We have chosen to feature this topic (as many blogs have), as there are many grey areas associated with treatment of PE. In the main, these are whether to thrombolyse or not and it takes skill on the risk:benefit front to do the right thing. There are many published guidelines and outcome trials to try to digest. Hopefully, this article will be of help to you all!?

This is based upon a guideline written by Dr Dave Popple (Cons Intensivist – Northampton) and Dr Fiona Olejnik (Senior Registrar in ITU and Anaesthesia – Northampton). Thanks to them.

Check out the Osmosis video on PE!

And Armando’s too!

1) THROMBOLYSIS FOR MASSIVE PULMONARY EMBOLISM

Definition

Acute PE with circulatory collapse:
- Sustained hypotension (SBP <90 mm Hg for at least 15 min or requiring inotropic support, not due to a cause other than PE, such as arrhythmia, hypovolemia, sepsis, or LV dysfunction)
- Pulselessness or persistent profound bradycardia (heart rate <40 bpm with signs or symptoms of shock)

Diagnosis

CTPA within 1 hour of suspicion
Echocardiography
- Increased RV size
- Decreased RV function
- Tricuspid regurgitation
- Abnormal septal wall motion
- McConnell’s sign (see video below)
- Clinical diagnosis if arrest imminent/in cardiac arrest
- 60/60 sign (See video below)

McDonnell’s Sign

60/60 Sign

Prognosis

Prognosis from pulmonary embolism is variable.
In general
- untreated PE = mortality of up to 30%
- treated with anticoagulation = mortality of 2-11%

In-hospital mortality varies dependent on the degree of haemodynamic compromise:

Arterial hypotension = 15.2% mortality
Cariogenic shock = 24.5% mortality
Cardiopulmonary resuscitation = 64.8% mortality

Regarding treatment choice between anticoagulation and thrombolysis, a fatality rate attributable to PE has been shown to be 8.4% in thrombolysed patients versus 42% in patients treated with conventional anticoagulation.

Thrombolysis regimen

In every patient in whom thrombolysis is contemplated, the risk of bleeding should always be considered.

Drugs Used

Alteplase

Where from:

Often obtainable from the Stroke unit / ED / CCU

Available as:

50mg or 20mg vials with water for injection

Administration:

10mg by intravenous injection over 1-2 minutes
- Followed by intravenous infusion of 90mg over 2 hours (FDA approved rate); max 1.5mg/kg in patients less than 65kg

More rapid infusion/bolus may be more effective (faster clot resolution) without increasing bleeding risk, but more studies are required. This should be reserved for patients either in cardiac arrest, or at risk of imminent cardiac arrest.

Precautions during Alteplase infusion:

Do not mix Alteplase with any other medications or infusion fluids via the same venflon.
Do not use IV tubing with infusion filters. Use Alteplase within 8 hours once mixed.
Avoid IM injections, central lines, arterial punctures, nasogastric tubes, tracheal intubation and/or suction and urinary catheterization if possible due to increased risk of bleeding.
Half life is 4-5mins with only 10% of initial value present in plasma at 20mins.

Concomittant Anticoagulant therapy

Anticoagulant therapy is generally discontinued during the thrombolytic infusion.
An activated partial thromboplastin time (aPTT) should be measured when infusion of the thrombolytic therapy is complete.
Heparin should be resumed without a loading dose when the aPTT is less than twice its upper limit of normal. If the aPTT exceeds this value, the test should be repeated every four hours until it is less than twice its upper limit of normal, at which time heparin should be resumed.

Potential complications / Risk Management:

Side-effect	Action
Sudden Hypotension	Check patient – if symptomatic, lay patient flat and monitor BP at frequent intervals. If hypotension persists, seek senior medical advice.
Severe Bleeding	Give fluid resuscitation as required. Inform senior medical staff. If heparin administered within 4 hours of onset of bleeding, protamine may be considered cautiously (as directed by the Unfractionated heparin policy) and the APTT ratio rechecked. Consider Tranexamic acid 1-2g IV to reverse fibrinolysis e.g. 1g slow bolus followed by 1g infusion.
Hypertension	If systolic BP >180mmHg or diastolic >105mmHg, consider buccal GTN 2-6mg or administering an IV bolus dose of metoprolol 2.5mg (provided there is no evidence of heart block, left ventricular failure, bradycardia or asthma). If ineffective, an IV infusion of glyceryl trinitrate may be commenced. Do not give sublingual nifedipine.
Allergic reaction	Give 0.5ml (500micrograms) Adrenaline (1mg in 1ml) 1:1000 IM, Consider Hydrocortisone 200mg and Chlorpheniramine 10mg IV. If reaction persists or is severe, consult senior medical staff.
Arrhythmias / Heart block/ Bradycardia / Ventricular Tachycardia	Check BP – if patient is symptomatic and/or hypotensive (<90mmHg systolic) administer IV atropine 500micrograms and repeat up to a maximum of 1mg until heart rate >60bpm. If ineffective, seek medical advice Follow UK Resuscitation Council guidelines.

