What is acute pulmonary embolism?
Acute pulmonary embolism (APE) is a major cause of death and illness in people in hospital. APE occurs when a piece of blood clot (the embolus) breaks off from a blood clot elsewhere in the body (deep vein thrombosis) and travels in the blood to the lungs. The embolus gets stuck in the lung blood vessel(s), and the consequences range from no symptoms to sudden death. The risk of dying from APE can be classified by clinical assessment, along with specialised medical imaging and blood tests. The risk of death determines what treatment the affected person should receive.
How is acute pulmonary embolism treated?
The main treatment for APE is blood thinning medications (anticoagulation). This stops new blood clots from forming whilst the body slowly dissolves the clot, but does not get rid of the blood clot. People with high-risk (massive) APE are so ill that an additional clot-busting medicine (thrombolytic) is recommended – as well as anticoagulation – to save their lives. The thrombolytic is usually given via a drip into an arm vein (systemic thrombolysis). The thrombolytic circulates in the blood to the lungs and dissolves the clot. Unfortunately, most people do not receive systemic thrombolysis because they have a risk factor (such as recent surgery), which makes the risk of major bleeding after receiving the thrombolytic too great. Systemic thrombolysis does not work in 8% of people who receive it, so they need another dose or an alternative treatment. Surgery for APE is an alternative rescue treatment, but it is not widely available.
For intermediate-risk (submassive) APE, giving the thrombolytic medicine is not recommended because the risk of major bleeding outweighs the benefit. These people generally only receive anticoagulation. However, some people at intermediate risk will get worse and die. Identifying this higher-risk subgroup so they can receive more aggressive treatment may reduce death and illness.
What did we want to find out?
There is a lot of interest in new catheter-directed treatments specifically designed for treating APE. The catheter device is a small, flexible plastic tube that is inserted through a small cut into a vein in the neck or groin. The treating doctor watches on a screen as they steer the tube painlessly through the person's veins into the blood clot in the lungs, using X-ray guidance. This avoids any big cuts and usually does not need general anaesthetic. The catheter delivers the thrombolytic medicine directly into the blood clot. This method may be more effective at dissolving the blood clots than medicines given into the bloodstream at the arm, which are normally redirected away from blocked lung vessels. A much smaller dose (about 10% to 20%) of the thrombolytic medicine can be used, compared with the dose given in the arm vein. This may reduce the chance of major bleeding, but with the same benefit in dissolving the clot. Other catheter devices can suck the blood clot directly from the blocked blood vessel (catheter embolectomy). This may be useful for people who cannot receive thrombolysis (e.g. because of recent surgery, previous stroke, or pregnancy) or if thrombolysis has not worked. Some studies suggest that the more clot cleared from the lungs, the smaller the chance that the affected person will develop chronic health problems.
Unfortunately, we do not know how catheter-based treatments compare with other treatments for people with high-risk and intermediate-risk APE. Catheter devices are expensive and have their own complications. We need to know the best APE treatments to save lives and prevent accidental harm.
What did we do?
We performed a detailed literature search for randomised controlled trials (RCTs) of catheter-based treatments of high-risk (massive) and intermediate-risk (submassive) APE. We chose RCTs because these provide the highest standard of evidence to inform treatment guidelines. We compared and summarised the results and rated our confidence in the evidence, based on factors such as trial methods and size.
What did we find?
One trial met our inclusion criteria. This trial looked at the benefit of the addition of catheter-directed thrombolysis to anticoagulation with heparin in 59 people with intermediate-risk APE. The trial showed no clear differences between catheter-directed thrombolysis plus anticoagulation versus anticoagulation alone in deaths, major and minor bleeding, recurrent APE and length of hospital stay. Quality of life was not assessed.
What are the limitations of the evidence?
We have very little confidence in the evidence because the trial staff and participants were aware of which treatment the participants received, and the trial involved a small number of participants.
There is a lack of solid evidence to inform clinicians, patients and health system funders about the role of catheter-based treatments in treating high-risk or intermediate-risk APE.
The evidence is up to date to March 2022.
There is a lack of evidence to support widespread adoption of catheter-based interventional therapies for APE. We identified one small trial showing no clear differences between ultrasound-augmented catheter-directed thrombolysis with alteplase plus systemic heparinisation versus systemic heparinisation alone in all-cause mortality, major and minor haemorrhage rates, recurrent APE and length of hospital stay. Quality of life was not assessed.
Multiple small retrospective case series, prospective patient registries and single-arm studies suggest potential benefits of catheter-based treatments, but they provide insufficient evidence to recommend this approach over other evidence-based treatments.
Researchers should consider clinically relevant primary outcomes (e.g. mortality and exercise tolerance), rather than surrogate markers (e.g. right ventricular to left ventricular (RV:LV) ratio or thrombus burden), which have limited clinical utility. Trials must include a control group to determine if the effects are specific to the treatment.
