CVS

When should we thrombolyse patients with pulmonary embolism?

د. حسين محمد جمعه
اختصاصي الامراض الباطنة
البورد العربي
كلية طب الموصل
2011

Introduction

Pulmonary embolism remains a common disease, with an incidence of about 60-70 per 100 000 of the general population.1 Postmortem studies, which reflect disease in the whole hospital rather than the emergency department, have found that only 30-45% of those who died of pulmonary embolism had the correct diagnosis before they died. This suggests that although over 80% of patients have a risk factor such as previous thromboembolic disease, immobilisation, morbid obesity, malignancy, cardiac failure, pregnancy, or recent surgery.

Hull diagnosed pulmonary embolism in 21% of those patients presenting to the emergency department with pleuritic chest pain.
Pulmonary embolism associated with reduced cardiac output or right ventricular embarrassment is suggested by nonspecific findings including
• Syncope
• Hypotension
• Tachycardia
• Loud second heart sound
• Cyanosis.


Treatment options for patients with pulmonary embolism
There are no robust data on the mortality of patients with untreated pulmonary embolism, as heparin was introduced in the 1960s before modern imaging was widely available, and thus no placebo arm is included in modern trials.
The mortality has been quoted at about 30%, which is reduced to 1-15% with anticoagulation. Recently, low molecular weight heparins have proved to be as effective as or superior to intravenous heparin.

Anticoagulation with heparin prevents propagation of the clot, tipping the balance in favour of endogenous fibrinolysis and allowing the clot to dissolve over weeks and months.
Thrombolytics are plasminogen activators, converting plasminogen to plasmin, which then degrades fibrinogen.

Thrombolysis may result in faster and more complete lysis of a clot, producing a more rapid improvement in pulmonary flow, right ventricular performance, and oxygenation, which could lower morbidity and mortality. Any deep vein thrombosis may also be more efficiently lysed and so recurrence reduced. But thrombolysis risks bleeding.
Is there a subset of patients at high risk of death in whom the benefits outweigh the risk?

Can we predict who is most at risk of death from pulmonary embolism?

It is intuitive that large pulmonary emboli in patients with less cardiorespiratory reserve should result in higher mortality.
Death occurs from circulatory obstruction, causing
Right heart failure
Systemic shock
Hypoperfusion.

In 1976, Alpert found that the presence of right ventricular failure rather than embolic size determined mortality. Alpert followed 144 patients with angiographically proved pulmonary embolism and found a mortality of 20 (13.8%), of whom eight were thought to have died despite the pulmonary embolism and 12 (8%) because of it. Nine (75%) of this group had right ventricular failure but the degree of arterial obstruction varied from 25 to 75%.

The mortality of those with >50% arterial occlusion on angiogram was 6% in those with no acute right heart failure 32% where right ventricular failure was present.
In 1993, Goldhaber suggested that echocardiographic evidence of right ventricular wall motion abnormality could define a high risk subgroup. The International Cooperative Pulmonary Embolism Registry was set up specifically to look at factors associated with three month mortality from pulmonary embolism. Data were obtained on 2454 patients from 52 North American and European centres, relying on diagnostic information supplied by the centres.


The following predicted mortality on multiple regression modelling
• Age >70 years (hazard ratio 1.6; 95% CI 1.1 to 2.3)
• Cancer (hazard ratio 2.3 CI 1.5 to 3.5)
• Congestive cardiac failure (hazard ratio 2.4 CI 1.5 to 3.7)
• Systolic hypotension (hazard ratio 2.9 CI 1.7 to 5.0)
• Tachypnoea (hazard ratio 2.0 CI 1.2 to 3.2)
• Right ventricular hypokinesis on echo (hazard ratio 2.0 CI 1.3 to 2.9).

The mortality in the haemodynamically unstable group was 56 of 96 (58.3%), compared with 317 of 2093 patients (15.1%) who were haemodynamically stable. Right ventricular hypokinesis on echo was also associated with higher mortality.

The Management Strategy and Prognosis of Pulmonary Embolism Registry included 1001 patients from 204 German centres divided into four subgroups based on cardiac performance.
Group 1: normotensive group but with pulmonary hypertension or right ventricular dysfunction on echocardiogram. Mortality 8.1%
Group 2: systemic hypotension (systolic blood pressure <90 or pressure drop >40). Mortality 15%
Group 3: cardiogenic shock. Mortality 25%
Group 4: those requiring cardiopulmonary resuscitation. Mortality 65%.

