A 40 year old woman was admitted to the emergency department (ED) after a syncopal episode. On admission she was in acute respiratory distress and described a two day history of sudden onset breathlessness. She had no previous medical history. Her only regular medication was the oral contraceptive pill. She had had a recent flu-like illness and been less active than usual. On arrival she had a respiratory rate of 30 breaths/minute with accessory muscle use. An ABG on 15L/min oxygen via non-rebreathe mask showed type I respiratory failure (PO₂ 8.4kPa). She was tachycardic (120bpm) and blood pressure was 98/50. Chest x-ray and bloods were unremarkable although her ECG revealed a sinus tachycardia with right axis deviation, Q waves and inverted T waves in lead III.

The patient had a bedside echocardiogram that revealed a severely dilated right ventricle with poor tricuspid annulus planar systolic excursion (TAPSE). A presumed diagnosis of a pulmonary embolism (PE) was made. Thrombolytic therapy was considered but rejected at this point, in view of the haemodynamic stability. The patient was commenced on enoxaparin at a dose of 1.5mg/kg.

CT pulmonary angiography confirmed the presence of bilateral pulmonary emboli. On return from CT the patient was sat up briefly at which time she became cyanotic and had a brief self-terminating seizure. During this time her blood pressure was not recordable, and significant hypotension secondary to obstructive shock was assumed to be the cause. At this point it was decided to proceed with thrombolysis. The patient was transferred to the Intensive Care Unit, made a rapid recovery without the need for vasopressors or intubation and ventilation, and was discharged from hospital a few days later.

What is the evidence for intravenous thrombolysis for intermediate-risk pulmonary embolism? 

Gary Misselbrook

The principle behind thrombolytic therapy for PE is to remove embolic material from the pulmonary arteries by promoting lysis of blood clots. Early studies using alteplase (a recombinant tissue plasminogen activator) revealed improvements in angiographic and haemodynamic parameters when compared to anticoagulation alone.¹ Current guidelines, both UK based (NICE²) and international (AHA³ and ESC⁴) support the use of thrombolysis in patients with massive or high-risk PE. This haemodynamically unstable patient subgroup can be defined by a systolic blood pressure <90mmHg or a pressure drop of ≥40mmHg for >15minutes if not caused by an arrhythmia, hypovolaemia or sepsis. This group compromises 5-10% of patients presenting with PE and are estimated to have a >15% risk of early death.⁵

However, there is a significant cohort of patients with PE who have right heart strain and/or myocardial injury but remain normotensive. This group of patients – referred to as intermediate-risk or submassive PEs – have increased rates of in-hospital death, even in the absence of hypotension or shock.⁶ The International Cooperative Pulmonary Embolism Registry (ICOPER) estimated this subgroup to have an increased 3-15% risk of early mortality.⁷ However, due to the significantly increased risk of major haemorrhage in patients receiving thrombolysis, thrombolytic therapy has remained controversial in management of intermediate-risk PE.

There has been interest in recent years in whether thrombolysis may potentially improve morbidity and mortality in patients presenting with intermediate-risk PEs. The MAPPETT-3 trial enrolled 256 haemodynamically stable patients with acute PE and RV dysfunction or pulmonary hypertension on Echo or right heart catheterization to receive either heparin and placebo or heparin and alteplase.⁶ Whilst the study was underpowered to detect an effect on mortality, the thrombolysis group showed lower requirements for treatment escalation (10.2% vs. 24.6%, P=0.004, NNT 7.5).

In addition to risk of death, secondary adverse outcomes such as persistent RV dysfunction, chronic thromboembolic pulmonary hypertension (CTEPH), and impaired quality of life may occur in patients with intermediate-risk PE.⁸ The MOPETT trial reported that low-dose thrombolysis in “moderate PE” decreased pulmonary artery systolic pressure by an average of 15mmHg at 28 months.⁹ In addition, there were no reported episodes of bleeding in either group. However, this study did not address the clinical significance of a reduction in pulmonary artery pressure and used older ‘anatomical’ definitions of submassive PE (rather than accepted ‘functional’ definitions) to identify patients.

As a result, the TOPCOAT study aimed to determine whether the use of thrombolysis improved patient-orientated outcomes.⁸ Unfortunately the trial was terminated early due to unforeseen administrative barriers and was therefore underpowered. Despite this, a modest improvement was noted in functional outcome (measured using a complex composite outcome involving quality of life scales, 6 minute walk tests, Echo findings) in the tenecteplase group at 90 days.

The largest trial investigating the efficacy and safety of thrombolysis on intermediate-risk PE was reported in 2014.¹⁰ The PEITHO trial enrolled 1006 haemodynamically stable patients with acute PE and RV dysfunction and raised troponin to receive either tenecteplase and heparin or placebo and heparin. A composite outcome of death or haemodynamic decompensation within seven days was significantly lower in the thrombolysis group (2.6% vs. 5.6%; OR 0.44, 95% CI 0.23-0.87, P=0.02, NNT 34). However, no significant difference in risk of mortality was noted at seven or 30 days between the two treatment groups (although the study was underpowered to detect an effect on mortality). Similarly to the MOPETT trial, the clinical significance of an outcome of haemodynamic decompensation is unclear considering this did not translate into an increased risk of mortality. As with previous studies, the rate of intracranial haemorrhage was 10-fold higher in the thrombolysis group (2% vs. 0.2%, P=0.003), with a resulting number needed to harm (NNH) of 55.

