Controversies of Thrombolytics for Pulmonary Embolism

Author: Brit Long, MD (@long_brit, EM Chief Resident at SAUSHEC, USAF) // Edited by: Jamie Santistevan, MD (@Jamie_Rae_EMdoc, EM Resident, University of Wisconsin) and Alex Koyfman, MD (@EMHighAK, EM Attending Physician, UTSW / Parkland Memorial Hospital)

Pulmonary embolism (PE) is a disease with significant morbidity and mortality, with an annual incidence of 100,000 cases in the U.S. which increases with age, from 1 per 1500 in early life to 1 in 300 per year above age 80 years.^1,2 As providers know, the clinical presentation varies, with up to 25% of patients experiencing sudden death, while other patients with large thrombus burden experiencing few symptoms.³

The American Heart Association (AHA) and European Society of Cardiology (ESC) classify acute pulmonary embolism into three different categories: non-massive, submassive, and massive. Acute management and treatment is based on the patient, vital signs, and signs of clinical shock/instability. ^4,5 Mortality for PE can reach 17% in the first three months,⁶ but rates of mortality in massive PE reach 30-50%.^7,8 Increased mortality is seen in patients older than 70 years and those with congestive heart failure, chronic obstructive pulmonary disease, cancer, presence of one lung, hypotension, tachypnea, hypoxia, altered mental status, renal failure, prior cerebrovascular accident (CVA), right ventricular (RV) dysfunction, and elevated cardiac biomarkers.^9-17

The benefits of thrombolysis is established for massive pulmonary embolism,¹⁸ but the use of thrombolytics for submassive PE is controversial in the literature due to different definitions of submassive PE, different outcomes and definitions of benefit, and the risk of life threatening hemorrhage. Thrombolytic use may reduce intravascular thrombus size and pulmonary resistance; however, there is risk of major bleeding, including intracerebral hemorrhage (ICH). Thus, the conundrum for physicians and patients.

Definitions of PE: Massive and Submassive

The definitions for massive PE, submassive PE, and nonmassive PE are shown in Table 1. ^5,19 Unfortunately, many guidelines classify acute PE using different nomenclature including non-massive or low-risk, submassive or moderate/intermediate-risk, and massive or high-risk. We will use non-massive, submassive, and massive for classification of PE in this post.

Table 1 – PE Definitions and Criteria^4,5,19,23

Submassive PE accounts for approximately 20% of all PE. Though mortality is 5%, morbidity can be severe, with increased risk of pulmonary hypertension, impaired quality of life, persistent RV dysfunction, and recurrent thrombus formation.^17-19

Current Guidelines

There are several guidelines for thrombolytic use in PE from the American Heart Association (AHA), The American College of Chest Physicians (ACCP), European Heart Association (EHA), and The American College of Emergency Physicians (ACEP), which are summarized in Table 2.^4,5,19,23

Table 2 – Thrombolytic use in submassive and massive PE^4,5,19,23

Treatments

Thrombolytics include alteplase, tenecteplase, and streptokinase. Before providing a thrombolytic medication, review the contradictions and discontinue heparin. Contraindications include prior intracranial hemorrhage (ICH), known structural intracranial cerebrovascular disease, suspected aortic dissection, known malignant intracranial neoplasm, ischemic stroke within three months, recent surgery encroaching on the brain or spinal cord, and recent closed-head or facial trauma with fracture or intracerebral injury.

Alteplase can be given as a full bolus at 10mg IV, followed by 90mg IV over 2 hours for patients greater than 65kg. For patients less than 65kg, adjust dosing so the medication does not exceed 1.5mg/kg. Half dose treatment can also be used, with alteplase given at 50mg IV bolus. Tenecteplase is dosed as a bolus, but it is not FDA approved for PE. Dosing for tenecteplase is weight-adjusted, with an IV bolus of 30-50mg over 5 seconds with a 5mg increase every 10kg from 60kg to 90kg.^4,5

PE and Cardiac Arrest – Thrombolytics

Patients with cardiac arrest provide an opportunity for bedside ultrasound (US) if suspecting PE. Evaluation of RV size and function is vital in these circumstances. If findings on US are consistent with PE such as RV dysfunction and/or enlargement, consideration should be given for systemic thrombolysis, catheter-directed thrombolysis, or surgical embolectomy. Cardiothoracic surgery should be consulted.^4,5,28,29

Massive PE – Thrombolytics

Thrombolysis is recommended for massive PE, as well as for patients undergoing cardiopulmonary resuscitation with US evidence of massive PE. Most guidelines state thrombolysis in patients with hemodynamic instability and massive PE is acceptable.^4,5,19,23 A meta-analysis including 154 patients with massive PE found thrombolysis decreased the risk of death and recurrent PE from 19% to 9.4%, with an odds ratio of 0.45 (95% CI 0.22 to 0.9).⁵ For massive PE, the NNT to prevent recurrent PE or death with thrombolysis was found to be 10. The number needed to harm (NNH) was 8, however.³¹ A separate study by Thabut et al. estimated the number needed to harm to be 17.³²