In a separate study of 317 patients with clinically suspected pulmonary embolism, Kasper found the in hospital/one year mortality from pulmonary embolism was:
13% in those with echocardiographic evidence of right ventricular dysfunction
1.3% in those without.
In this study, transthoracic echocardiography was used, with one of the A criteria or two of the B criteria being used to diagnose right ventricular dysfunction.


Table 1 Criteria for right ventricular dysfunction (after Kasper18)

A criteria (1 of)

End diastolic diameter of right ventricle > left ventricle

End diastolic diameter of right ventricle >30 mm

B criteria (2 of)

Tricuspid regurgitation jet > 3.8 m/s or > 2.5 m/s in the absence of inspiratory collapse of the inferior vena cava

Pulmonary artery >12 mm/m2 of body area

Right ventricular wall >5 mm

Loss of inspiratory collapse of the inferior vena cava

Please note - there are many criteria for right ventricular dysfunction - these are the criteria used in this study. They are comprehensive but complex. They are not the only echocardiographic criteria for right ventricular dysfunction.

If those with acute rather than chronic right ventricular afterload stress are considered alone, then the in hospital mortality rises to 23.5% in this study. Thus the acute mortality of pulmonary embolism is largely dependent on the resulting cardiovascular performance, being worst if the patient is in arrest, better if the patient is in shock, better still if normotensive with right ventricular dysfunction, and best of all with normal pulmonary and systemic haemodynamics.


The simplest way to determine right ventricular function in the emergency department is by echo. It may also help identify other causes of chest pain and cardiovascular embarrassment such as myocardial infarction and aortic dissection.

What is the evidence for the use of thrombolysis in patients with pulmonary embolism?

The literature search identified 10 randomised trials(20-29) comparing thrombolysis to heparin in patients with pulmonary embolism (as outlined in table 2). Five trials excluded patients with shock (defined usually as systolic blood pressure <90 mm Hg). Nine delivered the thrombolysis intravenously and one delivered it into the pulmonary artery.

Five used recombinant tissue plasminogen activator, three streptokinase, and two urokinase. None used tenecteplase. Only one trial looked specifically at patients with shock28 and one investigated patients without shock but with evidence of right heart strain or pulmonary hypertension or right ventricular dysfunction. The first nine trials in the table, which involved 461 patients in total, were included in a meta-analysis by Thabut et al in 2002.30

This meta-analysis concluded that in this unselected group of patients the use of thrombolytics to treat pulmonary embolism was not associated with a reduction in mortality (relative risk 0.63; 95% CI 0.32 to 1.23) or recurrence of disease (relative risk = 0.59; 95% CI 0.30 to 1.18) but did confer a risk of haemorrhage over heparin (relative risk = 1.76 95% CI 1.04 to 2.98). Major haemorrhage is defined here as intracerebral, retroperitoneal, or other bleeding requiring surgery or a blood transfusion.

A further meta-analysis of the same 461 patients and nine trials by Agnelli and colleagues,31 also published in 2002, concluded that thrombolytic therapy conferred no mortality advantage over heparin, (relative risk = 0.59; 95% CI 0.27 to 1.25) and also resulted in no change in disease recurrence (relative risk = 0.60; 95% CI 0.29 to 1.15) or risk of major haemorrhage (relative risk = 1.49; 95% CI 0.85 to 2.81).

In this paper, major haemorrhage was defined as fatal, intracranial, associated with a decrease in haemoglobin of at least 2 g/dl, or requiring a transfusion of two or more units of red blood cells. Agnelli et al also examined the combined endpoint of recurrence and/or death, which occurred in 25/241 (10.4%) patients thrombolysed and 38/220 (17.3%) treated with heparin. This gives a significantly lower relative risk of death or recurrence (relative risk = 0.55; 95% CI 0.33 to 0.96).

These meta-analyses involved relatively few patients, and the inclusion of so many trials where "shock" was an exclusion criterion weakens their power. With one exception,28 the other trials did not provide enough information to allow subset analysis of those with shock or right ventricular dysfunction. The trials of thrombolysis in patients with pulmonary embolism may be underpowered to detect a treatment advantage.

Alternatively the benefits of thrombolysis may outweigh the risks in only those few patients at high risk of death from pulmonary embolism.
If thrombolysis is in fact effective, it is essential to use it in a subgroup where the potential benefit of therapy outweighs the risk.

Use of thrombolysis in different groups of patients

Patients with pulmonary embolism and systemic hypotension
The use of thrombolysis in this group is widely advocated, reflecting the high mortality rate of such patients and encouraging case reports. However, only one small randomised trial exists. In 1995, Jerges-Sanches et al compared thrombolysis with streptokinase to intravenous heparin in eight patients.


