http://informahealthcare.com/hop ISSN: 2154-8331 (print) Hosp Pract, 2015; 43(1): 22–27 DOI: 10.1080/21548331.2015.1001302
REVIEW
Systemic thrombolysis for acute pulmonary embolism Billie Bartel
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Avera McKennan Hospital and University Health Center, Sioux Falls, SD, USA Abstract
Keywords:
Acute pulmonary embolism is a frequent cause of hospitalization and is associated with a wide range of symptom severity. Anticoagulants are the mainstay of treatment for acute pulmonary embolism; however, in patients with massive or submassive pulmonary embolism, advanced therapy with thrombolytics may be considered. The decision to use thrombolytic therapy for acute pulmonary embolism should be based on careful risk–benefit analysis for each patient, including risk of morbidity and mortality associated with the embolism and risk of bleeding associated with the thrombolytic. Alteplase is currently the thrombolytic agent most studied and with the most clinical experience for this indication, although the most appropriate dose remains controversial, especially in patients with low body weight. When considering thrombolysis, unfractionated heparin is the preferred initial anticoagulant due to its short duration of action and its reversibility should bleeding occur.
Thrombolytic, fibrinolytic, pulmonary embolism, alteplase History Received 11 June 2014 Revised 8 July 2014 Accepted 9 July 2014 Published online 6 January 2015
Introduction
Materials and methods
Acute pulmonary embolism (PE) is a frequent cause of hospital admissions. Acute PE carries an overall early mortality rate of approximately 10%, and patients with acute PE can present with a wide range of symptom severity. The majority of patients present with a normal blood pressure and preserved right ventricular function. The clinical prognosis for these patients is generally very good, with a low estimated mortality rate [1-3]. Evidence of right ventricular dysfunction with a normal blood pressure, termed a submassive PE, occurs in approximately 30% to 60% of patients with acute PE and carries an increased risk of adverse outcomes and early mortality [4-6]. An acute PE is termed massive if a patient is experiencing hypotension, shock, cardiac arrest, or respiratory failure due to the embolism. A massive PE occurs in approximately 5% of patients and carries an early mortality rate of 30%; mortality may be as high as 70% if cardiopulmonary arrest occurs [1-3,7]. Prompt initiation of anticoagulation is the cornerstone of therapy for acute PE. In patients with massive or submassive PE, advanced therapy with thrombolysis (also termed fibrinolysis), catheter-assisted embolectomy, or surgical embolectomy may be treatment options in addition to anticoagulation. This article reviews the current evidence regarding the use of systemic intravenous thrombolysis for massive and submassive PE, and discusses practical considerations when using systemic thrombolytics for this indication.
To assess and evaluate the current evidence for thrombolysis in acute PE, a literature search was conducted using PubMed and the following search terms: pulmonary embolism in combination with thrombolytic, fibrinolytic, and alteplase. Reference lists from identified articles were reviewed to ensure that a comprehensive literature search was completed. Thirtytwo primary literature studies are included in this review.
Indications for thrombolysis The decision to use thrombolytic therapy for acute PE should be based on careful risk–benefit analysis for each patient. Current clinical guidelines recommend the use of thrombolytics for massive PE in the absence of contraindications (Table 1). The utility of thrombolytics in patients with submassive PE has been controversial (Table 2), although new data have been published since these guidelines were last updated [1,8,9]. Massive pulmonary embolism A massive PE is associated with an increased risk of death, with mortality rates up to 70% if untreated. Mortality can be reduced by > 50% in patients with prompt initiation of therapy [1]. Thrombolytic therapy should be considered as a therapeutic option in these high-risk patients due to faster resolution of obstruction compared with treatment with anticoagulants (eg, heparin) alone [1]. Randomized clinical trials
Correspondence: Billie Bartel, PharmD, Avera McKennan Hospital and University Health Center, 1325 S Cliff Avenue, Sioux Falls, SD 57105, USA. Tel: +1 605 322 8559. E-mail: [email protected] 2015 Informa UK Ltd.
Systemic thrombolysis for Acute PE
DOI: 10.1080/21548331.2015.1001302
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Table 1. Consensus guideline recommendations for thrombolysis in massive PE [1,8,9]. Consensus guideline 2012 American College of Chest Physicians 2011 American Heart Association 2008 European Society of Cardiology
Recommendation Consider in patients with acute PE associated with hypotension (SBP < 90 mm Hg) and without a high risk of bleeding over anticoagulation alone [1] Reasonable for patients with massive PE and acceptable risk of bleeding complications [8] Should be used in patients with high-risk PE presenting with cardiogenic shock and/or persistent hypotension [9]
Level of recommendation Grade 2C Class IIa; level of evidence, B Class I; level of evidence, A
Abbreviations: PE = Pulmonary embolism; SBP = Systolic blood pressure.
Table 2. Consensus guideline recommendations for thrombolysis in submassive PE [1,8,9]. Consensus guideline
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2012 American College of Chest Physicians 2011 American Heart Association
2008 European Society of Cardiology
Recommendation Consider in patients with PE with a low risk of bleeding and high risk of developing hypotension [1] Consider for patients with submassive PE with clinical evidence of adverse prognosis (new hemodynamic instability, worsening respiratory insufficiency, severe RV dysfunction, or major myocardial necrosis) and a low risk of bleeding [8] Consider in patients with intermediate-risk PE (evidence of RV dysfunction or myocardial injury) [9]
Level of recommendation Grade 2C Class IIb; level of evidence, C
Class IIb; level of evidence, B
Abbreviations: PE = Pulmonary embolism; RV = Right ventricle.
