Thrombolysis therapy for Pulmonary Embolism Journal Club Dr Sarah Lambert July 2017

Evidence base

WUTH Policy for thrombolysis Massive PE causing haemodynamic instability Systolic <90mmHg Pressure drop of ≥40mmHg for more than 15 minutes Hypotension is NOT caused by Cardiac arrhythmia Hypovolaemia Sepsis CTPA ECHO Acute right ventricular dysfunction (with no other explanation) Free floating thrombus in the right atrium or right ventricle

Streptokinase and Heparin versus Heparin Alone in Massive Pulmonary Embolism: A Randomized Controlled Trial Jerjes-Sánchez et al. Journal of Thrombosis and Thrombolysis (January 1995) Single centre RCT Streptokinase and IV heparin verses IV heparin alone Outcomes/measurements not stated in the paper Inclusion criteria >15 years old Previously fit and well PE diagnosis by high clinical suspicion or V/Q scan >9 segments obstructed on V/Q scan +/- cardiogenic shock <9 segments obstructed but right heart strain

Streptokinase + heparin [n=4] Results Streptokinase + heparin [n=4] Heparin alone [n=4] Age 51 +/- 22.8 49 +/- 10.28 Onset PE (hr) 2.5 34.75 Time to improvement (hr) 1 n/a Death 4 (100%) [p=0.02] RV akinesia 4 PASP 97 32 93.75 91.25 No adverse bleeding observed Study terminated due to 100% death rate in control group Follow up at 2 years – all patients that received thrombolysis were Functional class 1 Normal PA pressure No recurrence of PE

Discussion points Randomisation? – all those assigned to control group had delayed presentation Researcher bias Patient bias Sample size small Diagnosis of PE confirmed by V/Q scan retrospectively Initial diagnosis made on clinical basis Variability in onset of symptoms to presentation Included patients they said they would exclude – patients that had delayed presentations was because of multiple PE episodes Outcomes/measures not stated in design Unknown who received mechanical ventilation/support Study terminated - deemed unethical to continue

Fibrinolysis for Patients with Intermediate Risk Pulmonary Embolism Meyer et al. The New England Journal of Medicine (2014) Randomised, double-blind trial (multicentre 76 sites, 13 countries) Tenectoplase plus heparin v’s placebo plus heparin Patient criteria Normotensive Right ventricular dysfunction on ECHO or CT Myocardial injury (raised troponin) Primary Outcome Death or haemodynamic decompensation within 7 days Safety outcomes Stroke, extracranial bleed, serious adverse events (30 days)

Methodology Study size – 1005 patients Randomisation within 2 hours of investigator being made aware of patient Fibrinolysis was given as single IV bolus Unfractionated heparin started immediately after randomisation with a bolus then infusion Analysis done by independent person

Results Efficacy Outcomes Tenectoplase + heparin [N=506] Placebo + heparin [n=499] Primary outcome (death/ haemodynamic collapse) 13 (2.6%) 28 (5.6) [P=0.02] Mechanical Ventilation 8 15 Hypotension (requiring support) 8 (3) 18 (14) CPR 1 5 Safety Outcomes Tenectoplase + heparin Placebo + heparin Major bleed 58 (11.5%) 12 (2.4%) Extracranial bleeding 32 (6.3%) 6 (1.2%) [P<0.001] Stroke 1 (0.2%) [P=0.003] Haemorrhagic Stroke 10 (2.0%) 1(0.2%) Death at 7 days 6 (1.2%) 9 (1.8%) [P=0.42] Death at 30 days 16 (3.2%) [P=0.42]

Conclusions Fibrinolysis in intermediate risk PE had a lower incidence of death within the first 7 days Fibrinolytic treatment associated with a 2% risk of haemorrhagic stroke and 6.3% risk of extracranial haemorrhage Mortality rate in control group may be under represented Higher risk of bleeding in patients >75 years (not significant) Weigh up the benefits verses increased side effects in this patient group

Discussion Large double blind study (gold standard) Results are in keeping with other studies Death rate could have been higher in the control group had they not been closely monitored and prompt correction of adverse features i.e. drop in blood pressure Some variability in treatment – In 303 patients (30.1%) heparin bolus was omitted due to already having received treatment fondiparinux or LMWH

Final thoughts Few trials evaluating the effectiveness of systemic thrombolysis in massive PE Widely accepted that thrombolysis is likely to reduce mortality in massive PE Multi-disciplinary decision despite protocol Benefit verses risk Not clear cut especially in ‘sub-massive’ PE or haemodynamically stable patient Reduced dose in elderly to reduce risk of bleeding? Bolus verses infusion Peripheral verses central Agent

Thank you Any questions

Diagnosis CTPA ECHO Massive PE causing haemodynamic instability Systolic <90mmHg Pressure drop of ≥40mmHg for more than 15 minutes Hypotension is NOT caused by Cardiac arrhythmia Hypovolaemia Sepsis CTPA ECHO Acute right ventricular dysfunction (with no other explanation) Free floating thrombus in the right atrium or right ventricle

Absolute Contraindications Taking oral anticoagulants (discuss with haematologist) Significant bleeding disorder at present or within 6 months Manifest or recent severe or dangerous bleeding Recent major trauma Surgery or head injury within 3 weeks Recent stroke (within 6 months) or history of haemorrhagic stroke GI bleed within a month Severe liver disease Haemorrhagic diasthesis Aortic dissection Any history of CNS damage Recent puncture of a non compressible blood vessel Bacterial endocarditis Pericarditis Acute pancreatitis

Relative contraindications Systolic >180mmHg Diastolic >100mmHg Prolonged chest compression Active peptic ulcer Other significant risk of haemorrhage Pregnant or 1 week post partum Other cautions – Risk of anaphylaxis is increased in patients taking ACE inhibitors