The trial was stopped early, as all four patients thrombolysed lived whereas the four treated with heparin died. But there was a major difference between the two groups: the four patients who had streptokinase were new presentations. Those receiving heparin were already receiving heparin treatment in other hospitals for small emboli when they suddenly suffered massive pulmonary emboli and were transferred to the trial centre (this difference occurred by chance).

Patients with cardiopulmonary arrest

Much of what we offer patients who have arrested as a result of pulmonary embolism is not substantiated by clinical trials.34 The mortality in this group has been reported as 65% in the MAPPET registry,17 and use of thrombolytics is widely advocated.14 33 In 2001, Bailen37 reviewed the literature on thrombolysis for fulminant pulmonary embolism with circulatory collapse requiring cardiopulmonary resuscitation, and found about 100 case reports and a retrospective series of 42 patients.

In this series, 21 patients received heparin and 21 received thrombolytics, resulting in no mortality difference but a higher return of spontaneous circulation in favour of thrombolysis. Many of this group were young people and had suffered postoperative or postpartum emboli. The high number of survivors and paucity of bleeding complications coupled with the poor prognosis of this group suggests that the use of thrombolysis may be beneficial in this setting.

In their 1999 review (predominantly of case reports), Newmann et al35 found a survival rate of 75% (50/67) for patients given thrombolysis after undergoing cardiopulmonary resuscitation for varied causes. Many of these patients underwent long periods of cardiopulmonary resuscitation, with surprisingly good neurological recovery. However, this type of study is likely to suffer from reporting bias. Newmann proposes that thrombolysis may have neuroprotective properties through lysing microvascular thrombi and improving cerebral microvascular flow.

The use of thrombolysis in patients who have arrested as a result of an unknown cause has been proposed, as most patients will have thrombolytic responsive disease - coronary ischaemia, or pulmonary embolism.35 Causes such as subarachnoid or intracerebral haemorrhage are contraindications for thrombolysis, but prognosis in this setting is dismal and other contraindications such as trauma or gastrointestinal haemorrhage are readily identifiable.

Bottiger36 performed a nonrandomised prospective trial comparing 50 mg of recombinant tissue plasminogen activator and intravenous heparin with conventional cardiopulmonary resuscitation and no anticoagulation in patients with >15 minutes of arrest (repeated at 30 minutes if no return of spontaneous circulation occurred), and found an improved rate of return of spontaneous circulation (68% v 44%) and higher rate of hospital discharge (15% v 8%) in the treatment arm. Based on this protocol, thirteen arrested patients would require treatment with thrombolysis to result in one extra survivor.

Patients with pulmonary embolism and with right ventricular dysfunction

Right ventricular dysfunction has been shown to predict disease recurrence and mortality. In a randomised controlled trial, Goldhaber16 found right ventricular function improved at 24 hours in 16/18 thrombolysed patients compared with 8/18 treated with heparin.

Konstantinides19 found a 30 day mortality of 4.7% in 169 patients who received thrombolysis, compared with 11.1% in 550 who were treated with heparin. Recurrence rates were 7.7% and 18.7% respectively. These data were from a multicentre registry (not a randomised trial) of 719 patients with echo or cardiac catheter evidence of right ventricular dysfunction or pulmonary hypertension but systolic pressures >90 mm Hg. However, the group receiving heparin were older, and more of them had congestive cardiac failure and chronic respiratory problems.

In a retrospective study of patients with echocardiographic evidence of right ventricular dysfunction, Hamel38 compared 64 patients treated with thrombolysis with 64 treated with heparin. There were no deaths or bleeding complications in the heparin group, but haemorrhage occurred in 15.6% of the thrombolysed group, and 6.3% died.

In a randomised trial of 256 patients with pulmonary embolism and evidence of right ventricular dysfunction (defined by echocardiography, right heart catheterisation, or ECG changes), Konstantinides found a 30 day mortality of 3.4% in those receiving 100 mg reteplase over two hours plus heparin and 2.2% in those treated with heparin alone (p = 0.71). The mortality in this study was unexpectedly low. There was only one fatal bleed in the heparin group and bleeding complications were not statistically different between the two groups.


Echocardiography is a widely available bedside test which helps diagnosis, risk stratification, and exclusion of alternative diagnoses such as right ventricular infarct, aortic dissection, and pericardial effusion or tamponade. Recombinant tissue plasminogen activator regimens showed better pulmonary flow at two hours but not subsequently compared with the other agents.