have found that thrombolytic therapy for massive PE improves hemodynamic parameters such as pulmonary artery hemodynamic measurements, arteriovenous oxygenation, pulmonary perfusion, and echocardiographic assessments at 24 hours when compared with anticoagulation with heparin [10-24]. When considering improvements in overall patient outcomes associated with thrombolysis, a meta-analysis conducted by Wan and colleagues [24] has summarized most of the original research to date. This meta-analysis included randomized trials comparing thrombolysis with heparin and assessing ‡ 1 clinical outcome, including PE, bleeding, and death. The primary efficacy outcome was the composite of recurrent PE or death. Secondary outcomes included the individual components of the primary outcome and safety outcomes, including major and nonmajor bleeding and intracranial hemorrhage. The meta-analysis included five studies evaluating patients with massive PE [24]. Analysis of these studies found a significant reduction in PE or death with thrombolytic therapy (9.4% vs 19.0%; odds ratio [OR], 0.45; 95% CI, 0.22–0.92). When evaluating PE and death individually, no significant difference was found (PE: 3.9% vs 7.1%; OR, 0.61; 95% CI, 0.23–1.62; death: 6.2% vs 12.7%; OR, 0.47; 95% CI, 0.2–1.1). No difference in major bleeding was noted (21.9% vs 11.9%; OR, 1.98; 95% CI, 1–3.92). Since Wan and colleagues’ [24] meta-analysis in 2004, only retrospective evaluations have further assessed the impact of thrombolytics on patient outcomes with massive PE. One retrospective cohort study conducted by Ibrahim and colleagues [25] evaluated the association between thrombolytics and 30-day mortality in 15 166 patients with a diagnosis of acute PE. When comparing propensity score-adjusted mortality, the 30-day mortality risk associated with thrombolysis varied with disease severity and was 0.7 (P = 0.30) for patients in the highest quintile of the score distribution. Age, sex, race, specific comorbidities, hemodynamic variables, and
specific laboratory values, including markers that may indicate shock, were included in the propensity scoring system; thus, the highest quintile most closely represented patients with massive PE. Riera-Mestre and colleagues [26] conducted an international retrospective cohort study of 15 944 patients with symptomatic acute PE identified from the multicenter international Computerized Registry of Patients with Venous Thromboembolism (RIETE), and evaluated the association between thrombolytics and all-cause mortality during the first 3 months after diagnosis using a matched-paired analysis [26]. In the subgroup of patients with hypotension (systolic blood pressure < 100 mm Hg), the investigators did not find thrombolytics to be associated with a lower risk of death (P = 0.37) [26]. Overall application of these more recent retrospective analyses has the potential limitations associated with the propensity analysis models and potential for exclusions of existing cofounders. In each of these analyses, patients with massive PE were only a small subgroup of the entire population analyzed, which also limits the interpretation of the study results. Current evidence suggests a hemodynamic and patient outcome benefit with thrombolysis in patients with massive PE compared with treatment with anticoagulation alone, although large prospective clinical trials evaluating patient outcomes specific to this subset of PE patients are lacking. Submassive pulmonary embolism Use of thrombolytics for submassive PE has been limited due to inconclusive evidence from clinical trials, though recent publications have prompted further consideration for use in this patient population. The Management Strategies and Prognosis of Pulmonary Embolism-3 (MAPPET-3) investigators conducted a randomized controlled clinical trial evaluating the composite primary end point of in-hospital mortality or clinical deterioration requiring escalation of treatment
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(defined as vasopressor use, rescue thrombolysis, mechanical ventilation, cardiopulmonary resuscitation, or emergency surgical embolectomy) in 256 patients with hemodynamically stable acute PE and either pulmonary hypertension or right ventricular dysfunction receiving thrombolytics plus heparin versus heparin alone [10]. The investigators found a significant improvement in the primary outcome in patients receiving thrombolytics (11% vs 24.6%; P = 0.006), though no difference in mortality alone (3.4% vs 2.2%; P = 0.71). Rates of major bleeding were similar between groups (0.8% vs 3.6%; P = 0.29), and no fatal or intracerebral bleeding occurred in either group. One notable limitation of this study is that its design allowed treating physicians to break randomization if the patient’s clinical condition was deteriorating; patients receiving heparin alone were 3 times more likely to break protocol and receive thrombolytic therapy when compared with the thrombolytic group [10]. Two small studies evaluating the use of thrombolytics in patients with submassive PE have demonstrated improvements in right ventricular function in patients receiving thrombolysis [22,23]. The Tenecteplase Italian Pulmonary Embolism Study (TIPES) was a multicenter, randomized, double-blind, placebo-controlled study evaluating the effect of thrombolytics versus heparin on right ventricle dysfunction in 58 patients [22]. Right ventricular dysfunction was assessed by echocardiography at 24 hours, and the investigators found the reduction in right to left ventricle end-diastolic dimension ratio was greater in patients randomized to thrombolytics (P = 0.04). Fasullo and colleagues [23] conducted a prospective, randomized, double-blind, placebo-controlled study of thrombolytics versus heparin in 72 consecutive patients with a first episode of submassive PE with right ventricle dysfunction and normal blood pressure. The primary efficacy end point was right ventricle dysfunction, assessed by echocardiograph, early (at 24 hours) and at 6 months. Thrombolysis resulted in significant early improvement of right ventricle function, and this improvement was also observed at the 6-month follow-up. Use of thrombolytics for submassive PE may also improve other hemodynamic parameters. In a prospective study of 200 patients with submassive PE, Kline and colleagues [27] found that in the 162 patients (out of 180 survivors [90]) who were available for follow-up at 6 months, pulmonary artery systolic pressure increased in 27% of patients treated with heparin alone versus 0% of patients treated with thrombolytics. Nearly half of the patients with increased pulmonary artery systolic pressure had symptoms consistent with New York Heart Association class III heart failure or exercise intolerance on a 6-minute walk test. More recently, the Moderate Pulmonary Embolism Treated with Thrombolysis (MOPETT) trial reviewed the effect of half-dose thrombolysis versus anticoagulation alone (enoxaparin or heparin) on pulmonary hypertension in 121 normotensive patients with symptomatic ‘moderate’ PE [28]. Patients were considered to have moderate PE if they had signs and symptoms of PE (‡ 2 of the following: chest pain, tachypnea, tachycardia, dyspnea, cough, oxygen desaturation, and elevated jugular venous pressure) plus > 70% involvement of thrombus in ‡ 2 lobar or left or right main pulmonary arteries on computed tomographic pulmonary angiogram, or by high
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probability ventilation/perfusion scan showing mismatch in ‡ 2 lobes. Evidence of right ventricular dysfunction or of elevation of biomarkers of right ventricular injury (troponin or brain natriuretic peptide) was not required for inclusion in the study. At 28 months, pulmonary hypertension developed in 16% of patients receiving thrombolytics versus 57% of patients receiving anticoagulation alone (P < 0.001). Thrombolysis was also associated with improvement in secondary end points including duration of hospitalization (2.2 vs 4.9 days; P < 0.001) and combination of death and recurrent PE (1.6% vs 10%; P = 0.0489), although no significant difference was seen in rate of death and recurrent PE when assessed independently (1.6% vs 5%; P = 0.30; 0% vs 5%; P = 0.08, respectively). No bleeding occurred in either group [28]. The Tenecteplase or Placebo: Cardiopulmonary Outcomes At Three Months (TOPCOAT) trial evaluated the composite of mortality and morbidity outcomes associated with administration of thrombolytics for submassive PE [29]. This randomized, double-blind, placebo-controlled trial included 83 patients with acute PE and normal blood pressure with evidence of right ventricular strain (as evidenced by echocardiography or elevated troponin I or T or elevated brain natriuretic peptide levels). The primary outcome assessed was the composite of death, circulatory shock, intubation, or major bleeding at 5 days, or recurrent PE, poor functional capacity, or health-related quality of life at 90 days. The overall composite end point occurred in 15% of the thrombolytic group and 37% of the placebo group (P = 0.017). Early adverse outcomes (at 5 days) occurred in one patient in the thrombolytic group and three patients in the placebo group, whereas late adverse outcomes (at 90 days) occurred in 5 and 13 patients in each group, respectively. Although overall functional capacity was improved at 90 days in patients receiving thrombolytics, incidence of right ventricular dilation or hypokinesis did not differ between groups (37.8% vs 33.35; P = 0.64) [29]. The recently published Pulmonary Embolism International Thrombolysis (PEITHO) trial is the largest prospective, randomized, double-blind study to date evaluating clinical outcomes in patients receiving thrombolytics for submassive PE [30]. It included 1005 normotensive patients with confirmed acute PE and documented right ventricular strain and elevated troponins; patients with hypotension or hemodynamic collapse were excluded. The primary efficacy end point was the composite of death or hemodynamic collapse within 7 days. The composite end point occurred in 2.6% of patients receiving thrombolysis compared with 5.6% of patients receiving anticoagulation alone (P = 0.02). This difference was largely driven by the reduced incidence of hemodynamic decompensation in the thrombolytic group (1.6% vs 5.0%; P = 0.002), as the incidence of death was similar between groups (1.2% vs 1.8%; P = 0.42). The incidence of major bleeding was significantly higher in patients receiving thrombolysis (6.3% vs 1.2%; P < 0.001), as was the incidence of stroke (2.4% vs 0.2%; P = 0.003) [30]. In the PEITHO trial, the benefit was limited to patients aged < 75 years; this patient group also experienced less intracranial bleeding, though the difference was not statistically significant [30].
