SPECIAL FEATURE
Treatment of Pulmonary Embolism in the ICU
By Eric C. Walter, MD, MSc
Pulmonary and Critical Care Medicine, Northwest Permanente and Kaiser Sunnyside Medical Center, Portland
Dr. Walter reports no financial relationships relevant to this field of study.
Venous thromboembolism (VTE) is the third most common cardiovascular condition behind myocardial infarction and stroke, with an incidence rate of about one per 1000 person-years.1,2 Nearly 5% of the population will experience VTE in their lifetime.3 VTE encompasses both deep vein thrombosis (DVT) and pulmonary embolism (PE). VTE treatment has changed significantly over the past several years. As recently as a few years ago, both DVT and PE required hospitalization for observation and treatment with IV anticoagulants. Today, DVT is commonly treated in the outpatient setting.3 PE may also be treated as outpatient, but inpatient treatment is still the norm, primarily because of the potential morbidity and mortality. In a population-based study, the 30-day mortality from PE was 16% and 19% depending on whether the diagnosis was probable or definite. One-year mortality was 29% and 32%, respectively.1 ICU clinicians are frequently involved in the treatment of acute PE. This review will focus on the acute phase of PE treatment, the time when ICU clinicians are most likely to be involved.
INITIAL TREATMENT
The initial objectives of PE treatment are to prevent clot extension and/or recurrence through the use of systemic anticoagulation. Although this may change as newer anticoagulants become available, heparin is still the anticoagulant of choice for the initial treatment of PE. Heparin therapy is classified as low molecular weight (LMWH) or unfractionated heparin. In the absence of renal insufficiency, fixed-dose LMWH is recommended over unfractionated heparin for all forms of VTE.3,4 LMWH has a lower risk of death (odds ratio [OR], 0.76) and major hemorrhage (OR, 0.57), and lower rates of recurrent VTE (OR, 0.68), compared to unfractionated heparin.5 Vitamin K antagonists (e.g., warfarin) should be started in parallel with heparin therapy and continued until the international normalized ratio (INR) is therapeutic for 24-48 hours.2-4 Vitamin K antagonists should not be started without heparin, as this practice increases the risk of recurrent clots compared to combination therapy.6
HIGH-RISK PE
High-risk, or massive, PE is generally defined as PE complicated by hemodynamic compromise as a result of right heart failure (usually defined as systolic blood pressure < 90 mm Hg).2 Some authors include the need for mechanical ventilation in this definition.7 Fortunately, high-risk PE is not common. In a large retrospective study from U.S. hospitals, only 3.4% of acute PE diagnoses were classified as high-risk (defined as in shock or ventilator dependent).7 Similar to previous studies, mortality was high, with an in-hospital mortality of 37%. Other studies have shown similar rates of high-risk PE (~ 5%) with similar risks of death.4
In patients with high-risk PE, thrombolytic therapy appears to decrease mortality, but at the risk of increased bleeding. As opposed to anticoagulation, which prevents clot extension and recurrence, thrombolytic therapy leads to more rapid clearing of clot, vein patency, and improved right ventricular (RV) function. In a retrospective, population-based study, mortality was 15% in high-risk patients who received thrombolytics compared to 47% in high-risk patients who did not receive thrombolytics (relative risk, 0.31; 95% confidence interval [CI], 0.30-0.32; P < 0.0001). Of note, patients in this study who received thrombolysis were younger and had fewer comorbidities than patients who did not receive thrombolysis. This may have biased the results to some degree. Several meta-analyses have reviewed the use of thrombolytics in high-risk PE, and the bulk of evidence suggests thrombolytic therapy for high-risk PE is associated with a reduction in mortality and recurrent PE, with an increased risk of major bleeding. However, the strength of the evidence is considered to be weak.
