Dr Eanna Mac Suibhne
Emergency Registrar

Peer review: Dr David McCreary

The Case

Gerard is a 55-year-old gentleman who has presented to your ED with a collapse episode while at home. It was an unwitnessed event but he reports it to be like a fainting episode. He slowly picked himself up and called an ambulance because he didn’t feel right. Recently, he reports having some chest pain and has become more short of breath on exertion in the past week. Gerard thought he was getting back to his old self after he underwent an ORIF of his tibia 5 weeks ago having fallen off some scaffolding at work. As you sit there with Gerard, you note that he is quite pale and sweaty, not entirely comfortable. His blood pressure reads a systolic of 95mmhg and has had a persistent tachycardia of 115 bpm since arriving in the department. The nurse hands you an ECG which shows a RBBB, which is new for Gerard since his pre-op ECG 5 weeks previously. An i-Stat troponin has come back elevated above the reference range.

No marks for guessing the diagnosis here…but what are we going to do about it? Do you anticoagulate or do you pull out the big-guns and thrombolyse this chap?

When do you push the button for thrombolysis in PE?

If you were to go with current literature basically it would suggest you should thrombolyse a massive PE and after that, well, the evidence is sketchy. About 10% of patients diagnosed with acute PE die within the first three months of diagnosis[1], so getting the correct treatment to the correct patient is important. The difficult decision relates to a particular subset of patients who have maintained hemodynamic stability yet have signs of RV dysfunction and who could potentially deteriorate. What to do?

When it comes to this topic it all seems to hinge on definitions and so let’s start with the question:

What’s the difference between a massive and a submassive PE?

Massive PE

Let’s first talk about massive PE, as there is little argument in the literature that thrombolysis is the appropriate treatment here. To be labelled with this ominous tag, a PE must satisfy certain criteria, which vary depending on where you are looking.

The definition had originally relied on anatomical criteria, those being occlusion of two or more lobar arteries or more than 50% occlusion of pulmonary vasculature. This view, however, has evolved to incorporate a patient’s hemodynamic status. A succinct definition is provided by the AHA:

an acute PE with sustained hypotension (systolic blood pressure <90 mm Hg for at least 15 minutes or requiring inotropic support, not due to a cause other than PE, pulselessness, or persistent profound bradycardia (heart rate <40 bpm with signs or symptoms of shock).

‘Shock secondary to another cause’; this point should not be skimmed over. Are you sure your patient is not hypotensive for another reason that you haven’t considered, e.g. sepsis, hypovolemia, arrhythmia, LV dysfunction etc?[2]

Approaches to help you consider this would be:

  1. Assess the clot burden on CT. For a PE to be the perpetrator of a patient’s compromised hemodynamics, there should be at least moderate to large clot burden on the CT. Patients who are hemodynamically unstable with a small amount of clot – it’s probably not going to be the PE that is causing the instability.
  2. Get your probe out. If the IVC and RV aren’t dilated, consider reassessing if it’s the PE that is causing the shock.

In patients with massive PE, systemic thrombolytic therapy has been shown to reduce mortality[3], decrease the risk of developing chronic thromboembolic pulmonary hypertension and improve quality of life[4] [5].

The Alfred guideline, summarised in the flow chart below, supports thrombolysis in the massive PE patient cohort in the context of no contraindications for its administration.

Submassive PE

For submassive PE, the definition again varies. Sticking with the AHA, they proposed the following definition for submassive PE:

Acute PE without systemic hypotension (systolic blood pressure ≥90 mm Hg) but with either RV dysfunction or myocardial necrosis.

RV dysfunction means the presence of at least 1 of the following:

  • RV dilation (apical 4-chamber RV diameter divided by LV diameter >0.9) or RV systolic dysfunction on echocardiography
  • RV dilation (4-chamber RV diameter divided by LV diameter >0.9) on CT
  • Elevation of BNP (>90 pg/mL) or N-terminal pro-BNP (>500 pg/mL); or
  • Electrocardiographic changes:
    • new RBBB (complete/incomplete)
    • anteroseptal ST elevation or depression
    • anteroseptal T-wave inversion)

Myocardial necrosis is defined as either of the following:

  • Elevation of troponin I (>0.4 ng/mL) or
  • Elevation of troponin T (>0.1 ng/mL)

Thrombolysis in this group is more controversial and the evidence is far from definitive in helping the clinician come to a decision. It is challenging to look for guidance here when the international organisations can’t agree on recommendations. Unfortunately there is no large, multi-centre RCT which has unequivocally proven the benefit of thrombolysis in submassive PE. Yet a recent meta-analysis suggests that systemic thrombolytic therapy reduces mortality in this patient group (OR 0.48; 95% CI 0.25 – 0.92)[6].  The trade-off is a significantly increased risk of major bleeding[7] . The decision to initiate thrombolysis is often taken in terms of the individual risk-to-benefit analysis.

What can thromboysis do for submassive PE?