Systemic thrombolysis for Acute PE
DOI: 10.1080/21548331.2015.1001302
Table 3. Contraindications to thrombolytics [1]. Major contraindications
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Relative contraindications
Active bleeding Previous intracranial hemorrhage Structural intracranial disease Ischemic stroke (within 3 months) Recent brain or spinal surgery Recent head trauma Bleeding diathesis Recent bleeding Recent surgery Recent invasive procedure Anticoagulation Pregnancy SBP > 180 mm Hg or DBP > 110 mm Hg Ischemic stroke (> 3 months prior) Traumatic cardiopulmonary resuscitation Pericarditis or pericardial fluid Age > 75 years Low body weight (< 60 kg) African-American race Diabetic retinopathy Female gender
Abbreviations: DBP = Diastolic blood pressure; SBP = Systolic blood pressure.
Since the PEITHO trial, two meta-analysis have examined the overall mortality benefit of thrombolysis for submassive PE [31,32]. Marti and colleagues [31] found a reduced risk of early all-cause mortality when using thrombolytics for intermediate risk (eg, submassive) PE versus anticoagulation alone (OR, 0.42; 95% CI, 0.17–1.03). Chatterjee and colleagues [32] evaluated 8 clinical trials (n = 1775), including patients with submassive PE, and found that thrombolysis was associated with lower all-cause mortality (OR, 0.48; 95% CI, 0.25–0.92), as well an increased risk of major bleeding (OR, 3.19; 95% CI, 2.07–4.92) [32]. The investigators noted the mortality benefit seen was largely attributed to the results from the most recent clinical trials (studies published in 2009 or later) [32]. Overall, new evidence suggests that consideration of thrombolysis in patients with submassive PE may be warranted due to improvements in short-term hemodynamic parameters and potential reduction in PE recurrence. However the current evidence on any potential longer term benefit associated with thrombolysis in this patient population remains unclear. Careful consideration of bleeding risks for each patient remains essential, as results from the PEITHO trial indicate a significant increased risk of bleeding with thrombolysis, especially in the older patient population.
Practical considerations
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Clinical trials have found that thrombolytic therapy for acute PE is associated with an overall incidence of major bleeding of 10.4%, and an incidence of intracranial bleeding of 0.5% [11]. This bleeding rate may be lower than what is actually seen in clinical practice, largely due to the strict exclusion criteria seen in most of these clinical trials. Analysis from the International Cooperative Pulmonary Embolism Registry (ICOPER) of patients receiving thrombolytics for acute PE in clinical practice has shown a 21.7% incidence of major bleeding and a 3% incidence of intracranial hemorrhage [33]. A recent case-control study evaluated 62 patients for risk factors associated with bleeding after thrombolysis for PE, with a focus on risk factors available to clinicians at the time of the clinical decision-making process [34]. Risk factors included in the analysis consisted of all the risk factors listed in Table 3 (with the exception of anticoagulation use and female sex) as well as poorly controlled hypertension at baseline, acute myocardial infarction, stool occult blood positive, presence of intra-aortic balloon pump, gastrointestinal bleeding within 3 months, suspected aortic dissection, left heart thrombus, acute pancreatitis, bilirubin > 3 mg/dL, and dementia. The investigators found major bleeding after thrombolysis was associated with low body weight (adjusted OR of 1.18 for each 10 kg below 100 kg; P = 0.035) and presence of ‡ 1 risk factors for bleeding (P = 0.004) in a multivariate analysis [34]. Thrombolytic selection Alteplase, streptokinase, and urokinase have been approved for treatment of acute PE by the US Food and Drug Administration (FDA). Streptokinase and urokinase are nonselective agents; their activity is not enhanced in the presence of fibrin. Streptokinase use is limited due to potential for antigenic reactions, and urokinase use is limited due to practical limitations associated with the availability of unconcentrated formulations [3]. Alteplase is fibrin-selective, resulting in less systemic fibrin generation and thus reduced bleeding risk, and has been the agent most used in clinical practice. Although not FDA approved for treatment of PE, tenecteplase (TNK) has also been studied for this indication and is the thrombolytic agent used in the recently published PEITHO trial [30]. Similar to alteplase, TNK is also fibrinselective with a higher affinity for fibrin and a longer halflife than alteplase. This enables administration via a single bolus dose rather than an infusion as with alteplase. These characteristics make TNK a promising future option for thrombolysis in acute PE.
Risk factors for bleeding Bleeding is the most concerning complication of thrombolytic therapy; if it occurs, it can be devastating. The bleeding risk must be considered when making the decision to administer thrombolytics. Currently, there is no validated riskprediction tool for bleeding with thrombolytic therapy in acute PE. Major and relative contraindications for thrombolytics have been included in consensus guidelines and are listed in Table 3.
