Systemic fibrinolysis (SF) in acute pulmonary embolism (PE) remains a hot topic in acute care medicine. This post will examine the available literature regarding the use of SF in different subtypes of PE. Before examining the literature, we first must review the relevant nomenclature.

Defining PE

The American Heart Association (AHA) defines “massive” pulmonary embolism as an acute PE that causes sustained hypotension (SBP<90 mmHg for 15 at least minutes or requiring inotropic support, without another cause) (1).

“Submassive” PE is an acute PE without hypotension, but with either right ventricular dysfunction (RVD) or myocardial necrosis. RVD can be qualified in a number of ways: RV dilation or systolic dysfunction on echocardiography, RV dilation on computed tomography (CT) scan, elevation of BNP, elevation of N-terminal pro-BNP, or electrocardiographic changes (new complete or incomplete right bundle branch block, anteroseptal ST elevation or depression, or anteroseptal T-wave inversion (1).

Myocardial necrosis is indicated by an elevated serum troponin level. Some trials have considered acute PE with a similar clinical severity to “submassive” as “intermediate risk” (2) or “moderate” (3). “Low risk” PE refers to an acute PE without features of massive or submassive PE.

Guideline recommendations

Systemic fibrinolysis (SF) therapy for acute PE should generally be reserved for patients who are at the highest risk of deterioration and death. The AHA and the American College of Chest Physicians make class IIA and grade IIC recommendations, respectively, to administer SF in massive PE to patients with an acceptable risk of bleeding (1, 4). Despite these recommendations however, clinicians do not consistently adhere to published guidelines regarding SF in these patients. In a large, prospective observational study of patients presenting with massive PE, Lin et al reported that only 12.1% of these patients actually received SF therapy (5). The two to three percent risk of intracranial hemorrhage (ICH) with SF therapy may be one reason why clinicians are reluctant (6).

PEITHO Trial

The body of evidence examining the use of SF therapy for submassive PE has expanded over the last decade. The Pulmonary Embolism Thrombolysis (PEITHO) trial is the largest interventional trial to date to examine this population. Meyer et al randomized normotensive patients with intermediate-risk PE (defined as both RVD and myocardial necrosis) to receive either tenecteplase (TNK) plus heparin or placebo plus heparin. The primary outcome of death from any cause or hemodynamic decompensation occurred in 2.6% of the TNK group versus 5.6% in the placebo group (OR 0.44; 95% CI 0.23 – 0.87, p=0.02). Major bleeding was reported in 6.3% of the TNK group versus 1.2% of the placebo group (OR 5.6; 95% CI 2.3 – 13.4; p<0.001). Similarly, ICH occurred in 2% of the TNK group versus 0.2% in the placebo group (2).

Although there was an overall benefit with SF with regards to the composite primary outcome, this was primarily driven by a prevention in patients developing hemodynamic decompensation. In fact, there was no statistically significant difference in mortality between groups. When considering the balance of risk and benefit, there was an unacceptable bleeding risk associated with fibrinolysis in this population.

Long-term benefits

Aside from acute outcomes, some studies have suggested that a possible benefit for SF in PE is in prevention of mortality and morbidity in the long term (3, 7). However, in a recently published follow-up study of the PEITHO trial (8), Konstantinides et al reported long-term outcome data at a median of 37.8 months and concluded that mortality rates did not differ between the TNK and placebo groups (20.3% and 18.0%, respectively; p=0.4). Additionally, patient-reported outcomes of persistent dyspnea, functional limitation as well as echocardiographic evidence of persistent pulmonary hypertension or RVD did not differ between the groups.

Combining the evidence

A meta-analysis of 16 randomized, controlled trials (RCTs) by Chatterjee et al reported that SF in acute PE was associated with a lower all-cause mortality (OR 0.5; 95%CI 0.3 – 0.9) but also reported an increased risk of major bleeding (OR 2.7; 95%CI 1.91 – 3.9) (9). Another meta-analysis of 6 RCTs examining SF for submassive PE reported no significant differences in all-cause mortality in patients who received SF for submassive PE compared to those who did not (RR 0.7; 95%CI 0.4 – 1.3) (10). It did however, report that adjuvant fibrinolytic therapy reduced the composite outcome of all-cause mortality or clinical deterioration in patients with submassive PE as compared to anticoagulation alone (1.4% versus 6.5%; RR 0.3; 95%CI 0.3 – 0.7).

Reduced dose fibrinolysis

Reduced dose fibrinolysis has been proposed to mitigate the bleeding risk associated with its use. The Moderate Pulmonary Embolism Treated with Thrombolysis (MOPETT) trial randomized 121 patients with moderate PE to receive “low-dose” alteplase (50 mg) plus a modified dose of anticoagulation, versus usual anticoagulation alone (3). The primary outcome of pulmonary hypertension (pulmonary artery systolic pressure greater than 40 mmHg) at a mean follow-up duration of 28 months, was observed in 16% of the alteplase group versus 57% of the comparator group (p<0.001). Importantly, no bleeding occurred in either group. Other clinical outcomes were not assessed.