Submassive PE – Thrombolytics

Several recent studies and meta-analyses have evaluated the use of thrombolytics in submassive PE. Of note, these studies vary in their outcomes and definitions for PE.^31,32 The MAPPET-3 trial in 2002 was a double blinded, randomized clinical trial including 256 patients with PE and pulmonary hypertension or RV dysfunction, but otherwise stable. Patients were given heparin with 100mg of alteplase or heparin and placebo, with a primary end point of in-hospital death or clinical deterioration. No difference was found for mortality, but for patients treated with heparin alone, more cases of deterioration were found (24.6% compared to 10.2%, P=0.004). No change in bleeding was found between groups.³³

The MOPPET trial in 2013 was a single center, unblinded randomized trial with 121 patients with PE, but this study differs in that it used half dose thrombolytics. This study is arguably the best supporter of thrombolytic use in PE. These patients had RV dysfunction, and these patients demonstrated greater rates of tachypnea, hypoxia, and tachycardia, potential signs of clinical decompensation. The moderate-risk PE patients were defined as > 70% thrombus in the lobar or main pulmonary arteries (by computed tomographic pulmonary angiography), rather than using biomarkers or RV dysfunction. The investigators used moderate-risk PE, instead of submassive PE. However, these patients had smaller incidence of RV enlargement (21%) and RV dysfunction (6%). The interventional group received thrombolytics at half dose, or 50mg alteplase, rather than full dose. The investigators used an anatomical definition of submassive PE based on the extent of thrombus. The primary outcome of pulmonary hypertension, as defined by echocardiography at 28 months, was decreased in the thrombolytic group (16% of patients vs. 57%, P < 0.001, NNT 2). No bleeding was found in either group, which brings in to question the quality of data collection. Unfortunately no functional outcome was assessed, and no short-term outcomes were evaluated. This 41% difference in the primary endpoint is suspicious due to use of surrogate outcomes, rather than direct patient outcome. The investigators did not use symptoms plus echocardiographic findings, but echocardiographic findings alone. Evaluating pulmonary hypertension may reflect quality of life and exercise tolerance, but this is not for certain.³⁴

The PEITHO trial is the largest double-blinded multicenter randomized control trial to date on submassive PE with 1006 patients which included patients with confirmed PE, abnormal RV on echocardiography or CT, and a positive troponin. Patients were randomized to heparin and placebo versus heparin plus weight-based tenecteplase bolus. The primary endpoint included death or hemodynamic collapse after 7 days, which was reduced in the thrombolytic group (2.6% vs. 5.6%, OR 0.44, 95% CI 0.23-0.87, P=0.02), but with an overall difference in hemorrhage of 9% between the groups. Those given thrombolytics also displayed 2% greater incidence of ICH. Major bleeding risk was greatly increased in patients over 75 years.³⁵

The TOPCOAT trial evaluated 83 patients with submassive PE randomized to tenecteplase with heparin or placebo with heparin. A short-term endpoint of death, need for intubation, or surgical thrombectomy was evaluated at 5 days, and the patients returned at 6 weeks for repeat echocardiogram and 6 minute walk test. Patient perception of wellness was measured. Thrombolytic use was associated with higher probability of favorable composite outcome. At three months, composite outcomes of recurrent PE or poor functional capacity of SF 36 score were assessed. Unfortunately, the only independent variable in the study statistically significant was self-assessment of health at 90 days using SF-36 (a survey used for a variety of disease endpoints).³⁶

Several meta-analyses have evaluated thrombolytic use in submassive PE. These meta-analyses have included the prior mentioned studies. Chatterjee in JAMA evaluated mortality benefits and bleeding risks in hemodynamically stable patients with RV dysfunction receiving thrombolysis. The analysis evaluated 2115 patients, finding a number need to harm (NNH) of 18 for major bleeding, which was not significant for patients less than 65 years, with a number needed to treat (NNT) of 59 for all-cause mortality benefit. The absolute risk reduction for mortality was 1.12%. The included studies have significant heterogeneity with varying definitions of instability, bleeding, RV dysfunction, and medication dosing.³⁷ Nakamura et al. conducted a meta-analysis of 6 studies with 1510 patients, finding a larger absolute risk difference for death of 1.6% (not significant).³⁸ The Cochrane database conducted a systematic review of 18 studies with 2197 patients, but the researchers state the low quality of evidence, large heterogeneity, and significant bias limits providers. Thrombolytics were associated with reduced odds of death (OR 0.57 with 95% CI 0.29-0.89), and higher rates of major and minor bleeding (OR 2.90 with 95% CI 1.95-4.31).³⁹

A fourth meta-analysis found a significant mortality difference for patients given thrombolytics, which disappeared when the massive PE patients were removed from analysis. A significant increase in rates of major bleeding was found in the thrombolytic group.⁴⁰ One meta-analysis evaluated thrombolytics versus anticoagulation in 1247 patients with submassive PE. This study found a significant reduction in recurrent PE or death (OR 0.37, 95% CI 0.21-0.66), with a significant increase in non-major bleeding (OR 4.12, 95% CI 2.37-7.17). However, major bleeding was not increased.⁴¹ All of these meta-analyses include studies with significant heterogeneity and differing definitions of submassive PE.