Thrombolytic dosing Alteplase, when used for the treatment of acute PE, is recommended at a dose of 100 mg infused over 2 hours intravenously (IV; 10 mg bolus, then 90 mg infused over 2 hours). This short infusion time is preferred to longer infusions due to more rapid thrombolysis and reduced risk of bleeding [1]. In cardiac arrest situations, bolus dosing of the entire alteplase dose (50 or 100 mg) is preferred due to limited drug
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distribution in the setting of impaired perfusion [1]. Tenecteplase, although not FDA approved for the treatment of PE, can be administered as a single bolus dose due to the pharmacokinetic properties discussed previously. The TNK doses (as used in clinical trials) are administered over 5 to 10 seconds and are weight-based as follows: 30 mg for weight < 60 kg; 35 mg for weight 61 to 70 kg; 40 mg for weight 71 to 80 kg; 45 mg for weight 81 to 90 kg; and 50 mg for weight > 90 kg [30]. A few small studies have evaluated the efficacy of a lower weight-based dosing strategy compared with standard dosing of alteplase and have shown potential for similar efficacy and reduced bleeding events [28,35,36]. Goldhaber and colleagues [35] conducted a randomized controlled trial comparing the efficacy of alteplase 0.6 mg/kg IV over 15 minutes (maximum dose of 50 mg) with alteplase 100 mg IV over 2 hours for the primary end point of PE resolution at 14 days. Eighty-seven hemodynamically stable patients were included in the treatment protocol (60 patients treated with bolus alteplase and 27 with standard dosing). At day 14, the mortality rate was 8.3% in the bolus group versus 3.7% in the control group (P = 0.66). One recurrent PE occurred in each treatment group. Eight patients in the bolus group and 6 patients in the control group had major bleeding events (P = 0.35). The China Venous Thromboembolism study group evaluated the efficacy and safety of alteplase 50 mg IV over 2 hours versus 100 mg IV over 2 hours in 118 patients with acute PE [36]. Patients were included in the study if they had acute PE and either hemodynamic instability or massive pulmonary artery obstruction. Overall improvement in right ventricular function, lung perfusion defects, and pulmonary artery obstruction at 24 hours and 14 days was similar between groups in both patients with hemodynamic compromise or with massive pulmonary artery obstruction. Mortality due to PE or bleeding was 2% in the 50-mg group and 6% in the 100 mg-group (P = 0.472), with less bleeding noted in the 50 mg-group (3% vs 10%; P = 0.288) and in patients weighing less than 65 kg (14.8% vs 41.2%; P = 0.049) [36]. Most recently, the MOPETT investigators reviewed the efficacy of half-dose (or ‘safe-dose’) alteplase (50 mg or 0.5 mg/kg IV over 2 hours in patients < 50 kg) versus anticoagulation alone in 121 normotensive patients with symptomatic ‘moderate’ PE. As described previously, the investigators found half-dose alteplase reduced the incidence of pulmonary hypertension at 28 months (P < 0.001), reduced the duration of hospitalization (P < 0.001), and reduced incidence of the composite of death and recurrent PE (P = 0.0489), with no bleeding events in either group [28]. Although application of these results to current practice is limited due to small study sizes, it appears that reduced- dose thrombolysis may allow for similar efficacy, with reduced bleeding risk, when compared with standard doses [28,35-38]. Practical application Thrombolytic therapy is most successful when administered early in the course of acute PE. When using thrombolytics for PE, intravenous unfractionated heparin is the
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anticoagulant of choice [1]. Heparin has a short half-life and an available reversal agent, which are advantageous properties should bleeding occur. Heparin has been used with thrombolytics extensively in clinical trials, whereas other anticoagulants have not been well studied in conjunction with thrombolytic therapy. Heparin should be administered in full therapeutic doses prior to administering thrombolytic therapy. The heparin infusion is most often suspended during infusion of the thrombolytic, though continuation of the heparin infusion may be acceptable in certain patients. If withheld, the activated partial thromboplastin time should be checked immediately following the thrombolytic infusion and every 4 hours as needed until the heparin infusion is able to be restarted. Heparin should be restarted (without a bolus and at the same infusion rate as prior) when the activated partial thromboplastin time is < 80 seconds [1]. Obstacles in clinical practice Providers encounter several obstacles when considering the use of thrombolytics for acute PE. One major obstacle is difficulty evaluating the overall risk–benefit considerations for each patient in the acute setting [3]. This is especially difficult in patients with relative contraindications to thrombolytic therapy but also with significant clinical symptoms associated with the acute PE, and in elderly patients. In addition, many patients’ symptoms may resolve with anticoagulation alone; thus, providers may choose to defer the decision for thrombolysis until each patient’s clinical course can be better determined [3]. If thrombolytic therapy is desired, existing clinical controversies such as the most optimal dosing regimen, especially in patients with lower body weight, is another factor for clinicians to consider [3]. Optimal administration techniques, including whether or not to administer concurrent anticoagulation, is another controversial decision clinicians must make [3]. Other obstacles are associated with the thrombolytic agents themselves, including high cost, necessary time for reconstitution, and limited duration of stability after reconstitution.
Conclusion Limited prospective studies have evaluated thrombolytic therapy for acute PE. Use of thrombolytic therapy for acute PE should always be based on careful risk–benefit analysis, should be considered in the treatment of massive PE, and may be an option for submassive PE. When using thrombolytics for acute PE, alteplase is currently the agent of choice.