Catheter-based fibrinolysis

Catheter based fibrinolysis is a relatively newer concept in acute PE treatment. The principle goal is to minimize the risk of bleeding by delivering lower doses of fibrinolysis directly into the pulmonary arterial circulation and optimally, directed towards the clot. A meta-analysis in 2017 by Bloomer et al demonstrated a combined risk of major bleeding or vascular injury of 4.7% and a 0.4% rate of ICH – considerably less than full dose systemic thrombolysis (11).  However, there is a lack of high quality studies supporting this technique and the literature base mainly consists of observational trials (11). A single small RCT of less than 60 patients demonstrated superiority in reversing RV strain at 24 hours compared to heparin alone (12).

Conclusions

Few randomized, high quality studies exist which report on the use of SF therapy in acute PE. Overall, SF in acute PE may be associated with improved survival, but is associated with a risk of major bleeding (4, 9). Clinicians must therefore consider the risks and benefits of SF therapy whilst making treatment decisions, and an individualized approach for each patient is important.

  • The body of evidence regarding SF in acute PE is immature, which mandates clinicians to carefully assess the risks and benefits of SF for each patient.
  • SF should be reserved for critically ill patients who are at a high risk of clinical deterioration, and who are deemed to have an acceptable risk of bleeding. This includes patients who fall into the “massive PE” category as per the definitions above.
  • There is a mounting body of evidence that SF for submassive PE does not improve patient outcomes, and is associated with an unacceptable risk of bleeding. Therefore, SF in these patients should not be routinely recommended.
  • Reduced-dose and catheter-based fibrinolysis offer promise as potential safe alternatives to systemic fibrinolysis. Larger trials should examine the utility and safety of these methods in an attempt to discover a safe and beneficial therapeutic option for patients with acute PE.

References

  1. Jaff MR, McMurtry MS, Archer SL, Cushman M, Goldenberg N, Goldhaber SZ, et al. Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association. Circulation. 2011;123(16):1788-830.
  2. Meyer G, Vicaut E, Danays T, Agnelli G, Becattini C, Beyer-Westendorf J, et al. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med. 2014;370(15):1402-11.
  3. Sharifi M, Bay C, Skrocki L, Rahimi F, Mehdipour M, Investigators M. Moderate pulmonary embolism treated with thrombolysis (from the “MOPETT” Trial). Am J Cardiol. 2013;111(2):273-7.
  4. Kearon C, Akl EA, Comerota AJ, Prandoni P, Bounameaux H, Goldhaber SZ, 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(2 Suppl):e419S-e96S.
  5. Lin BW, Schreiber DH, Liu G, Briese B, Hiestand B, Slattery D, et al. Therapy and outcomes in massive pulmonary embolism from the Emergency Medicine Pulmonary Embolism in the Real World Registry. Am J Emerg Med. 2012;30(9):1774-81.
  6. Goldhaber SZ, Visani L, De Rosa M. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER). Lancet. 1999;353(9162):1386-9.
  7. Kline JA, Nordenholz KE, Courtney DM, Kabrhel C, Jones AE, Rondina MT, 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(4):459-68.
  8. Konstantinides SV, Vicaut E, Danays T, Becattini C, Bertoletti L, Beyer-Westendorf J, et al. Impact of Thrombolytic Therapy on the Long-Term Outcome of Intermediate-Risk Pulmonary Embolism. J Am Coll Cardiol. 2017;69(12):1536-44.
  9. Chatterjee S, Chakraborty A, Weinberg I, Kadakia M, Wilensky RL, Sardar P, et al. Thrombolysis for pulmonary embolism and risk of all-cause mortality, major bleeding, and intracranial hemorrhage: a meta-analysis. JAMA. 2014;311(23):2414-21.
  10. Nakamura S, Takano H, Kubota Y, Asai K, Shimizu W. Impact of the efficacy of thrombolytic therapy on the mortality of patients with acute submassive pulmonary embolism: a meta-analysis. J Thromb Haemost. 2014;12(7):1086-95.
  11. Bloomer TL, El-Hayek GE, McDaniel MC, Sandvall BC, Liberman HA, Devireddy CM, et al. Safety of catheter-directed thrombolysis for massive and submassive pulmonary embolism: Results of a multicenter registry and meta-analysis. Catheter Cardiovasc Interv. 2017;89(4):754-60.
  12. Kucher N, Boekstegers P, Muller OJ, Kupatt C, Beyer-Westendorf J, Heitzer T, et al. Randomized, controlled trial of ultrasound-assisted catheter-directed thrombolysis for acute intermediate-risk pulmonary embolism. Circulation. 2014;129(4):479-86.

Authors

  • Dr. Mike Hickey is an FRCPC Emergency Medicine and critical care physician, having completed his residency at the University of Ottawa.

  • Dr. Peter Reardon is an FRCPC Emergency Medicine and Critical Care physician, having done his training at the University of Ottawa.