2) THROMBOLYSIS FOR SUBMASSIVE PULMONARY EMBOLISM

Definition

Acute PE without systemic hypotension (SBP ≥90 mm Hg) but with either RV dysfunction or myocardial necrosis
RV dysfunction – 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)
- Elevation of N-terminal pro-BNP (>500 pg/mL); or
- Electrocardiographic changes (new complete or incomplete right bundle-branch block, anteroseptal ST elevation or depression, or anteroseptal T-wave inversion)
Myocardial necrosis
- Elevation of troponin T (>100 ng/L)

N.B. Submassive pulmonary embolism is sometimes also referred to as intermediate-risk PE

Prognosis

The presence of RV dysfunction identifies normotensive patients who have a significantly higher risk of death. The role of fibrinolysis in these patients remains controversial.

Indicators for considering thrombolysis

Thrombolysis and/or catheter-based therapies may be considered on a case-by-case basis when the benefits are assessed by the clinician to outweigh the risk of haemorrhage.

Examples of such patients include those who have;
- A large clot burden
- Severe RV enlargement/dysfunction
- High oxygen requirement
- Are severely tachycardic.
- Become unstable despite anticoagulation

Note that scoring systems such as the Pulmonary Embolism Severity Index (PESI) are generally used to risk stratify patients in order to predict mortality. Their role in risk stratification for choosing thrombolytic therapy over conventional anticoagulation is unclear.

What’s the Evidence…we did mention trials!

Evidence base for submassive PE

PEITHO trial, 2014

Details

MCRCT
N = 1006 patients
(Mean age 70 years) in 13 countries in Europe and Israel,
Included patients with confirmed PE, an abnormal RV on echocardiography or CT, and a positive troponin I or T test result

What they did

Randomization to a group (stratification by center):
- Tenecteplase 30-50 mg IV once over 5-10 seconds (dose varied by weight)
- Placebo
Both groups were initiated on UFH immediately after randomization with goal aPTT 2.0-2.5x ULN (factor Xa levels 0.3-0.7 units/mL)
- UFH was bolused unless already given or if prior administration of therapeutic LMWH/fondaparinux
- UFH initiation was delayed for 12 hours following the administration of any therapeutic LMWH or 24 hours following the administration of any fondaparinux
Other anticoagulants were disallowed until 48 hours after randomization

Results

Primary Outcome

All-cause mortality or hemodynamic decompensation at 7 days
- 2.6% vs. 5.6% (OR 0.44; 95% CI 0.23-0.87; P=0.02; NNT 33)

Hemodynamic decompensation well defined here, by need for CPR, SBP <90 mmHg for ≥15 minutes, drop in SBP by ≥40 mmHg for ≥15 min with findings of end organ hypoperfusion, or need for catecholamines to maintain organ perfusion and SBP >90 mmHg, including dopamine infused at >5 mcg/kg/min.

Time until outcome: 1.54 vs. 1.79 days

Secondary Outcomes

All-cause mortality
- At 7 days: 1.2% vs. 1.8% (OR 0.65; 95% CI 0.23-1.85; P=0.42)
- At 30 days: 2.4% vs. 3.2% (OR 0.73; 95% CI 0.34-1.57; P=0.42)
Hemodynamic decompensation at 7 days
- 1.6% vs. 5.0% (OR 0.30; 95% CI 0.14-0.68; P=0.002; NNT 29)
Recurrent PE at 7 days
- 0.2% vs. 1.0% (OR 0.20; 95% CI 0.02-1.68; P=0.12; NNT 125)
- Fatal: 0% vs. 0.6%
- Non-fatal: 0.2% vs. 0.4%
Serious adverse events at 30 days
- 10.8% vs. 11.8% (OR 0.91; 95% CI 0.62-1.34; P=0.63)

The Bottom Line

Among patients with submassive PE being treated with unfractionated heparin, administration of tenecteplase reduces a composite endpoint of all-cause mortality or hemodynamic decompensation at 7 days when compared to placebo, though this was driven by reduced hemodynamic decompensation.
Tenecteplase was associated with an increased rate of bleeding.
Tenecteplase group had higher rates of prior LMWH and/or fondaparinux use
Use of composite endpoint
Industry funding
Lower dose thrombolysis may have less side-effects (see MOPPET trial)
Does not assess morbidity for chronic pulmonary hypertension

MOPPET Trial, 2013

Details

Open-label SC RCT, N = 121
Enrolled relatively ill PE patients
- Tachypnoeic, hypoxic, tachycardic patients with >70% thrombotic occlusion of lobar or main pulmonary arteries, RV dysfunction, elevated troponins, elevated BNP

What they did

Randomization to either:
- Thrombolysis: tPA 0.5 mg/kg (max 50 mg), given as 10 mg bolus followed by remainder over 2 hours
- Control: no tPA given
Echocardiogram within 2 hours and before administration of tPA
Repeat echocardiogram at 24-48 hours and every 6 months
All patients received LMWH (preferred) or UFH, as well as warfarin