Declaration of interest The author reports no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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Systemic thrombolysis for Acute PE
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DOI: 10.1080/21548331.2015.1001302
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pulmonary embolism: a randomized controlled trial. J Thromb Thrombolysis 1995;2:227–9. Becattini C, Agnelli G, Salvi A, et al. TIPES Study Group. Bolus tenecteplase for right ventricle dysfunction in hemodynamically stable patients with pulmonary embolism. Thromb Res 2010;125: e82–6. Fasullo S, Scalzo S, Maringhini G, et al. Six-month echocardiographic study in patients with submassive pulmonary embolism and right ventricle dysfunction: comparison of thrombolysis with heparin. Am J Med Sci 2011;341:33–9. Wan S, Agnelli G, Quinlan DJ, et al. Thrombolysis compared with heparin for the initial treatment of pulmonary embolism: a metaanalysis of the randomized controlled trials. Circulation 2004;110:744–9. Ibrahim SA, Stone RA, Obrosky S, et al. Thrombolytic therapy and mortality in patients with acute pulmonary embolism. Arch Intern Med 2008;168:2183–90. Riera-Mestre A, Jimenez D, Muriel A, et al. Thrombolytic therapy and outcome of patients with an acute symptomatic pulmonary embolism. J Thromb Haemost 2012;10:751–9. Kline JA, Steuerwald MT, Marchick MR, et al. Prospective evaluation of right ventricular function and functional status 6 months after acute submassive pulmonary embolism: frequency of persistent or subsequent elevation in estimated pulmonary artery pressure. Chest 2009;136:1202–10. Sharifi M, Bay C, Skrocki L, et al. Moderate pulmonary embolism treated with thrombolysis (from the “MOPETT” trial). J Cardiol 2013;111:273–7. Kline JA, Nordenholz KE, Courtney DM, et al. Treatment of submassive pulmonary embolism with tenecteplase or placebo: cardiopulmonary outcomes at 3 months: multicenter double-blind, placebo-controlled randomized trial. J Thromb Haemost 2014;12: 459–68. Meyer G, Vicaut E, Danays T, et al. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med 2014;370: 1402–11. Marti C, John G, Konstantinides S, et al. Systemic thrombolytic therapy for acute pulmonary embolism: a systematic review and meta-analysis. Eur Heart J 2014; Epub ahead of print. 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. Goldhaber SZ, Visani L, De Rosa M. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER). Lancet 1999;353:1386–9. Curtis GM, Lam SW, Reddy AJ, Bauer SR. Risk factors associated with bleeding after alteplase administration for pulmonary embolism: a case-control study. Pharmacotherapy 2014;34:818–25. Goldhaber SZ, Agnelli G, Levine MN. Reduced dose bolus alteplase vs. conventional alteplase infusion for pulmonary embolism thrombolysis: an international multicenter randomized trial. Chest 1994;106:718–24. Wang C, Zhai Z, Yang Y, et al. Efficacy and safety of low dose recombinant tissue-type plasminogen activator for the treatment of acute pulmonary thromboembolism: a randomized, multicenter, controlled trial. Chest 2010;137:254–62. Sors H, Pacouret G, Azarian R, et al. Hemodynamic effects of bolus vs. 2-h infusion of alteplase in acute massive pulmonary embolism: a randomized controlled multicenter trial. Chest 1994; 106:712–17. Le Conte P, Huchet L, Trewick D, et al. Efficacy of alteplase thrombolysis for ED treatment of pulmonary embolism with shock. Am J Emerg Med 2003;21:438–40.
REVIEW
Systemic thrombolysis for acute pulmonary embolism Billie Bartel
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Avera McKennan Hospital and University Health Center, Sioux Falls, SD, USA Abstract
Keywords:
Acute pulmonary embolism is a frequent cause of hospitalization and is associated with a wide range of symptom severity. Anticoagulants are the mainstay of treatment for acute pulmonary embolism; however, in patients with massive or submassive pulmonary embolism, advanced therapy with thrombolytics may be considered. The decision to use thrombolytic therapy for acute pulmonary embolism should be based on careful risk–benefit analysis for each patient, including risk of morbidity and mortality associated with the embolism and risk of bleeding associated with the thrombolytic. Alteplase is currently the thrombolytic agent most studied and with the most clinical experience for this indication, although the most appropriate dose remains controversial, especially in patients with low body weight. When considering thrombolysis, unfractionated heparin is the preferred initial anticoagulant due to its short duration of action and its reversibility should bleeding occur.
Thrombolytic, fibrinolytic, pulmonary embolism, alteplase History Received 11 June 2014 Revised 8 July 2014 Accepted 9 July 2014 Published online 6 January 2015
Introduction
Materials and methods
Acute pulmonary embolism (PE) is a frequent cause of hospital admissions. Acute PE carries an overall early mortality rate of approximately 10%, and patients with acute PE can present with a wide range of symptom severity. The majority of patients present with a normal blood pressure and preserved right ventricular function. The clinical prognosis for these patients is generally very good, with a low estimated mortality rate [1-3]. Evidence of right ventricular dysfunction with a normal blood pressure, termed a submassive PE, occurs in approximately 30% to 60% of patients with acute PE and carries an increased risk of adverse outcomes and early mortality [4-6]. An acute PE is termed massive if a patient is experiencing hypotension, shock, cardiac arrest, or respiratory failure due to the embolism. A massive PE occurs in approximately 5% of patients and carries an early mortality rate of 30%; mortality may be as high as 70% if cardiopulmonary arrest occurs [1-3,7]. Prompt initiation of anticoagulation is the cornerstone of therapy for acute PE. In patients with massive or submassive PE, advanced therapy with thrombolysis (also termed fibrinolysis), catheter-assisted embolectomy, or surgical embolectomy may be treatment options in addition to anticoagulation. This article reviews the current evidence regarding the use of systemic intravenous thrombolysis for massive and submassive PE, and discusses practical considerations when using systemic thrombolytics for this indication.
To assess and evaluate the current evidence for thrombolysis in acute PE, a literature search was conducted using PubMed and the following search terms: pulmonary embolism in combination with thrombolytic, fibrinolytic, and alteplase. Reference lists from identified articles were reviewed to ensure that a comprehensive literature search was completed. Thirtytwo primary literature studies are included in this review.
Indications for thrombolysis The decision to use thrombolytic therapy for acute PE should be based on careful risk–benefit analysis for each patient. Current clinical guidelines recommend the use of thrombolytics for massive PE in the absence of contraindications (Table 1). The utility of thrombolytics in patients with submassive PE has been controversial (Table 2), although new data have been published since these guidelines were last updated [1,8,9]. Massive pulmonary embolism A massive PE is associated with an increased risk of death, with mortality rates up to 70% if untreated. Mortality can be reduced by > 50% in patients with prompt initiation of therapy [1]. Thrombolytic therapy should be considered as a therapeutic option in these high-risk patients due to faster resolution of obstruction compared with treatment with anticoagulants (eg, heparin) alone [1]. Randomized clinical trials
Correspondence: Billie Bartel, PharmD, Avera McKennan Hospital and University Health Center, 1325 S Cliff Avenue, Sioux Falls, SD 57105, USA. Tel: +1 605 322 8559. E-mail: [email protected] 2015 Informa UK Ltd.
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DOI: 10.1080/21548331.2015.1001302
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Table 1. Consensus guideline recommendations for thrombolysis in massive PE [1,8,9]. Consensus guideline 2012 American College of Chest Physicians 2011 American Heart Association 2008 European Society of Cardiology
Recommendation Consider in patients with acute PE associated with hypotension (SBP < 90 mm Hg) and without a high risk of bleeding over anticoagulation alone [1] Reasonable for patients with massive PE and acceptable risk of bleeding complications [8] Should be used in patients with high-risk PE presenting with cardiogenic shock and/or persistent hypotension [9]
Level of recommendation Grade 2C Class IIa; level of evidence, B Class I; level of evidence, A
Abbreviations: PE = Pulmonary embolism; SBP = Systolic blood pressure.
