoagulant therapy

Thrombolytic therapy

Anticoagulation prevents additional thrombus from forming but does not directly dissolve the PE clot that already exists. In contrast, thrombolytic therapy constitutes primary treatment of PE because it dissolves fibrin. When successful, this direct approach results in hemodynamic improvement with reversal of right ventricular hypokinesis, normalization of right ventricular size, and reduction of abnormally high pulmonary arterial pressures. Fibrinolysis may also serve as a medical embolectomy that reduces the source of thrombus in the pelvic, upper extremity, and deep leg veins, thereby lessening the likelihood of recurrent PE. Finally, thrombolytic therapy might decrease long-term elevations of pulmonary vascular resistance by improving pulmonary capillary blood flow, which might theoretically decrease the likelihood of developing chronic thromboembolic pulmonary hypertension.

Thrombolysis of PE mostly utilizes recombinant human tissue plasminogen activator (TPA). The FDA approved dose is 100 mg over 2 h via a continuous peripheral intravenous infusion. In the United States, TPA is administered without concomitant heparin and without a 10 mg bolus-loading dose. In Europe, TPA is usually prescribed with concomitant intravenous unfractionated heparin infusion as a 10 mg bolus dose followed by 90 mg of TPA as a continuous infusion over 2 h. When successful, there is usually clinical improvement by the second hour of therapy. Patients experience a sense of improved well-being, often with resolution of tachypnea as well as lessening or elimination of a requirement for supplemental oxygenation. A side effect is nuisance bleeding, especially gingival oozing and development of ecchymosis at sites where phlebotomy was previously attempted but failed.

Even the most ardent supporters of thrombolysis admit that there exist several major limitations to this strategy. First, it elevates the risk of major, catastrophic bleeding, including gastrointestinal and intracranial hemorrhage. Second, though approved only for treatment of ‘massive PE,’ there is no study demonstrating a survival benefit, other than a single trial of eight patients in which four received streptokinase plus heparin and four received anticoagulation alone [24]. In fact, an observational study from the International Cooperative Pulmonary Embolism Registry suggested that patients with massive PE receiving thrombolysis might not experience any clinical benefit whatsoever with respect to decreasing mortality or major cardiovascular events [25]. While these findings might seem counterintuitive, they mimic observations seen when patients with massive anterior myocardial infarction and cardiogenic shock receive thrombolysis. The physiologic explanation is that in patients with massive PE, an adverse metabolic cascade leading to multisystem organ failure has often advanced so far as to be irreversible.

For patients with submassive PE, defined as right ventricular dysfunction and troponin elevation despite normal systemic arterial pressure, definitive evidence to prove the efficacy of fibrinolysis does not yet exist. MAPPET-3, the largest completed randomized trial of thrombolytic therapy vs. heparin alone, studied patients with submassive PE who had the combination of normal blood pressure and right ventricular dysfunction [26]. TPA, compared with placebo, halved the frequency of escalation of therapy – defined as the need for pressors, mechanical ventilation, cardiopulmonary resuscitation, or open-label thrombolysis – and did not increase major bleeding. Open-label thrombolysis was the major endpoint that drove MAPPET-3 in favor of TPA. Because the decision to use open-label thrombolysis after the initial randomization treatment was subjective, the trial has been criticized, and its findings remain controversial. A meta-analysis of 748 patients in 11 prior randomized thrombolysis trials found that in the subset of trials that included major PE, the mortality rate was halved but the major bleeding rate doubled among thrombolysis-treated subjects [3].

A large ongoing European randomized controlled trial of tenecteplase in submassive PE (defined as preserved blood pressure but elevated troponin level and right ventricular enlargement) has enrolled about 250 of a required 1100 patients. The principal endpoint is death or cardiovascular collapse.

Thrombolytic therapy is not used often in the United States. Among 15 116 patient discharges with a primary diagnosis of PE, only 2.4% received fibrinolysis. The overall 30-day mortality was 17.4% for those receiving thrombolysis compared with 8.6% for those who did not. Counterintuitively, excess mortality risk was the highest among those PE patients who had a low overall clinical risk but who, nevertheless, received thrombolysis [27].

Catheter embolectomy

Catheter-directed interventions are appropriate when anticoagulation alone has not achieved the desired clinical response and when thrombolysis is contraindicated or has failed to improve the patient’s clinical condition. For these patients, catheter-directed therapy provides a less extreme advanced treatment option than surgical pulmonary embolectomy. A catheter-based approach might be particularly suitable in an elderly patient too frail for surgery or in any patient with severe underlying pulmonary disease that makes successful cardiopulmonary bypass unlikely. Multiple catheter-directed interventions are available, including clot fragmentation, suction thrombectomy, and rheolytic thrombectomy [28]. Some patients with contraindications to full systemic doses of TPA can tolerate catheter-directed intervention with small doses of thrombolytic therapy. Experienced operators will usually attempt catheter thrombectomy without adjunctive thrombolysis and will reserve combined mechanico-pharmacological intervention for those patients who do not respond to mechanical intervention alone [29].

Surgical embolectomy

Surgical pulmonary embolectomy with cardiopulmonary bypass is effective for managing patients with massive PE and systemic arterial hypotension or submassive PE with right ventricular dysfunction [30] in whom contraindications preclude thrombolysis. Other indications include PE patients who require surgical excision of a right atrial thrombus or closure of a patent foramen ovale as well as ‘rescue’ when thrombolysis has failed clinically [31]. At Brigham and Women’s Hospital, 47 patients underwent surgical embolectomy in a 4-year period, with a 96 % survival rate [32]. We perform the procedure on a warm, beating heart, without aortic cross-clamping or cardioplegic or fibrillatory arrest. We avoid blind instrumentation of the fragile pulmonary arteries and limit extraction to directly visible clot.

Inferior vena caval filter insertion

The two major indications for placement of an inferior vena caval (IVC) filter are: (i) major hemorrhage that precludes anticoagulation, and (ii) recurrent PE despite anticoagulation. Eight-year follow-up of a randomized controlled trial of filters shows that filters reduce the risk of PE but increase the risk of DVT [33]. For patients with a temporary contraindication to anticoagulation, placement of a retrievable filter may be appropriate. Retrievable filters can be left in place for weeks to months or can remain permanently, if necessary, because of a trapped large clot or persistent contraindication to anticoagulation [34].

Conclusions

  1. Top of page
  2. Abstract
  3. Disease burden
  4. Team approach
  5. Risk stratification
  6. Advanced treatment options
  7. Conclusions
  8. Disclosure of Conflict of Interests
  9. References

Treatment of acute PE has many options, which should be matched to the patient’s clinical acuity and risk profile. Well-designed protocols will enable practitioners to mobilize their hospital team quickly, to prognosticate accurately, and to develop individualized therapeutic plans that may require specialized expertise for advanced therapy.

References

  1. Top of page
  2. Abstract
  3. Disease burden
  4. Team approach
  5. Risk stratification
  6. Advanced treatment options
  7. Conclusions
  8. Disclosure of Conflict of Interests
  9. References
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