Results

Primary Endpoint
- Pulmonary hypertension – 16% vs. 57% (P<0.001; NNT 2)
- Pulmonary hypertension or recurrent PE – 16% vs. 63% (P<0.001; NNT 2)
  Long-term reduction in the incidence of pulmonary hypertension compared to anticoagulation alone (ARR 40% at 28 months, 57% vs 16% risk of pulmonary hypertension/ recurrent PE) without excess bleeding
Secondary endpoints
- Recurrent PE – 0% vs. 5% (P=0.08)
- All-cause mortality – 1.6% vs. 5% (P=0.30)
- All-cause mortality or recurrent PE – 1.6% vs. 10% (P=0.049; NNT 12)
- Hospital length of stay – 2.2 vs. 4.9 days (P<0.001)
- Major or minor bleeding – 0 in each group

The bottom line

Open-label, single center
Small sample size renders event rate small
Questionable data collection. No bleeding events recorded; the published experience using LMWH and UFH in DVT/PE suggests major bleeding rates of 1.0% and 2.1%, respectively.
The composite outcome of pulmonary hypertension or recurrent PE was reduced with low-dose tPA, but this was driven by a reduction in pulmonary hypertension without a statistically significant decline in rates of recurrent PE
Surrogate endpoint of pulmonary hypertension is inferior to mortality
Funding sources not disclosed
Incomplete reporting of statistics in outcomes (eg, 95% CIs not provided)
This does not help sort out the management of submassive PE, as that definition differs from the term “moderate PE” used in this trial!

MAPPET-3 trial, 2002

Details

DB RCT
n = 256 patients with acute pulmonary embolism and pulmonary hypertension or RV dysfunction but without arterial hypotension or shock

What they did

Heparin plus 100 mg of alteplase
Heparin plus placebo over a period of two hours

Results

The primary end point of in-hospital death or clinical deterioration requiring an escalation of treatment, (defined as catecholamine infusion, secondary thrombolysis, endotracheal intubation, cardiopulmonary resuscitation, or emergency surgical embolectomy or thrombus fragmentation by catheter)
- No difference was shown for in-hospital mortality (3.4% versus 2.2%; P=0.71)
More cases of clinical deterioration requiring therapy escalation in the group of patients treated with heparin alone (24.6 versus 10.2%; P=0.004)
Only 31% of patients had Echo confirmed RV strain
No significant difference in the incidence of major bleeding between the two groups

RIETE, 2006

retrospective cohort study of 15,944 patients with an objectively confirmed symptomatic acute PE, identified from the multicenter, international, prospective, Registro Informatizado de la Enfermedad TromboEmbólica (RIETE registry)
In the normotensive subgroup, analysis of propensity score-matched pairs (n = 217 pairs) showed a statistically significant and clinically meaningful increased risk of death for thrombolysis compared with no thrombolysis (OR 2.32; 95% CI, 1.15-4.68; P = 0.018)

ICOPER registry, 1999

Intracranial bleeding occurred in 3% of patients who received thrombolytics versus 0.3% of those who did not
The incidence of any major bleeding was 22% versus 9% in these groups (Goldhaber 1999).

Cather Directed Thrombolysis

If you have the resources, time and cash…

SEATTLE-2 Trial

PERFECT Trial

Nicely put by RebelEM:

Problems with studies

Inconsistent definitions of submassive PE, e.g. RV strain or elevated BNP are likely to be more important than just pulmonary hypertension or new RBBB on an ECG, or other anatomical definitions
Lack of functional outcomes
Probably practice misalignment due to lack of stratification of risk within the submassive PE group
Echocardiography is insensitive in distinguishing acute RV dysfunction from pre-existing changes

The Key things

Here is one of the presentations on the matter…to thrombolyse, or not to thrombolyse?!

It should be a multi-disciplinary decision making process.
Think about age here (≥65 years vs <65 years) and functional status too.
- Full dose systemic thrombolysis works, we know that! But there’s that niggling but real risk of a fatal bleed. So it’s effectively Russian Roulette! If this is made clear and you have patient input on the decision, then it’s informed and you all take the risk I guess.
- Low dose systemic thrombolysis has less bleeding with equal efficacy compared to full dose systemic thrombolysis. But, you would think that this should be the ‘way’ in 100% of cases then? Well, we don’t really have a substantive set of mortality outcome data we can hang our hats on, but in those over the age of 65 years who have increased risk of major bleeding and ICH, it could be the best and safest option.
- The evidence for Catheter Directed Thrombolysis is very scant and not compared to systemic thrombolysis, but it does appear to be more expensive , your centre may not do it so it means transfer out and it may cause longer length of ICU stay compared to systemic thrombolysis. It MAY be another option to consider in patients with increased risk of bleeding (i.e. Patients 65 years and older) while balancing cost and use of resources
- CDT and low dose systemic thrombolysis improve symptoms, hemodynamics, RV/LV size, other echo parameters and PA pressures, but long-term clinical correlates are still lacking