Acute pulmonary embolism (APE) is a major cause of acute morbidity and mortality. APE results in long-term morbidity in up to 50% of survivors, known as post-pulmonary embolism (post-PE) syndrome.
APE can be classified according to the short-term (30-day) risk of mortality, based on a variety of clinical, imaging and laboratory findings. Most mortality and morbidity is concentrated in high-risk (massive) and intermediate-risk (submassive) APE. The first-line treatment for APE is systemic anticoagulation.
High-risk (massive) APE accounts for less than 10% of APE cases and is a life-threatening medical emergency, requiring immediate reperfusion treatment to prevent death. Systemic thrombolysis is the recommended treatment for high-risk (massive) APE. However, only a minority of the people affected receive systemic thrombolysis, due to comorbidities or the 10% risk of major haemorrhagic side effects. Of those who do receive systemic thrombolysis, 8% do not respond in a timely manner. Surgical pulmonary embolectomy is an alternative reperfusion treatment, but is not widely available.
Intermediate-risk (submassive) APE represents 45% to 65% of APE cases, with a short-term mortality rate of around 3%. Systemic thrombolysis is not recommended for this group, as major haemorrhagic complications outweigh the benefit. However, the people at higher risk within this group have a short-term mortality of around 12%, suggesting that anticoagulation alone is not an adequate treatment. Identification and more aggressive treatment of people at intermediate to high risk, who have a more favourable risk profile for reperfusion treatments, could reduce short-term mortality and potentially reduce post-PE syndrome.
Catheter-directed treatments (catheter-directed thrombolysis and catheter embolectomy) are minimally invasive reperfusion treatments for high- and intermediate-risk APE. Catheter-directed treatments can be used either as the primary treatment or as salvage treatment after failure of systemic thrombolysis. Catheter-directed thrombolysis administers 10% to 20% of the systemic thrombolysis dose directly into the thrombus in the lungs, potentially reducing the risks of haemorrhagic side effects. Catheter embolectomy mechanically removes the thrombus without the need for thrombolysis, and may be useful for people with contraindications for thrombolysis.
Currently, the benefits of catheter-based APE treatments compared with existing medical and surgical treatment are unclear despite increasing adoption of catheter treatments by PE response teams. This review examines the evidence for the use of catheter-directed treatments in high- and intermediate-risk APE. This evidence could help guide the optimal treatment strategy for people affected by this common and life-threatening condition.
To assess the effects of catheter-directed therapies versus alternative treatments for high-risk (massive) and intermediate-risk (submassive) APE.
We used standard, extensive Cochrane search methods. The latest search was 15 March 2022.
We included randomised controlled trials (RCTs) of catheter-directed therapies for the treatment of high-risk (massive) and intermediate-risk (submassive) APE. We excluded catheter-directed treatments for non-PE. We applied no restrictions on participant age or on the date, language or publication status of RCTs.
We used standard Cochrane methods. The main outcomes were all-cause mortality, treatment-associated major and minor haemorrhage rates based on two established clinical definitions, recurrent APE requiring retreatment or change to a different APE treatment, length of hospital stay, and quality of life. We used GRADE to assess certainty of evidence for each outcome.
We identified one RCT (59 participants) of (ultrasound-augmented) catheter-directed thrombolysis for intermediate-risk (submassive) APE.
We found no trials of any catheter-directed treatments (thrombectomy or thrombolysis) in people with high-risk (massive) APE or of catheter-based embolectomy in people with intermediate-risk (submassive) APE.
The included trial compared ultrasound-augmented catheter-directed thrombolysis with alteplase and systemic heparinisation versus systemic heparinisation alone. In the treatment group, each participant received an infusion of alteplase 10 mg or 20 mg over 15 hours. We identified a high risk of selection and performance bias, low risk of detection and reporting bias, and unclear risk of attrition and other bias. Certainty of evidence was very low because of risk of bias and imprecision.
By 90 days, there was no clear difference in all-cause mortality between the treatment group and control group. A single death occurred in the control group at 20 days after randomisation, but it was unrelated to the treatment or to APE (odds ratio (OR) 0.31, 95% confidence interval (CI) 0.01 to 7.96; 59 participants).
By 90 days, there were no episodes of treatment-associated major haemorrhage in either the treatment or control group. There was no clear difference in treatment-associated minor haemorrhage between the treatment and control group by 90 days (OR 3.11, 95% CI 0.30 to 31.79; 59 participants).
By 90 days, there were no episodes of recurrent APE requiring retreatment or change to a different APE treatment in the treatment or control group.
There was no clear difference in the length of mean total hospital stay between the treatment and control groups. Mean stay was 8.9 (standard deviation (SD) 3.4) days in the treatment group versus 8.6 (SD 3.9) days in the control group (mean difference 0.30, 95% CI −1.57 to 2.17; 59 participants).
The included trial did not investigate quality of life measures.