The primary reason to give thrombolytics in submassive PE is to reduce the risk of cardiac arrest, yet the goal isn’t to normalise pulmonary pressure, but to cut back pressure sufficiently to prevent cardiac death. This allows for an improvement in right ventricular function, thus reducing the risk of acute RV failure. We have trials, MAPPET and PEITHO which demonstrate that thrombolysis decreases the risk of hemodynamic deterioration, but at the expense of increase major bleeding (11.5% vs 2.4%; NNH = 20) and ICH (2.4% vs 0.2%; NNH = 46)[8].

So, is there any way we can achieve our goal of unburdening the RV and reduce the likelihood of major haemorrhage? How about a reduced dose to offset the risk? We administer heparin on a weight-based dose, so why should it be a one dose for all comers when it comes to tpA dose. Let’s look at this.

Again, evidence is sparse here. Wang et al[9] in 2010 conducted a prospective RCT comparing 50 mg vs. 100 mg tPA infused peripherally over two hours among 118 patients with submassive or massive PE. That study found no difference in hemodynamics between the two doses and an increased risk of haemorrhage with 100 mg tPA, particularly among patients weighing below 65 kg. Another study The OPTALYSE PE trial[10] was a prospective trial comparing different regimens of alteplase administered via catheter-directed thrombolysis.  There was no apparent difference in efficacy between doses of ~8 mg and ~24 mg. Full dose thrombolysis is traditionally considered to be 100 mg IV alteplase over 2 hours with the initial 10mg given as a push, yet there is no evidence supporting the use of this dose, as compared to a lower dose. Half-dose, 50 mg alteplase, has been shown to have identical efficacy compared to 100 mg alteplase, with fewer bleeding complications[11]. So, it would seem that half-dose thrombolytics improve surrogate outcomes (i.e. mortality; not the primary outcome in any of these studies) and the added benefit of less major bleeding or ICH.

So where does that leave us?

In terms of take-home points, this is a murky field as Submassive PE is a spectrum of disease and not all patients will require thrombolytics. Following your own hospital’s guidelines will keep you in the green zone. The Alfred’s guideline has categorised PE’s as either massive or submassive, with submassive being subcategorised to high risk or low/ standard risk. The criteria for a patient to enter the low/ standard risk group have been determined to be haemodynamic stability and an absence of the markers of adverse prognosis that define massive of submassive PE. Thrombolysis is recommended for the ‘High Risk’ submassive group. See the flow chart below.

Exerpt from The Alfred’s Clinical Guideline for the Management of PE. Current version as of date of publication unless otherwise stated.

There is a recommendation that patients under 65kg should not receive a dose in excess on 1.5mg/kg, thereby reducing the risk of major bleeding. Half dose thrombolytics seem to be a good option, watch this space. Clinical decision making should be guided by objective findings and any decisions made, should be made in conjunction with the patient, senior medical staff and our specialty colleagues who will be admitting the patient.

🤔 Take Home  – What were those definitions again? 🤔


  • Sustained hypotension (systolic <90 x 15mins)
  • OR needing inotropes
  • OR sustained HR <40bpm with shock
  • OR cardiac arrest (obvs)

Submassive – High-Risk

  • RV dysfunction or myocardial injury:
    • RV dilation (echo or CT)
    • RV systolic dysfunction (echo)
    • ↑BNP
    • ECG Changes
    • ↑Troponin

Submassive – Low-Risk

  • None of the above


  1. Aujesky D et al. Weekend versus weekday admission and mortality after acute pulmonary embolism. Circulation 2009;119:962-968
  2. Jaff MR, 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 Apr 26;123(16):1788-830.
  3. Jerjes-Sanchez C, et al. Streptokinase and heparin versus heparin alone in massive pulmonary embolism: a randomized controlled trial. J Thromb Thrombolysis 1995;2:227-9
  4. Sharifi M, et al. “MOPETT” Investigators. Moderate pulmonary embolism treated with thrombolysis (from the “MOPETT” Trial). Am J Cardiol 2013;111:273-7
  5. Kline JA, 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
  6. Chatterjee S, et al. Thrombolysis for pulmonary embolism and risk of all-cause mortality, major bleeding, and intracranial hemorrhage: a meta-analysis. JAMA 2014;311:2414-21
  7. Marti C, et al. Systemic thrombolytic therapy for acute pulmonary embolism: a systematic review and meta-analysis. Eur Heart J. 2015 Mar 7;36(10):605-14..
  8. Meyer G, et al. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med. 2014 Apr 10;370(15):1402-11. doi: 10.1056/NEJMoa1302097. PMID: 24716681.
  9. Wang C, 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(2):254-262.
  10. Tapson V, et al. A Randomized Trial of the Optimum Duration of Acoustic Pulse Thrombolysis Procedure in Acute Intermediate-Risk Pulmonary Embolism: The OPTALYSE PE Trial. JACC Cardiovasc Interv. 2018;11(14):1401-141
  11. Wang C, et al. China Venous Thromboembolism (VTE) Study Group. 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 Feb;137(2):254-62.
Eanna Mac Suibhne

Eanna Mac Suibhne

Emergency Registrar

Eanna is an Irish-trained Emergency physician whose interests broadly include trauma, toxicology and sports injury management. The search of experiencing working in an MTC has resulted in sticks being upped and his recent move to Melbourne. The freely available great coffee was a happy coincidence.