Table 2. Consensus guideline recommendations for thrombolysis in submassive PE [1,8,9]. Consensus guideline
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2012 American College of Chest Physicians 2011 American Heart Association
2008 European Society of Cardiology
Recommendation Consider in patients with PE with a low risk of bleeding and high risk of developing hypotension [1] Consider for patients with submassive PE with clinical evidence of adverse prognosis (new hemodynamic instability, worsening respiratory insufficiency, severe RV dysfunction, or major myocardial necrosis) and a low risk of bleeding [8] Consider in patients with intermediate-risk PE (evidence of RV dysfunction or myocardial injury) [9]
Level of recommendation Grade 2C Class IIb; level of evidence, C
Class IIb; level of evidence, B
Abbreviations: PE = Pulmonary embolism; RV = Right ventricle.
have found that thrombolytic therapy for massive PE improves hemodynamic parameters such as pulmonary artery hemodynamic measurements, arteriovenous oxygenation, pulmonary perfusion, and echocardiographic assessments at 24 hours when compared with anticoagulation with heparin [10-24]. When considering improvements in overall patient outcomes associated with thrombolysis, a meta-analysis conducted by Wan and colleagues [24] has summarized most of the original research to date. This meta-analysis included randomized trials comparing thrombolysis with heparin and assessing ‡ 1 clinical outcome, including PE, bleeding, and death. The primary efficacy outcome was the composite of recurrent PE or death. Secondary outcomes included the individual components of the primary outcome and safety outcomes, including major and nonmajor bleeding and intracranial hemorrhage. The meta-analysis included five studies evaluating patients with massive PE [24]. Analysis of these studies found a significant reduction in PE or death with thrombolytic therapy (9.4% vs 19.0%; odds ratio [OR], 0.45; 95% CI, 0.22–0.92). When evaluating PE and death individually, no significant difference was found (PE: 3.9% vs 7.1%; OR, 0.61; 95% CI, 0.23–1.62; death: 6.2% vs 12.7%; OR, 0.47; 95% CI, 0.2–1.1). No difference in major bleeding was noted (21.9% vs 11.9%; OR, 1.98; 95% CI, 1–3.92). Since Wan and colleagues’ [24] meta-analysis in 2004, only retrospective evaluations have further assessed the impact of thrombolytics on patient outcomes with massive PE. One retrospective cohort study conducted by Ibrahim and colleagues [25] evaluated the association between thrombolytics and 30-day mortality in 15 166 patients with a diagnosis of acute PE. When comparing propensity score-adjusted mortality, the 30-day mortality risk associated with thrombolysis varied with disease severity and was 0.7 (P = 0.30) for patients in the highest quintile of the score distribution. Age, sex, race, specific comorbidities, hemodynamic variables, and
specific laboratory values, including markers that may indicate shock, were included in the propensity scoring system; thus, the highest quintile most closely represented patients with massive PE. Riera-Mestre and colleagues [26] conducted an international retrospective cohort study of 15 944 patients with symptomatic acute PE identified from the multicenter international Computerized Registry of Patients with Venous Thromboembolism (RIETE), and evaluated the association between thrombolytics and all-cause mortality during the first 3 months after diagnosis using a matched-paired analysis [26]. In the subgroup of patients with hypotension (systolic blood pressure < 100 mm Hg), the investigators did not find thrombolytics to be associated with a lower risk of death (P = 0.37) [26]. Overall application of these more recent retrospective analyses has the potential limitations associated with the propensity analysis models and potential for exclusions of existing cofounders. In each of these analyses, patients with massive PE were only a small subgroup of the entire population analyzed, which also limits the interpretation of the study results. Current evidence suggests a hemodynamic and patient outcome benefit with thrombolysis in patients with massive PE compared with treatment with anticoagulation alone, although large prospective clinical trials evaluating patient outcomes specific to this subset of PE patients are lacking. Submassive pulmonary embolism Use of thrombolytics for submassive PE has been limited due to inconclusive evidence from clinical trials, though recent publications have prompted further consideration for use in this patient population. The Management Strategies and Prognosis of Pulmonary Embolism-3 (MAPPET-3) investigators conducted a randomized controlled clinical trial evaluating the composite primary end point of in-hospital mortality or clinical deterioration requiring escalation of treatment
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(defined as vasopressor use, rescue thrombolysis, mechanical ventilation, cardiopulmonary resuscitation, or emergency surgical embolectomy) in 256 patients with hemodynamically stable acute PE and either pulmonary hypertension or right ventricular dysfunction receiving thrombolytics plus heparin versus heparin alone [10]. The investigators found a significant improvement in the primary outcome in patients receiving thrombolytics (11% vs 24.6%; P = 0.006), though no difference in mortality alone (3.4% vs 2.2%; P = 0.71). Rates of major bleeding were similar between groups (0.8% vs 3.6%; P = 0.29), and no fatal or intracerebral bleeding occurred in either group. One notable limitation of this study is that its design allowed treating physicians to break randomization if the patient’s clinical condition was deteriorating; patients receiving heparin alone were 3 times more likely to break protocol and receive thrombolytic therapy when compared with the thrombolytic group [10]. Two small studies evaluating the use of thrombolytics in patients with submassive PE have demonstrated improvements in right ventricular function in patients receiving thrombolysis [22,23]. The Tenecteplase Italian Pulmonary Embolism Study (TIPES) was a multicenter, randomized, double-blind, placebo-controlled study evaluating the effect of thrombolytics versus heparin on right ventricle dysfunction in 58 patients [22]. Right ventricular dysfunction was assessed by echocardiography at 24 hours, and the investigators found the reduction in right to left ventricle end-diastolic dimension ratio was greater in patients randomized to thrombolytics (P = 0.04). Fasullo and colleagues [23] conducted a prospective, randomized, double-blind, placebo-controlled study of thrombolytics versus heparin in 72 consecutive patients with a first episode of submassive PE with right ventricle dysfunction and normal blood pressure. The primary efficacy end point was right ventricle dysfunction, assessed by echocardiograph, early (at 24 hours) and at 6 months. Thrombolysis resulted in significant early improvement of right ventricle function, and this improvement was also observed at the 6-month follow-up. Use of thrombolytics for submassive PE may also improve other hemodynamic parameters. In a prospective study of 200 patients with submassive PE, Kline and colleagues [27] found that in the 162 patients (out of 180 survivors [90]) who were available for follow-up at 6 months, pulmonary artery systolic pressure increased in 27% of patients treated with heparin alone versus 0% of patients treated with thrombolytics. Nearly half of the patients with increased pulmonary artery systolic pressure had symptoms consistent with New York Heart Association class III heart failure or exercise intolerance on a 6-minute walk test. More recently, the Moderate Pulmonary Embolism Treated with Thrombolysis (MOPETT) trial reviewed the effect of half-dose thrombolysis versus anticoagulation alone (enoxaparin or heparin) on pulmonary hypertension in 121 normotensive patients with symptomatic ‘moderate’ PE [28]. Patients were considered to have moderate PE if they had signs and symptoms of PE (‡ 2 of the following: chest pain, tachypnea, tachycardia, dyspnea, cough, oxygen desaturation, and elevated jugular venous pressure) plus > 70% involvement of thrombus in ‡ 2 lobar or left or right main pulmonary arteries on computed tomographic pulmonary angiogram, or by high
