Which Patients with Pulmonary Embolism should get Thrombolysis?

The diagnosis of pulmonary embolism(PE) is an almost common occurrence in the emergency department. The question of which patients to thrombolyse can be a difficult one to answer. Certainly there is consensus over patients with massive PEs needing thrombolysis. The same cannot be said for those patients with a submissive PE, because our greatest fear is the complication of intra-cranial haemorrhage.

CASE

A 78 yo male presents with shortness of breath. He has a past medical history of hypertension. His vitals are HR 114, BP 128/80,RR 28,  Sats 91% on room air. He has no chest pain and is sitting up feeling very comfortable with supplementary oxygen.

Should this patient be offered thrombolysis? Would you give thrombolysis?

Let’s begin by defining the different sizes of PE.

Massive PE

Traditionally this has been defined by the angiographic burden, however a more appropriate definition may be related to what we see clinically. I prefer the American Heart Association(AHA)(1) definition:

“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, such as arrhythmia, hypovolemia, sepsis, or left ventricular [LV] dysfunction), pulselessness, or persistent profound bradycardia (heart rate <40 bpm with signs or symptoms of shock).”

Submassive PE

Submassive PE is defined by the AHA(1) as:

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

1 RV dysfunction means the presence of at least RV dilation or RV systolic dysfunction on echocardiography, RV dilation on CT, Elevation of BNP (>90 pg/mL), Elevation of N-terminal pro-BNP (>500 pg/mL); or

2 Electrocardiographic changes (new complete or incomplete right bundle-branch block, anteroseptal ST elevation or depression, or anteroseptal T-wave inversion)

3 Myocardial necrosis is defined as either of Elevation of troponin I (>0.4 ng/mL) or Elevation of troponin T (>0.1 ng/mL)

Who Gets Thrombolysis?

It’s generally accepted that massive pulmonary embolism gets thrombolysed, although there may be some contraindications. What do we do with submassive PE’s? Are some of them deserving of lysis? Until now it has been accepted that those patients with haemodynamic stability and RV dysfunction and myocardial necrosis should be candidates for thrombolysis.

There is no doubt that the use of thrombolytic significantly reduces clot size. This may have the direct result of decreasing pulmonary pressures, which may themselves lead to future complications. However, there is no significant effect on patient mortality(2). In fact, in normotensive patients thrombolytics are associated with increased mortality(3), with the primary complication being intracranial haemorrhage, in up to 6.4% of patients(4).

There are several trials, however two are considered major trials, the MOPETT and the PEITHO trials. Even with these, the question still hasn’t really been answered. The two trials use a different type of lytic agent and different endpoints.

The MOPETT Trial(5)

This trial wanted to address the concerns of full dose thrombolysis and potential intracranial bleeding, by proposing a ‘safe dose’ of 0.5mg/kg to a maximum of 50mg (50%)  of the regular dose of tPA. It was given as 10mg over one minute and the rest within a 2 hour period.

This was a single centre, small numbered study, that really didn’t find any statistically significant results in reduction of pulmonary hypertension. It is questionable as to whether the patients chosen, were all appropriate, as not all met the criteria of submissive PE. What did come out of it was that there were no cases of intra-cerebral bleed with half dose tPA. This is a very important finding.

The PEITHO Trial (6)

This was a trial of 1006 patients treated with Tenecteplase. Although the results didn’t for the most reach statistical significance, the trend towards haemodynamic compromise was much higher in the placebo group than the Tenecteplase group. The rate of major bleeding was 6.3% in the thrombolytic group and the rate of intra-cranial bleeding was 2% with tenecteplace versus 0.2% with placebo. Those at greater risk appeared to be those patients older than 75 years.

Pulmonary Embolism Severity Index

The Pulmonary Embolism Severity Index is a validated score that provides independent predictors of 30 day mortality and can be used to determine those patients at higher risk(6). This may help us in determining those patients that will have a worst outcome if not treated.

