a)    What is meant by the term intermediate risk pulmonary embolism (PE) (submassive PE)?
(30% marks)

b)    Discuss the role of thrombolysis in patients presenting with intermediate risk PE. (70% marks)
 

[Click here to toggle visibility of the answers]

College answer

Latest definition according to European Society of Cardiology guideline [European Heart Journal (2020) 41, 543_603]

Intermediate Risk Pulmonary embolism can be either:

:PE without haemodynamic instability in a patient with evidence of RV dysfunction (dilatation on ECHO/CT, ECG changes, BNP) and myocardial necrosis (troponin)

or:

PE without haemodynamic instability in a patient who has one or more of the following features- age>80, cancer, Chronic heart failure, PR>110, SBP<100, SaO2< 90%. In addition, they may have either RV dysfunction or elevated cardiac troponin or none of these.

Intermediate Risk Pulmonary embolism is when PE presents without haemodynamic instability (SBP<90mmHg) but with evidence of RV dysfunction (dilatation on ECHO/CT, ECG changes, BNP) or myocardial necrosis (troponin).

 

Rationale for using thrombolysis (reperfusion treatment) is that it leads to faster improvement in pulmonary obstruction. However, the treatment decision needs to be balanced with the risk of life- threatening bleeding.

  1. In High –Risk PE (Cardiac arrest/ Obstructive shock/persistent hypotension), thrombolysis is recommended as it reduces mortality.
  2. Benefits less clear in Intermediate risk PE and thus a difficult clinical decision to make. Low mortality rate for Intermediate risk PE makes it difficult to justify the use of thrombolytic therapy in view of the risk of life-threatening bleed.
  3. In Intermediate risk PE thrombolysis is hypothesised to improve functional outcomes (mainly dyspnoea) and new onset pulmonary hypertension, but there is lack of good quality evidence.
  1. In Intermediate risk PE rescue thrombolysis is recommended only for patients who show signs of haemodynamic deterioration on anticoagulation therapy. All patients with intermediate risk PE should be observed in a monitored area for signs of deterioration.
  1. Establishing multidisciplinary Pulmonary embolism management team may help in the decision-making process ( low level evidence).

Discussion

The first part of this question is easy. The terms are actually interchangeable (Rali & Criner, 2018);  "submassive" appears to be an AHA classification, whereas "intermediate risk" is from the ACCP, but basically both involve the same features:

  • Confirmed PE
  • No shock
  • The presence of either RV dysfunction or elevated biomarkers

The ESC also split the category into "intermediate to low risk" for those who only have one of RV dysfunction and biomarkers, whereas the "intermediate to high risk" group has both.  The college mention the 2019 ESC guidelines, in case anybody needs that reference as a link.

Now, the role of thrombolysis is a more delicate question.

First of all, from an initial reading of the question text did the college mean "systemic" or "catheter directed", or both? One would have to assume both. 

Rationale for thrombolysis in this group: 

  • Prevention of long-term morbidity (eg. VTE-associated pulmonary hypertension).
  • Decrease clot burden
  • Improve systemic haemodynamics by improving LV filling
  • Prevent further RV injury

Full dose systemic thrombolysis for submassive PE:

  • PEITHO trial (2014) - multi-centre RCT, 1005 patients; no mortality benefit, higher risk of bleeding but better haemodynamics. 
  • TOPCOAT trial (2014) - multi-centre RCT, 83 patients randomised: fewer adverse outcomes, better functional capacity, and greater quality of life at 3 months
  • Overall, meta-analysis by Riera-Mestre et al (2014)  found that there was a very slight improvement in mortality; NNT to avoid one death was 125 patients.
  • In contrast, the numbers needed to harm (NNH) for a major bleed were 27, and for an intracranial haemorrhage were 91.
  • Overall, full dose systemic thrombolysis is associated with significant risk in this group.

Low dose systemic thrombolysis for submassive PE

  • MOPETT trial (2013) - single-centre RCT, 121 patients randomised; much less pulmonary hypertension was observed at 28 months (16% vs 57%).
  • Wang et al (2010) found neither any difference in bleeding complications nor in efficacy between the full dose and low dose groups
  • The role for this strategy is unclear; it may have merit in patients who are unable to access catheter-directed thrombolysis

Catheter-directed thrombolysis for submassive PE

  • EXPRESS (D'Auria et al, 2019) 339 patients, low mortality overall but a clear improvement with catheter-directed thrombolysis (3% vs 10%)
  • Pei et al (2019) scraped together 28 studies (total n=2135) into a meta-analysis, the results of which were highly positive:
    • Cardiac index improved by 0.68 L/m2
    • PA pressure reduced by a mean difference of almost 17 mm Hg
    • Very low mortality overall, 2.9% in hospital 
  • Overall, this appears to be the safest and most effective technique of delivering thrombolysis

References

Konstantinides, Stavros V., et al. "2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS) The Task Force for the diagnosis and management of acute pulmonary embolism of the European Society of Cardiology (ESC)." European Heart Journal 41.4 (2020): 543-603.

Krishnan, Abhinav C., et al. "Effectiveness of Catheter Directed Thrombolysis for Massive and Submassive Pulmonary Embolism Compared to Systemic Thrombolysis or No Thrombolysis." Circulation 140.Suppl_1 (2019): A17230-A17230.

Bhamani, Amyn, Joanna Pepke-Zaba, and Karen Sheares. "Lifting the fog in intermediate-risk (submassive) PE: full dose, low dose, or no thrombolysis?." F1000Research 8 (2019).

Levis, Joel T. "ECG diagnosis: Pulmonary embolism." The Permanente Journal 15.4 (2011): 75.

Rali, Parth M., and Gerard J. Criner. "Submassive pulmonary embolism." American Journal of Respiratory and Critical Care Medicine 198.5 (2018): 588-598.

Wang, Chen, 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 137.2 (2010): 254-262.

D'Auria, Stephen, et al. "EXPRESS: Outcomes of Catheter-Directed Thrombolysis versus Standard Medical Therapy in a Retrospective Propensity Matched Cohort of Patients with Acute Submassive Pulmonary Embolism." Pulmonary Circulation (2019): 2045894019898368.

Pei, Dorothy T., et al. "Meta-analysis of Catheter Directed Ultrasound Assisted Thrombolysis in Pulmonary Embolism." The American journal of cardiology (2019).