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probability ventilation/perfusion scan showing mismatch in ‡ 2 lobes. Evidence of right ventricular dysfunction or of elevation of biomarkers of right ventricular injury (troponin or brain natriuretic peptide) was not required for inclusion in the study. At 28 months, pulmonary hypertension developed in 16% of patients receiving thrombolytics versus 57% of patients receiving anticoagulation alone (P < 0.001). Thrombolysis was also associated with improvement in secondary end points including duration of hospitalization (2.2 vs 4.9 days; P < 0.001) and combination of death and recurrent PE (1.6% vs 10%; P = 0.0489), although no significant difference was seen in rate of death and recurrent PE when assessed independently (1.6% vs 5%; P = 0.30; 0% vs 5%; P = 0.08, respectively). No bleeding occurred in either group [28]. The Tenecteplase or Placebo: Cardiopulmonary Outcomes At Three Months (TOPCOAT) trial evaluated the composite of mortality and morbidity outcomes associated with administration of thrombolytics for submassive PE [29]. This randomized, double-blind, placebo-controlled trial included 83 patients with acute PE and normal blood pressure with evidence of right ventricular strain (as evidenced by echocardiography or elevated troponin I or T or elevated brain natriuretic peptide levels). The primary outcome assessed was the composite of death, circulatory shock, intubation, or major bleeding at 5 days, or recurrent PE, poor functional capacity, or health-related quality of life at 90 days. The overall composite end point occurred in 15% of the thrombolytic group and 37% of the placebo group (P = 0.017). Early adverse outcomes (at 5 days) occurred in one patient in the thrombolytic group and three patients in the placebo group, whereas late adverse outcomes (at 90 days) occurred in 5 and 13 patients in each group, respectively. Although overall functional capacity was improved at 90 days in patients receiving thrombolytics, incidence of right ventricular dilation or hypokinesis did not differ between groups (37.8% vs 33.35; P = 0.64) [29]. The recently published Pulmonary Embolism International Thrombolysis (PEITHO) trial is the largest prospective, randomized, double-blind study to date evaluating clinical outcomes in patients receiving thrombolytics for submassive PE [30]. It included 1005 normotensive patients with confirmed acute PE and documented right ventricular strain and elevated troponins; patients with hypotension or hemodynamic collapse were excluded. The primary efficacy end point was the composite of death or hemodynamic collapse within 7 days. The composite end point occurred in 2.6% of patients receiving thrombolysis compared with 5.6% of patients receiving anticoagulation alone (P = 0.02). This difference was largely driven by the reduced incidence of hemodynamic decompensation in the thrombolytic group (1.6% vs 5.0%; P = 0.002), as the incidence of death was similar between groups (1.2% vs 1.8%; P = 0.42). The incidence of major bleeding was significantly higher in patients receiving thrombolysis (6.3% vs 1.2%; P < 0.001), as was the incidence of stroke (2.4% vs 0.2%; P = 0.003) [30]. In the PEITHO trial, the benefit was limited to patients aged < 75 years; this patient group also experienced less intracranial bleeding, though the difference was not statistically significant [30].
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DOI: 10.1080/21548331.2015.1001302
Table 3. Contraindications to thrombolytics [1]. Major contraindications
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Relative contraindications
Active bleeding Previous intracranial hemorrhage Structural intracranial disease Ischemic stroke (within 3 months) Recent brain or spinal surgery Recent head trauma Bleeding diathesis Recent bleeding Recent surgery Recent invasive procedure Anticoagulation Pregnancy SBP > 180 mm Hg or DBP > 110 mm Hg Ischemic stroke (> 3 months prior) Traumatic cardiopulmonary resuscitation Pericarditis or pericardial fluid Age > 75 years Low body weight (< 60 kg) African-American race Diabetic retinopathy Female gender
Abbreviations: DBP = Diastolic blood pressure; SBP = Systolic blood pressure.
Since the PEITHO trial, two meta-analysis have examined the overall mortality benefit of thrombolysis for submassive PE [31,32]. Marti and colleagues [31] found a reduced risk of early all-cause mortality when using thrombolytics for intermediate risk (eg, submassive) PE versus anticoagulation alone (OR, 0.42; 95% CI, 0.17–1.03). Chatterjee and colleagues [32] evaluated 8 clinical trials (n = 1775), including patients with submassive PE, and found that thrombolysis was associated with lower all-cause mortality (OR, 0.48; 95% CI, 0.25–0.92), as well an increased risk of major bleeding (OR, 3.19; 95% CI, 2.07–4.92) [32]. The investigators noted the mortality benefit seen was largely attributed to the results from the most recent clinical trials (studies published in 2009 or later) [32]. Overall, new evidence suggests that consideration of thrombolysis in patients with submassive PE may be warranted due to improvements in short-term hemodynamic parameters and potential reduction in PE recurrence. However the current evidence on any potential longer term benefit associated with thrombolysis in this patient population remains unclear. Careful consideration of bleeding risks for each patient remains essential, as results from the PEITHO trial indicate a significant increased risk of bleeding with thrombolysis, especially in the older patient population.
Practical considerations
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Clinical trials have found that thrombolytic therapy for acute PE is associated with an overall incidence of major bleeding of 10.4%, and an incidence of intracranial bleeding of 0.5% [11]. This bleeding rate may be lower than what is actually seen in clinical practice, largely due to the strict exclusion criteria seen in most of these clinical trials. Analysis from the International Cooperative Pulmonary Embolism Registry (ICOPER) of patients receiving thrombolytics for acute PE in clinical practice has shown a 21.7% incidence of major bleeding and a 3% incidence of intracranial hemorrhage [33]. A recent case-control study evaluated 62 patients for risk factors associated with bleeding after thrombolysis for PE, with a focus on risk factors available to clinicians at the time of the clinical decision-making process [34]. Risk factors included in the analysis consisted of all the risk factors listed in Table 3 (with the exception of anticoagulation use and female sex) as well as poorly controlled hypertension at baseline, acute myocardial infarction, stool occult blood positive, presence of intra-aortic balloon pump, gastrointestinal bleeding within 3 months, suspected aortic dissection, left heart thrombus, acute pancreatitis, bilirubin > 3 mg/dL, and dementia. The investigators found major bleeding after thrombolysis was associated with low body weight (adjusted OR of 1.18 for each 10 kg below 100 kg; P = 0.035) and presence of ‡ 1 risk factors for bleeding (P = 0.004) in a multivariate analysis [34]. Thrombolytic selection Alteplase, streptokinase, and urokinase have been approved for treatment of acute PE by the US Food and Drug Administration (FDA). Streptokinase and urokinase are nonselective agents; their activity is not enhanced in the presence of fibrin. Streptokinase use is limited due to potential for antigenic reactions, and urokinase use is limited due to practical limitations associated with the availability of unconcentrated formulations [3]. Alteplase is fibrin-selective, resulting in less systemic fibrin generation and thus reduced bleeding risk, and has been the agent most used in clinical practice. Although not FDA approved for treatment of PE, tenecteplase (TNK) has also been studied for this indication and is the thrombolytic agent used in the recently published PEITHO trial [30]. Similar to alteplase, TNK is also fibrinselective with a higher affinity for fibrin and a longer halflife than alteplase. This enables administration via a single bolus dose rather than an infusion as with alteplase. These characteristics make TNK a promising future option for thrombolysis in acute PE.