The 2012 American College of Chest Physicians (ACCP) Task Force on Antithrombotic Therapy for VTE disease gives a weak recommendation for the use of thrombolysis in patients with high-risk PE who do not have a high risk of bleeding (grade 2C).4 Others have given stronger recommendations.2,3,7 Some suggest it be considered even in the presence of an increased risk of bleeding (except for an increased risk of central nervous system bleeding).2 When thrombolytics are used, a short infusion duration (≤ 2 hours) is recommended due to a decreased risk of bleeding compared to longer infusions. Additionally, the use of a peripheral vein is recommended over infusion directly into the pulmonary artery, as the latter is associated with more bleeding complications as well. Both of these are grade C recommendations.4
INTERMEDIATE-RISK PE
By far the most controversial arena in the treatment of acute PE involves the use of thrombolytics in intermediate-risk patients. Intermediate-risk PE, also termed submassive PE, is usually defined as patients with acute PE who are hemodynamically stable but with signs of right ventricular (RV) dysfunction.2,3 RV dysfunction can be assessed with imaging and/or lab testing. Signs of RV dysfunction on chest CT or echocardiography include RV dilation, increased right-to-left ventricular diameter ratio, or hypokinesis of the RV free wall. Elevated brain natriuretic peptide (BNP) and troponin levels are lab markers suggesting RV dysfunction. Many different scoring systems, using variations of imaging and lab results, have been proposed to help risk stratify patients with acute PE. To date, there is no universally accepted, well-discriminating scoring system.
Thrombolytic therapy in patients with intermediate-risk PE was studied in a 2002 randomized, controlled trial comparing heparin plus alteplase (n = 118) with heparin alone (n = 138).8 The primary outcome of death, or need for treatment escalation, occurred less frequently in the heparin plus alteplase group compared with those who received heparin alone. However, there was no difference in mortality (3.4% vs 2.2%, P = 0.71). The major difference in outcome was an increased need for treatment escalation among patients given heparin alone. The majority of treatment escalations included the use of thrombolytics in response to a clinical deterioration (hypotension or worsening respiratory failure). For years, both proponents and critics of thrombolysis in intermediate-risk PE have used this publication to defend their point of view. Critics argue that thrombolytics do not change mortality, and that rather than preemptively giving thrombolytics to all intermediate-risk patients, only those patients who develop shock or respiratory failure need treatment. Proponents argue that thrombolytics prevent this clinical deterioration. The 2012 ACCP guidelines addressed this question and concluded the increased risk of bleeding outweighed the “less-certain” benefits of thrombolytics. They recommend against their use for most patients with acute PE not associated with hypotension (grade 1C).4
In 2014, the publication of a new randomized, controlled trial9 and meta-analysis10 provided additional data but did not quell the controversy. Meyer et al reported results from the Pulmonary Embolism Thrombolysis (PEITHO) trial, a large trial that randomized intermediate-risk patients with acute PE to either tenecteplase plus heparin (n = 506) or heparin plus placebo (n = 499).9 Patients had to be normotensive but with signs of RV dysfunction (via echo or chest CT) and myocardial injury (positive troponin I or T test). The primary outcome of death or hemodynamic decompensation within 7 days occurred less frequently in the tenecteplase group compared to the placebo group (2.6% vs 5.6%; OR 0.44; 95% CI, 0.23¨C0.87). However, similar to the previous trial in this population, the difference was driven almost exclusively by more hemodynamic decompensation in the placebo group, as 7-day mortality did not differ between groups (1.2% vs 1.8%; OR 0.65; 95% CI, 0.23¨C1.85). There was also no difference in 30-day mortality (2.4% vs 3.2%). The tenecteplase group did have significantly more major extracranial bleeding (6.3% vs 1.2%) and hemorrhagic stroke (2.0% vs 0.2%).
Since this trial was published, Chatterjee and colleagues published a meta-analysis of thrombolysis for PE.10 They pooled results from 16 randomized, controlled trials (including PEITHO) comparing thrombolytic therapy vs anticoagulant therapy for acute PE. They concluded that thrombolytic therapy was associated with a decreased all-cause mortality (2.17% vs 3.89%; OR 0.53; 95% CI, 0.32-0.88). As expected, major bleeding occurred more frequently in the thrombolytic cohort (9.24% vs 3.42%; OR 2.73; 95% CI, 1.91-3.91). These results equate to a number needed to treat of 59 (to prevent one death) and a number needed to harm of 18 (to cause one major bleed). When the analysis was limited to trials specifically enrolling intermediate-risk patients (70.9% of all patients), thrombolytic therapy was still associated with a significant reduction in mortality (1.39% vs 2.92%; OR 0.48; 95% CI, 0.25-0.92). Thrombolytics remained associated with a more than three-fold greater risk of major bleeding (7.74% vs 2.25%; OR 3.19; 95% CI, 2.07-4.92). In a prespecified analysis, this risk of bleeding did appear to be greatest in patients older than 65 years.