Goldhaber compared recombinant tissue plasminogen activator at a dose of 100 mg over two hours with the same agent at 0.6 mg/kg over 15 minutes, and found similar improvements in all parameters as measured by echo, angiography, and ventilation-perfusion scan. Tebe49 compared recombinant tissue plasminogen activator 100 mg over two hours with reteplase 10 units at baseline and repeated at 30 minutes, and found no difference in all measured pulmonary haemodynamics.

No single agent or regimen has been shown to be more effective than any other, though the theoretical risk of worsening hypotension with streptokinase in patients with circulatory compromise suggests other thrombolytic agents may be preferable.

How should you give thrombolytics?

Despite the theoretical advantages of higher local concentration at the clot site, the delivery of thrombolysis via pulmonary artery catheter offers no advantage in terms of mortality, morbidity, or haemorrhage over peripheral administration and carries the risks of a more invasive procedure (according to the results of a single trial).
Bolus therapy may be expected to produce more rapid thrombolysis with improved outcome but two trials found this method of administration offered no advantage over infusion regimens.

What are the complications of thrombolysis?

The major complication of thrombolysis is haemorrhage, although allergy, hypotension, fever, nausea, and vomiting may occur.
The overall risk of haemorrhage with thrombolysis is reported as
6-20%, with no significant differences between the alternative agents.

The most feared bleeding complication is intracerebral haemorrhage, which has a reported incidence of 0.6-3%.
The risk factors associated with intracranial bleeding are:
• Increasing age (0.4% at <65 years and 2.1% at >75 years)
• Increasing dose of thrombolytic
• Chronic hypertension
• Female sex
• Low body mass (with weight <70 kg being associated with a fourfold increase)
• Pulmonary catheterisation.


The risk of bleeding largely defines the contraindications to thrombolysis.
These relative contraindications are
• active or recent (within six weeks) bleeding
• intracranial disease,
• trauma, visceral biopsy,
• surgery, or
• gastrointestinal bleed,
• haemorrhagic disorder,
• hepatic or renal failure,
• pregnancy, puncture of a non-compressable vessel,
• pericarditis.

What time window do you have to give thrombolysis?

The time frame for thrombolysis for pulmonary embolism is different to that for myocardial infarction. Trials have delivered thrombolysis up to seven days after the embolic event and demonstrated improvements in pulmonary perfusion. However delivering therapy as early as possible makes good sense - and is recommended by the British Thoracic Society guidelines. Indeed 75% of those who die from pulmonary embolism do so within one hour of the event.

What are the alternatives to thrombolysis in critically ill patients?

Given the risk of haemorrhage with thrombolysis and the improving surgical techniques, alternative methods of treating massive pulmonary embolism have been explored, including pulmonary catheterisation and surgical embolectomy. The former has been shown to improve cardiac output and has a mortality of 11% with a "success" rate of 91% in a series of non-shocked patients with moderate to severe right ventricular dysfunction.

Cardiac catheterisation, mechanical fragmentation techniques, high velocity jet fragmentation, and combinations of mechanical clot disruption with low/usual dose thrombolysis have all been described in case reports and case series but there is no evidence from trials. It is unlikely that adherent clot more than 48-72 hours old is removable.

There is no randomised trial of medical versus surgical therapy. Surgical embolectomy has been used in critically ill patients and when thrombolysis is contraindicated. Perioperative mortality rates are reported as 29-44% in this group. Gulba reported a series of 23 surgically and 24 medically treated patients with systolic blood pressure <100 mm Hg, and reported survival rates of 77% and 67% respectively. In a series of 29 patients including those with right ventricular dysfunction but normal systolic blood pressure, Aklog69 reported a mortality of 11% at one month.


Conclusions
The use of thrombolysis in patients who have had a cardiac arrest thought to be due to pulmonary embolus is supported by some evidence and appears to improve survival to hospital discharge in one study. Thrombolysis may be beneficial in patients with massive pulmonary embolism with systemic hypotension (although good quality evidence of benefit is lacking)

In those without shock but with right ventricular dysfunction on echo, there are studies showing more rapid clot lysis and faster normalisation of cardiac function when treated by thrombolysis and heparin as opposed to heparin alone (but thrombolysis has not been shown to reduce mortality and in this subgroup confers a risk of haemorrhage) Thrombolysis should only be used in these patients on an individual basis with careful consideration of opposing risk factors
For patients with no cardiovascular compromise, thrombolysis is not advisable.