Risk factors for bleeding Bleeding is the most concerning complication of thrombolytic therapy; if it occurs, it can be devastating. The bleeding risk must be considered when making the decision to administer thrombolytics. Currently, there is no validated riskprediction tool for bleeding with thrombolytic therapy in acute PE. Major and relative contraindications for thrombolytics have been included in consensus guidelines and are listed in Table 3.
Thrombolytic dosing Alteplase, when used for the treatment of acute PE, is recommended at a dose of 100 mg infused over 2 hours intravenously (IV; 10 mg bolus, then 90 mg infused over 2 hours). This short infusion time is preferred to longer infusions due to more rapid thrombolysis and reduced risk of bleeding [1]. In cardiac arrest situations, bolus dosing of the entire alteplase dose (50 or 100 mg) is preferred due to limited drug
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distribution in the setting of impaired perfusion [1]. Tenecteplase, although not FDA approved for the treatment of PE, can be administered as a single bolus dose due to the pharmacokinetic properties discussed previously. The TNK doses (as used in clinical trials) are administered over 5 to 10 seconds and are weight-based as follows: 30 mg for weight < 60 kg; 35 mg for weight 61 to 70 kg; 40 mg for weight 71 to 80 kg; 45 mg for weight 81 to 90 kg; and 50 mg for weight > 90 kg [30]. A few small studies have evaluated the efficacy of a lower weight-based dosing strategy compared with standard dosing of alteplase and have shown potential for similar efficacy and reduced bleeding events [28,35,36]. Goldhaber and colleagues [35] conducted a randomized controlled trial comparing the efficacy of alteplase 0.6 mg/kg IV over 15 minutes (maximum dose of 50 mg) with alteplase 100 mg IV over 2 hours for the primary end point of PE resolution at 14 days. Eighty-seven hemodynamically stable patients were included in the treatment protocol (60 patients treated with bolus alteplase and 27 with standard dosing). At day 14, the mortality rate was 8.3% in the bolus group versus 3.7% in the control group (P = 0.66). One recurrent PE occurred in each treatment group. Eight patients in the bolus group and 6 patients in the control group had major bleeding events (P = 0.35). The China Venous Thromboembolism study group evaluated the efficacy and safety of alteplase 50 mg IV over 2 hours versus 100 mg IV over 2 hours in 118 patients with acute PE [36]. Patients were included in the study if they had acute PE and either hemodynamic instability or massive pulmonary artery obstruction. Overall improvement in right ventricular function, lung perfusion defects, and pulmonary artery obstruction at 24 hours and 14 days was similar between groups in both patients with hemodynamic compromise or with massive pulmonary artery obstruction. Mortality due to PE or bleeding was 2% in the 50-mg group and 6% in the 100 mg-group (P = 0.472), with less bleeding noted in the 50 mg-group (3% vs 10%; P = 0.288) and in patients weighing less than 65 kg (14.8% vs 41.2%; P = 0.049) [36]. Most recently, the MOPETT investigators reviewed the efficacy of half-dose (or ‘safe-dose’) alteplase (50 mg or 0.5 mg/kg IV over 2 hours in patients < 50 kg) versus anticoagulation alone in 121 normotensive patients with symptomatic ‘moderate’ PE. As described previously, the investigators found half-dose alteplase reduced the incidence of pulmonary hypertension at 28 months (P < 0.001), reduced the duration of hospitalization (P < 0.001), and reduced incidence of the composite of death and recurrent PE (P = 0.0489), with no bleeding events in either group [28]. Although application of these results to current practice is limited due to small study sizes, it appears that reduced- dose thrombolysis may allow for similar efficacy, with reduced bleeding risk, when compared with standard doses [28,35-38]. Practical application Thrombolytic therapy is most successful when administered early in the course of acute PE. When using thrombolytics for PE, intravenous unfractionated heparin is the
Hosp Pract, 2015; 43(1):22–27
anticoagulant of choice [1]. Heparin has a short half-life and an available reversal agent, which are advantageous properties should bleeding occur. Heparin has been used with thrombolytics extensively in clinical trials, whereas other anticoagulants have not been well studied in conjunction with thrombolytic therapy. Heparin should be administered in full therapeutic doses prior to administering thrombolytic therapy. The heparin infusion is most often suspended during infusion of the thrombolytic, though continuation of the heparin infusion may be acceptable in certain patients. If withheld, the activated partial thromboplastin time should be checked immediately following the thrombolytic infusion and every 4 hours as needed until the heparin infusion is able to be restarted. Heparin should be restarted (without a bolus and at the same infusion rate as prior) when the activated partial thromboplastin time is < 80 seconds [1]. Obstacles in clinical practice Providers encounter several obstacles when considering the use of thrombolytics for acute PE. One major obstacle is difficulty evaluating the overall risk–benefit considerations for each patient in the acute setting [3]. This is especially difficult in patients with relative contraindications to thrombolytic therapy but also with significant clinical symptoms associated with the acute PE, and in elderly patients. In addition, many patients’ symptoms may resolve with anticoagulation alone; thus, providers may choose to defer the decision for thrombolysis until each patient’s clinical course can be better determined [3]. If thrombolytic therapy is desired, existing clinical controversies such as the most optimal dosing regimen, especially in patients with lower body weight, is another factor for clinicians to consider [3]. Optimal administration techniques, including whether or not to administer concurrent anticoagulation, is another controversial decision clinicians must make [3]. Other obstacles are associated with the thrombolytic agents themselves, including high cost, necessary time for reconstitution, and limited duration of stability after reconstitution.
Conclusion Limited prospective studies have evaluated thrombolytic therapy for acute PE. Use of thrombolytic therapy for acute PE should always be based on careful risk–benefit analysis, should be considered in the treatment of massive PE, and may be an option for submassive PE. When using thrombolytics for acute PE, alteplase is currently the agent of choice.
Declaration of interest The author reports no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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DOI: 10.1080/21548331.2015.1001302
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