Question 16

Theory:

• Thrombolytic agents activate plasminogen to plasmin and can be used to accelerate clot lysis in pulmonary embolus.
• Can be given systemically or catheter directed via a pulmonary artery catheter.
• By reducing clot burden, aim is to decrease pulmonary hypertension, decrease right ventricular dysfunction and improve mortality
• Side effects of thrombolysis therapy can be devastating and include intracranial haemorrhage and massive GI or other bleeding.
• Potential benefits of thrombolysis weighed up against risks of haemorrhage.
• Usual contraindications to thrombolysis: recent intracranial haemorrhage, recent major surgery, active bleeding etc

Evidence:

Systemic Thrombolysis

• Large randomized controlled trials supporting the use of systemic thrombolytics in pulmonary embolus are lacking
• Meta-analysis of thrombolysis revealed that in subgroup of haemodynamically unstable patients (n = 154) thrombolysis decreased the composite end point of death or recurrent pulmonary embolus.
• A commonly accepted indication is persistent hypotension (Massive PE) in a number of guidelines (Level of evidence not great – 2C)
• More controversial is the role of thrombolysis in haemodynamically stable patients.
• Recent meta-analysis: no difference in recurrent PE or mortality but increased major bleeding

In the following groups:

• Submassive PE:
  • Definition: pulmonary embolus with SBP >90 mmHg andmyocardial necrosis or right ventricular dysfunction  on echocardiography – worse prognosis than without pulmonary hypertension/EV dysfunction.
• Evidence of mortality benefit is lacking.
• Recent NEJM article showed thrombolysis prevented deterioration in RV dysfunction with no mortality benefit. Increased haemorrhage and stroke rate vs heparin anticoagulation.
• Cardiopulmonary resuscitation
• Evidence of benefit is lacking from clinical trials – based on case reports and series
• Large clot burden
• Lower dose (“safe dose”) thrombolysis has been investigated in this group and found improvement in pulmonary hypertension (persisted until 28months) but no improvement in mortality and no increased risk of bleeding

Catheter directed thrombolysis:

•  Can be directed via PAC.
• Can be used in patients where systemic thrombolytics have failed or risk of systemic thrombolysis considered too great.
• Evidence of mortality benefit is lacking but may be improved RV dysfunction
• Small studies

In practice:

• Usually thrombolysis for patients with massive PE (i.e. Persistent hypotension)
• Consider on a case by case basis patients with submassive PE (right ventricular dysfunction on echocardiography)
• Consider safe dose thrombolysis for patients with large clot burden.
• Consider thrombolysis in CPR
• Role of catheter directed thrombolysis uncertain.

Additional comments:

This is an area of enormous practical significance AND a common problem. Candidates were not expected to know the details of individual studies, but to be able to show a reasonable understanding of the state of play of the evidence.

A satisfactory answer was expected to include the following:

• Rationale for using thrombolysis with risks and benefits
• Indications
• Discussion of use in sub-massive PE and cardiac arrest
• Reference to evidence

In general, candidates who failed gave either clearly inaccurate statements or superficial answers.

Discussion

The following topic headings were structured according to the examiner's impression of what a "satisfactory answer" might contain.

Rationale:

• Plasminogen activators can produce clot lysis
• Clot bulk is the major pathophysiological contributor to the mortality and morbidity from PE
• Other thrombotic diseases (eg. AMI and stroke) seem to benefit from thrombolytic therapy
• Ergo, thrombolysis should reduce mortality and morbidity from PE.

Benefits:

• Decrease clot burden
• Improve systemic haemodynamics by improving LV filling
• Prevent further RV injury
• Prevent progression to pulmonary hypertension
• Relieve mechanical obstruction in obstructive cardiac arrest due to PE

Risks:

• Major bleeding : risk is doubled from 12% to 22%, (Wan et al, 2004)
• This risk of bleeding is probably underestimated by clinical trial data.

Indications:

• Indicated in massive PE ("a pulmonary embolism of sufficient size to cause systemic arterial hypotension")
  • This is supported by the 2014 ESC guidelines and 2012 ACCP Guidelines
• Indicated in cardiac arrest due to PE:
  • 2010 Australian Resuscitation Council guidelines ( Guideline 11.10)
    weak Class B recommendation based on expert opinion - "consider using ";
  • 2015 (AHA) - "Special Circumstances" guidelines statetement:
    recommends thrombolysis (Class IIA), suspending normal contraindications.
• Use in sub-massive PE is more controversial:
  • PEITHO (2014), TOPCOAT (2014), MOPETT (2013) - weak trend towards improved mortality; prevents progression to pulmonary hypertension with (perhaps) improved functional outcomes. Increased risk of major haemorrhage, including intracranial. The college were probably referring to PEITHO as the "recent NEJM article"

Practical application

• The dose of alteplase is 0.9mg/kg:
  • 10% of the dose over 1 minute;
  • 90% of the dose over the subsequent hour
  • Maximum dose is 90mg.
• For cardiac arrest, as little as 10mg (bolus) is required to overcome the mechanical obstruction (Gabrilovich, 2013) - then,  CPR should continue for 30 minutes.

Evidence in support of thrombolysis for massive PE:

• 2004 meta-analysis (Wan et al);  small sub-group (n = 154) of haemodynamically unstable PE patients.
• Within this small subgroup thrombolytic therapy reduced the risk of their composite endpoint of death and recurrent PE (from 19% to 9%).
• On the basis of this, all current guidelines seem to recommend thrombolysis for haemodynamically unstable massive PE.

Evidence for and against thrombolysis in sub-massive PE:

• PEITHO trial (2014) - referred to it as "a recent NEJM article" in the model answer. Improved haemodynamics but unchanged 7-day mortality and a greatly increased risk of  major haemorrhage and haemorrhagic stroke.
• TOPCOAT trial (2014) - with thrombolysis, fewer adverse outcomes, better functional capacity, and greater quality of life at 3 months.
• MOPETT trial (2013) - referred to in the model answer ("lower dose (“safe dose”) thrombolysis has been investigated"). Much less pulmonary hypertension was observed at 28 months, but there was no effect on mortality.
• Risk is greater than benefit, as mentioned in the model answer: "recent meta-analysis" looking at the use of thrombolysis in haemodynamically stable patients (they probably meant this 2014 paper by Riera-Mestre et al) found that NNT to avoid one death was 125 patients., but NNH for a major bleed were 27, and for ICH were 91.