The scoring system is shown below:

Predictors	β-Coefficients (95% CI)	Points Assigned
Demographic            characteristics
Age, per yr	0.03 (0.02–0.03)		Age, in yr
Male sex	0.17 (0.02–0.32)		+10
Comorbid illnesses
Cancer	0.87 (0.71–1.03)		+30
Heart failure	0.31 (0.14–0.49)		+10
Chronic lung disease	0.30 (0.12–0.47)		+10
Clinical findings
Pulse ⩾ 110/min	0.60 (0.44–0.76)		+20
Systolic blood pressure < 100 mm Hg	0.86 (0.67–1.04)		+30
Respiratory rate ⩾ 30/min	0.41 (0.23–0.58)		+20
Temperature < 36°C	0.42 (0.25–0.59)		+20
Altered mental status*	1.50 (1.30–1.69)		+60
Arterial oxygen saturation < 90%†	0.58 (0.37–0.79)		+20

Interpretation of the scoring:

⩽ 65 class I, very low risk;

66–85 class II, low risk;

86–105 class III, intermediate risk;

106–125 class IV, high risk;

>125 class V, very high risk.

How does this apply to our patient?

The patient in the case above, would fall into the HIGH RISK group in terms of poor outcome. He would score a 78(age) + 10(male) + 20(HR) =108. Thrombolysis should be considered in him, however I would consider half dose if tPA were being given and would get advice on Tenecteplase.

My Overall Approach

Given the risk of intra-cerebral bleeding I would thrombolyse only massive PE’s. In those that are haemodynamically stable I would look for RV strain or cardiac necrosis, I would still probably only anticoagulant that submissive PE group, and use thrombolytics if their haemodynamic status began to be compromised.

The alternative is to calculate a PE Index and decide and then probably give half dose thrombolytic to the high risk group. Further, I would consult with a pulmonary hypertension expert……yes you heard right. They are at the large tertiary centres and give advice on this very matter.

What about special cases?

Recent Surgery

The risk of bleeding if patient have had recent surgery is significant in the first 2 weeks after surgery. That risk falls two weeks following surgery.

Is all surgery the same? No, brain or spinal surgery does not carry the same risks.

Please consult with the surgeons prior to giving.

What about PE in pregnancy?

Massive PE should be treated with thrombolysis.

Submassive PE should be treated with LMWH (warfarin has teratogenic effects)

If there is a high risk of bleeding then consider IVC filter.

Recent Stroke

There is some concern with giving thrombolysis within 3-6 months of ischaemic stroke, in an increased rate of intracranial haemorrhage(7), although the evidence does not appear to be consistent. Specialist advise should be sought.

Space Occupying Lesions

There appears to be an increased risk of haemorrhage in all except meningiomas(8). Expert advice should be sought.

References

1. 1 Jaff MR, McMurtry MS, Archer SL, 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;123:1788–830.
2. Konstantinides S, Geibel A, Heusel G, et al. Heparin plus alteplase compared with heparin alone in patients with submassive pulmonary embolism. N Engl J Med 2002;347:1143–50
3. Riera-Mestre A, Jimenez D, Muriel A, et al. Thrombolytic therapy and outcome of patients with an acute symptomatic pulmonary embolism. J Thromb Haemost 2012;10:751–9
4. Berkowitz SD, Granger CB, Pieper KS, Lee KL, Gore JM, Simoons M, Armstrong PW, Topol EJ, Califf RM, Global Utilization of Strepto- kinase and Tissue plasminogen activator for Occluded coronary arteries (GUSTO-I) Investigators. Incidence and predictors of bleeding after contemporary thrombolytic therapy for myocardial infarction. Circulation 1997;95:2508e2516.
5. Sharifi M et al. Moderate Pulmonary Embolism Treated With Thrombolysis.   January 15, 2013 Volume 111, Issue 2, Pages 273–277
6. Aujesky D, Obrosky DS, Stone RA, et al. Derivation and validation of a prognostic model for pulmonary embolism. Am J Respir Crit Care Med 2005;172:1041–6
7. Torbicki A, Perrier A, Konstantinides S, et al. Guidelines on the diagnosis and management of acute pulmonary embolism: the Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). Eur Heart J 2008;29:2276–315
8. Kondziolka D, Bernstein M, Resch L, et al. Significance of hemorrhage into brain tumors: clinicopathological study. J Neurosurg 1987;67:852–7.