Thus, the decision to use thrombolytic therapy in patients who are hemodynamically stable remains challenging. For every one life saved, the tradeoff could be up to three patients with major bleeding events. It would be helpful to have a clearer understanding of what types of major bleeding events occurred, as the long-term consequences of a gastrointestinal bleed requiring transfusion and intracranial bleeding can be dramatically different. Unfortunately, the Chaterjee meta-analysis does not provide this level of detail. However, at least for the intermediate-risk patients, we can look at PEITHO to try to address this question. PEITHO accounted for 40% of the weighted analysis among the intermediate-risk patients. Hemorrhagic stroke occurred in 10 patients (2.0%) who received thrombolysis, as compared to one patient (0.2%) who received placebo. Of these 10 patients, four died, and most of the remaining patients had persistent mild-to-moderate disability.9 Consequently, it is prudent to strongly consider the potential morbidity associated with the bleeding risk that comes with thrombolytic therapy. Two reviews this year have taken the same stance as the ACCP guidelines and have recommended against the routine use of thrombolytic therapy in normotensive patients.2,3 Of note, these reviews were published prior to the Chatterjee meta-analysis.
OTHER ISSUES
Inferior Vena Cava Filters
The use of retrievable inferior vena cava (IVC) filters among patients with VTE is increasing.11 There is a general consensus that IVC filters should be used in patients with VTE and contraindications to anticoagulation.2-4 The use of IVC filters in other patient populations is debated. Several large, retrospective epidemiologic studies using hospital discharge data (all from the same group, Stein et al) have reported that IVC filters were associated with lower mortality among unstable patients (independent on the use of thrombolytic therapy), stable patients who received thrombolytics, and patients who had pulmonary artery embolectomy.7,11,12 An accompanying editorial recommended that IVC filters (and thrombolytics) be used in all unstable patients who do not have contraindications.13 Others feel additional studies are needed before this recommendation can be made.2 The 2012 ACCP guidelines only recommend an IVC filter in patients with contraindications to anticoagulation. It is worth mentioning that these guidelines were published prior to the Stein studies.
|
Table 1. Clinical Signs and Treatment of Acute Pulmonary Embolism |
|||
|
Low risk |
Intermediate risk |
High risk |
|
|
Clinical Signs |
Normotensive Normal right Ventricular function |
Normotensive Right ventricular dysfunction |
Hypotension and/or mechanical ventilation |
|
Initial |
Anticoagulation |
Anticoagulation |
Anticoagulation |
|
Thrombolysis |
Not indicated |
Remains controversial May reduce mortality Increased risk of bleeding |
Generally recommended Probably reduces mortality |
Pulmonary Artery Embolectomy
Pulmonary artery embolectomy is rarely performed for acute PE. From 1999 to 2008, only 0.18% of acute PE was treated with surgical embolectomy.12 Evidence for both catheter-based and surgical embolectomy is weak. The 2012 ACCP guidelines give a weak recommendation (grade 2C) for these techniques when there is a contraindication to thrombolysis, failed thrombolysis, or shock that is likely to cause death before thrombolysis can take effect (usually a few hours).4 Outcomes after thrombectomy are difficult to assess, as studies are small and use different patient populations. Using nationwide hospital discharge data from 1999-2008, the case fatality rate among stable patients with acute PE who underwent thrombectomy was 24%. If the patients were unstable, mortality was 40%.12 Mortality was decreased if an IVC filter was placed in addition to embolectomy. The authors noted that these results reflected a nationwide average mortality and that outcomes may be better at select centers with more expertise. Supporting this argument is a more recent single-center series that reported excellent outcomes after embolectomy in a combination of 20 intermediate and high-risk patients (5% mortality).14 A criticism of these small case series, however, is that we do not know what mortality would have been had patients only been treated with anticoagulation or thrombolysis and not embolectomy.
