A pulmonary embolus is a potentially fatal blood clot that lodges in the main artery of the lungs, straining the right side of the heart and affecting blood circulation. Patients with this condition are at risk for new emboli forming (recurrence). In the case of a massive pulmonary embolism, treatment to restore blood flow is urgently required. Heparin thins the blood, but newer drugs that actively break up the clots (thrombolytics) may act more quickly and may be more effective. These newer drugs include streptokinase, urokinase, and recombinant tissue-type plasminogen activator. The major complication of this treatment is bleeding.
Review authors searched the literature and included 18 studies in this update (evidence current to 16 April 2018). These trials involved 2197 adult participants with pulmonary embolism, who were randomly assigned to a thrombolytic agent followed by heparin versus heparin alone or heparin plus placebo or surgical procedure. We were able to combine data from 17 clinical trials with a total of 2167 patients. Thrombolytics seemed to lower the likelihood of death or recurrence of blood clots over heparin. However, after exclusion of four very low-quality studies, this benefit disappeared. On the other hand, thrombolytics caused more side effects, including major and minor bleeding events (haemorrhagic events) and stroke, than heparin alone. Limited information from five trials shows that thrombolytics were better at improving blood flow through the lungs; seven included studies show that they can improve heart function.
Quality of the evidence
The quality of the evidence is low because of several important design limitations, potential influence of pharmaceutical companies, and small sample sizes. We need more large and rigorous trials to examine whether thrombolytic therapy is truly beneficial for pulmonary embolism.
Low-quality evidence suggests that thrombolytics reduce death following acute pulmonary embolism compared with heparin. The included studies used a variety of thrombolytic drugs. Thrombolytic therapy may be helpful in reducing the recurrence of pulmonary emboli but may cause major and minor haemorrhagic events and stroke. More high-quality, blinded randomised controlled trials assessing safety and cost-effectiveness of therapies for pulmonary embolism are required.
Thrombolytic therapy is usually reserved for patients with clinically serious or massive pulmonary embolism (PE). Evidence suggests that thrombolytic agents may dissolve blood clots more rapidly than heparin and may reduce the death rate associated with PE. However, there are still concerns about the possible risk of adverse effects of thrombolytic therapy, such as major or minor haemorrhage. This is the third update of the Cochrane review first published in 2006.
To assess the effects of thrombolytic therapy for acute pulmonary embolism.
The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase, and CINAHL databases and the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers to 16 April 2018. We undertook reference checking to identify additional studies.
We included randomised controlled trials (RCTs) that compared thrombolytic therapy followed by heparin versus heparin alone, heparin plus placebo, or surgical intervention for patients with acute PE. We did not include trials comparing two different thrombolytic agents or different doses of the same thrombolytic drug.
Two review authors (JY, QH) assessed the eligibility and quality of trials and extracted data. We calculated effect estimates using the odds ratio (OR) with 95% confidence interval (CI) or the mean difference (MD) with 95% CI. We assessed the quality of the evidence using GRADE criteria.
We identified no new studies for inclusion in this 2018 update. We included in the review 18 trials with a total of 2197 participants. We were not able to include one study in the meta-analysis because it provided no data that we could extract. Most of the studies carried a high risk of bias because of high or unclear risk related to randomisation and blinding. Meta-analysis showed that, compared with heparin alone, or heparin plus placebo, thrombolytics plus heparin can reduce the odds of death (OR 0.57, 95% CI 0.37 to 0.87, 2167 participants, P = 0.01, low-quality evidence) and recurrence of PE (OR 0.51, 95% CI 0.29 to 0.89, 1898 participants, P = 0.02, low-quality evidence). Effects on mortality weakened when we excluded from analysis four studies at high risk of bias (OR 0.66, 95% CI 0.42 to 1.06, 2054 participants, P = 0.08). The incidence of major and minor haemorrhagic events was higher in the thrombolytics group than in the control group (OR 2.90, 95% CI 1.95 to 4.31, 1897 participants, P < 0.001, low-quality evidence; OR 3.09, 95% CI 1.58 to 6.06, 1553 participants, P = 0.001, very low-quality evidence, respectively). We downgraded the quality of the evidence to low or very low because of design limitations, potential influence of pharmaceutical companies, and small sample sizes. Length of hospital stay (mean difference (MD) -0.89, 95% CI -3.13 to 1.34) and quality of life were similar between the two treatment groups. Limited information from a small number of trials indicated that thrombolytics may improve haemodynamic outcomes, perfusion lung scanning, pulmonary angiogram assessment, echocardiograms, pulmonary hypertension, coagulation parameters, clinical outcomes, and survival time to a greater extent than heparin alone. However, the heterogeneity of the studies and the small number of participants involved warrant caution when results are interpreted. Similarily, fewer participants from the thrombolytics group required escalation of treatment. None of the included studies reported on post-thrombotic syndrome or compared the costs of different treatments.