Catheter-Directed Treatment

Catheter-directed thrombolysis utilizes a catheter to direct thrombolytics with ultrasound assistance. A 2014 industry-sponsored study evaluated 59 patients with acute PE and RV enlargement based on echocardiogram, with patients randomized to ultrasound-directed thrombolytic with unfractionated heparin and heparin alone. RV dilatation at 24 hours was improved in the catheter-directed thrombolytic group. No bleeding complications were found in the intervention group. ²⁸ The SEATTLE II trial was a multicenter, single-arm trial which evaluated US-facilitated, catheter-directed, low-dose thrombolysis. Investigators included 31 patients with massive PE and 119 patients with submassive PE. Treatment decreased RV dilatation, reduced pulmonary hypertension, decreased clot burden, and minimized risk of ICH. One patient suffered major bleeding with a groin hematoma and transient hypotension. ²⁹

What should the emergency physician do?

For the patient with massive PE, the AHA, ACCP, EHA, and ACEP recommend thrombolytics.^4,5,19,23 Literature supports thrombolytic use in the patient with submassive PE to reduce long-term pulmonary hypertension, but increased bleeding risk is present.

TOPCOAT and MOPPET demonstrate a benefit in long-term outcomes when using thrombolytics in patients with submassive PE. The question is whether the benefits provided to the patient outweigh the risk of major bleeding, specifically ICH at 2%. Studies have utilized different primary outcomes, so how patients may truly benefit is uncertain, except for long-term pulmonary hypertension.^34,36 Patients with no prior lung disease and ample pulmonary reserve may show little benefit with thrombolytics, while the patient with conditions such as heart failure or obstructive lung disease may have greater benefit but at the same time increased risk for bleeding with thrombolytics, as demonstrated in the PEITHO trial.³⁵ The trials also utilize differing protocols and doses. The risk of utilizing thrombolytics is major bleeding, particularly ICH. PEITHO demonstrated a bleeding rate of 11.5% with full dose tenecteplase, compared to 2.4% in the heparin alone group. However, this trial utilized heparin drips targeting aPTT levels of 2-2.5 times the upper limit of normal with full dose thrombolytics.³⁵ The JAMA meta-analysis found a NNH of 18 for major bleeding (increased risk in those over 65).³⁷ No increased risk of bleeding was present in patients less than 65 years.^33-41

Shared Decision-Making

In submassive PE, the benefits and risks of bleeding should be discussed in a shared decision-making model with the patient, family, and admitting team, with thrombolytics considered on a case-by-case basis. The AHA, EHA, and ACCP support thrombolytics in patients with submassive PE and low bleeding risk.^4,5,19

1) Patient factors including comorbidities, age, medications, and independence/functional ability must be taken into account. Patients over 65 years of age or with significant comorbidities have significant increased bleeding risk compared to younger patients.

2) The absence of contraindications must be ensured.

3) The entire picture including clinical course, ultrasound, biomarkers (troponin and BNP), and CT results should be considered.

4) Clinical decompensation including hypoxia, worsening tachypnea or tachycardia, and even brief episodes of hypotension requires consideration of thrombolysis.

If the patient is a thrombolytic candidate with bleeding risk, using half dose thrombolytics while discontinuing anticoagulation can demonstrate improved long-term functional outcomes, with lower risk of bleeding. If thrombolytics at a one-time half dose is not sufficient, a second similar dose can be provided while observing the patient for clinical improvement or decline. Starting anticoagulation after a period of observation for bleeding and decompensation may reduce bleeding.⁴²

Catheter-directed treatments provide a separate avenue for management. With an extremely low risk of major bleeding, these agents are optimal first line treatment options, especially in patients with increased risk of bleeding (such as patients over 65 years of age), patients with clinical decompensation, and in patients who fail to improve with initial thrombolytics.^28,29,43

Summary

– Submassive PE presents a challenge for physicians. Current literature including meta-analyses have inconsistent definitions of submassive PE, lack functional outcomes, have differing primary outcomes and assessments, and use different treatment protocols with thrombolytics and anticoagulation agents.

– Support exists for improvement in long-term outcomes with thrombolytics, with increased risk of major bleeding in high-risk patients.

– The risks and benefits of thrombolytic treatment should be considered on a case-by-case basis.

– Shared decision-making with the patient discussing the risks and benefits of treatment is recommended.

– Further studies that assess risk stratification, functional outcomes, and treatment protocols with thrombolytic dosing are needed.

References/Further Reading:

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