A further meta-analysis was performed in 2014 following the publication of these recent studies.¹¹ The authors stratified the 2115 patients into low, intermediate and high-risk PE according to haemodynamic parameters and RV dysfunction. The meta-analysis identified 8 trials comprising 1775 patients with intermediate-risk PE for sub-group analysis (of which PEITHO, MAPPETT and MOPETT contributed 78% of patients). Analysis revealed that patients with intermediate-risk PE had significantly lower all-cause mortality when treated with thrombolytic therapy (1.39% vs. 2.92%; OR 0.48, 95% CI 0.25-0.92, P=0.03). Whilst major bleeding was significantly higher in all patients treated with thrombolysis (OR 3.19, 95% CI 2.07-4.92), there was no increase in risk of major bleeding in a subgroup of patients ≤65years with intermediate-risk PE (2.84% vs. 2.27%; OR 1.25, 95% 0.50-3.14, P=0.89).

Whilst meta-analyses have been of benefit in collating large numbers of patients from various studies, the lack of standardisation in definitions for haemodynamic instability, major and minor bleeding, and RV dysfunction; and varying doses and types of thrombolysis used, may explain the inconsistency in results between trials and limits the validity of these meta-analyses. A recent review article highlights this point and calls for further studies that assess risk stratification, functional outcomes, and treatment protocols to be performed.¹²

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Lessons learnt

• Current evidence does not support the routine use of thrombolytic therapy in haemodynamically stable patients with acute PE.
• It is still unclear whether long-term sequelae may be prevented by use of thrombolysis in the acute setting; further research is needed to address this.
• The rate of major haemorrhage in all patients receiving thrombolysis for PE is approximately 10-fold higher compared to standard anticoagulation with heparin alone.^7,10,11
• Haemodynamically stable patients under 66 years of age with RV dysfunction and myocardial injury may have a significant reduction in mortality and no significantly increased risk of major haemorrhage when given thrombolytics.^10,11
• In patients with intermediate-risk PE, haemodynamic decompensation and a high bleeding risk, other options for reperfusion include surgical embolectomy or percutaneous catheter-directed thrombolysis where facilities for this exist.⁴

Current guidelines^2-4 did not support the routine use of thrombolysis prior to her collapse and subsequent seizure, since although she had evidence of RV strain, there were no signs of significant haemodynamic compromise. However, the ESC and AHA state that thrombolysis should be considered if clinical signs of haemodynamic decompensation appear in this group of patients,^3,4.

A pragmatic approach would be to consider the use of thrombolysis in young patients with a low risk of bleeding, who present with acute PE and significant right ventricular dysfunction. There remains an overall low mortality rate from intermediate-risk PE (2.92%¹¹) and high bleeding risk from thrombolysis (2.84%¹¹), therefore balancing these risks is challenging requiring individual consideration of each case. A bleeding complication in this group of patients could be potentially life threatening with a high risk of long-term disability.

In patients over 65 years I would not support the use of thrombolysis for PE unless there was significant haemodynamic compromise, at which time the risk of major haemorrhage should be fully discussed with the patient and relatives.

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References

1. Dalla-Volta S, Palla A, Santolicandro A et al. PAIMS2: alteplase combined with heparin versus heparin alone in massive pulmonary embolism: a randomised controlled trial. J Thromb Thrombolysis. 1995; 2:227-229
2. National Institute for Health and Care Excellence (NICE). Venous thromboembolic diseases: diagnosis, management and thrombophilia testing (CG144). 2012, updated 2015. Available at: https://www.nice.org.uk/guidance/cg144/evidence/full-guideline-186726349 [Accessed 28th March 2016]
3. American Heart Association. Management of Massive and Submassive Pulmonary Embolism, Iliofemoral Deep Vein Thrombosis, and Chronic Thromboembolic Pulmonary Hypertension. Circulation. 2011; 123:1788-1830
4. The Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology. 2014 ESC Guidelines on the diagnosis and management of acute pulmonary embolism. European Heart Journal. 2014; 35:3033–3080
5. Wood KE. Major pulmonary embolism: review of a pathophysiologic approach to the golden hour of hemodynamically significant pulmonary embolism. Chest. 2002; 121(3):877-905
6. Konstantinides S, Geibel A, Heusel G et al. Heparin plus alteplase compared with heparin alone in patients with submassive pulmonary embolism. NEJM. 2002; 347(15):1143-1150
7. Goldhaber SZ, Visani L, De Rosa M. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER). Lancet. 1999; 353(9162):1386-1389
8. Kline JA, Nordenholz KE, Courtney DM et al. Treatment of submassive pulmonary embolism with tenecteplase or placebo: cardiopulmonary outcomes at 3 months: multicenter, double-blind, placebo controlled, randomized trial. Journal of Thrombosis and Haemostasis. 2014; 12(4):459-468
9. Sharifi M, Bay C, Skrocki L et al. Moderate pulmonary embolism treated with thrombolysis. American Journal of Cardiology. 2013; 111(2):273-277
10. Meyer G, Vicaut E, Danays T et al. Fibrinolysis for Patients with Intermediate Risk Pulmonary Embolism. NEJM. 2014; 370:1402-11
11. Chatterjee S, Chakraborty A, Weinberg I et al. Thrombolysis for Pulmonary Embolism and Risk of All-Cause Mortality, Major Bleeding, and Intracranial Hemorrhage: a Meta-analysis. JAMA. 2014; 311(23):2414-2421
12. Long B, Koyfman A. Current controversies in thrombolytic use in acute pulmonary embolism. J Emerg Med. 2016; doi: 10.1016/j.jemermed.2016.02.024. [Epub ahead of print]