Newer Anticoagulants
Over the past 5 years, several newer anticoagulants have become available. These drugs are direct factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban) and direct factor IIa inhibitors (dabigatran). All except for edoxaban have received FDA approval for the treatment of VTE, and it is likely that edoxaban will be approved soon. Several phase 3 clinical trials have shown these anticoagulants to be at least as effective as, and probably safer than, heparin therapy followed by warfarin.2,3 Unlike warfarin, these new agents have the distinct advantage of not needing monitoring — a potential cost savings and quality of life benefit for patients. An ongoing concern has been the lack of a reversal agent. However, at least in short-term trials (3-12 months), this was not a significant clinical problem, as major bleeding occurred less frequently than with warfarin. These agents may not be appropriate for patients with renal impairment. Cost is a significant barrier, but the use of newer anticoagulants is likely to increase over the next several years.
SUMMARY
Pulmonary embolism is a common and potentially life-threatening disorder. Immediate anticoagulation is first-line therapy (see Table). High-risk PE is usually defined as PE with hemodynamic compromise or need for mechanical ventilation. Thrombolysis is indicated for high-risk PE. Intermediate-risk PE is defined as PE with signs of RV dysfunction, and the use of thrombolysis in this population is controversial. Thrombolysis may decrease the risk of mortality, but is associated with a substantial increase in the risk of major bleeding. IVC filters are uniformly recommended when there are contraindications to anticoagulation. There is limited evidence to guide the use of IVC filters in other clinical settings. Similarly, there are limited data for thrombectomy, but this is generally recommended for unstable patients if there is a contraindication to thrombolysis. Newer anticoagulants are likely to gain increasing clinical acceptance. In short-term trials, they have been shown to be as effective as heparin plus vitamin K antagonist therapy, and they may be safer.
REFERENCES
- Tagalakis V, et al. Incidence of and mortality from venous thromboembolism in a real-world population: The Q-VTE Study Cohort. Am J Med 2013;126:e13-e21.
- Konstantinides S, et al. Management of venous thromboembolism: An update. Eur Heart J 2014;35:2855-2863.
- Wells PS, et al. Treatment of venous thromboembolism. JAMA 2014;311:717-728.
- Kearon C, 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-e4194S.
- Erkens PM, et al. Fixed dose subcutaneous low molecular weight heparins versus adjusted dose unfractionated heparin for venous thromboembolism. Cochrane Database Syst Rev. 2010:CD001100.
- Brandjes DP, et al. Acenocoumarol and heparin compared with acenocoumarol alone in the initial treatment of proximal-vein thrombosis. N Engl J Med 1992;327:1485-1489.
- Stein PD, et al. Thrombolytic therapy in unstable patients with acute pulmonary embolism: Saves lives but underused. Am J Med 2012;125:465-470.
- Konstantinides S, et al. Heparin plus alteplase compared with heparin alone in patients with submassive pulmonary embolism. N Engl J Med 2002;347:1143-1150.
- Meyer G, et al. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med 2014;370:1402-1411.
- Chatterjee S, et al. Thrombolysis for pulmonary embolism and risk of all-cause mortality, major bleeding, and intracranial hemorrhage: A meta-analysis. JAMA 2014;311:2414-2421.
- Stein PD, et al. Impact of vena cava filters on in-hospital case fatality rate from pulmonary embolism. Am J Med 2012;125:478-484.
- Stein PD, et al. Case fatality rate with pulmonary embolectomy for acute pulmonary embolism. Am J Med 2012;125:
471-477. - Dalen JE. Thrombolytics and vena cava filters decrease mortality in patients with unstable pulmonary embolism. Am J Med 2012;125:429-430.
- Worku B, et al. Pulmonary embolectomy in the treatment of submassive and massive pulmonary embolism. Cardiology 2014;129:106-110.
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