Clot-busting drugs for infections of the lining of the lung

Background

Empyema and complicated parapneumonic effusion are conditions involving infected fluid gathering between the lung and the chest wall (the pleural space). They are treated by draining the fluid with a tube inserted through the chest into the fluid (a 'chest tube'), along with antibiotics. If this does not work, then surgery is usually needed to drain the fluid. Fibrinolytic drugs ('clot-busting drugs') may make the infected pleural fluid thinner, less sticky and easier to drain via a chest tube, meaning that surgery may not be needed.

Review question

We wanted to know if fibrinolytics reduced the need for people with infections in the pleural space to have surgery to fix the infection. We also wanted to see if these medicines reduced the chance of people dying due to these infections; whether the fibrinolytic treatment worked overall; and whether these medicines caused serious side effects. We also wanted to know if one fibrinolytic medicine was more effective than another.

Study characteristics

We searched for studies up to August 2019. We included 10 studies with a total of 993 patients comparing fibrinolytics with a placebo and compared these to look for differences. We also included two studies comparing different fibrinolytics with a total of 149 patients and compared these separately.

Key findings

We found some low-certainty evidence that fibrinolytics moderately reduced the need for surgery. There was no clear evidence that fibrinolytics changed the risk of death. There was some low-certainty evidence which showed that there may be a risk of more side effects (mostly bleeding) with fibrinolytics but this is uncertain. We found no clear evidence that any single fibrinolytic was better than another.

Certainty of the evidence

We considered the certainty of the evidence identified comparing fibrinolytic with placebo to vary from moderate (risk of death) to very low (overall treatment failure). This was mostly due to some studies having one or more domains at high risk of bias as well as concerns that not all studies of this treatment appear to have been published. We considered the evidence comparing individual fibrinolytics to be of low certainty due to not enough patients in the studies as well as one study being at a high risk of bias.

Authors' conclusions: 

In patients with complicated infective pleural effusion or empyema, intrapleural fibrinolytic therapy was associated with a reduction in the requirement for surgical intervention and overall treatment failure but with no evidence of change in mortality. Discordance between the negative largest trial of this therapy and other studies is of concern, however, as is an absence of significant effect when analysing low risk of bias trials only. The reasons for this difference are uncertain but may include publication bias. Intrapleural fibrinolytics may increase the rate of serious adverse events, but the evidence is insufficient to confirm or exclude this possibility.

Read the full abstract...
Background: 

Pleural infection, including parapneumonic effusions and thoracic empyema, may complicate lower respiratory tract infections. Standard treatment of these collections in adults involves antibiotic therapy, effective drainage of infected fluid and surgical intervention if conservative management fails. Intrapleural fibrinolytic agents such as streptokinase and alteplase have been hypothesised to improve fluid drainage in complicated parapneumonic effusions and empyema and therefore improve treatment outcomes and prevent the need for thoracic surgical intervention. Intrapleural fibrinolytic agents have been used in combination with DNase, but this is beyond the scope of this review.

Objectives: 

To assess the benefits and harms of adding intrapleural fibrinolytic therapy to standard conservative therapy (intercostal catheter drainage and antibiotic therapy) in the treatment of complicated parapneumonic effusions and empyema.

Search strategy: 

We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and Embase, ClinicalTrials.gov and the World Health Organization (WHO) trials portal. We contacted trial authors for further information and requested details regarding the possibility of unpublished trials. The most recent search was conducted on 28 August 2019.

Selection criteria: 

Parallel-group randomised controlled trials (RCTs) in adult patients with post-pneumonic empyema or complicated parapneumonic effusions (excluding tuberculous effusions) who had not had prior surgical intervention or trauma comparing an intrapleural fibrinolytic agent (streptokinase, alteplase or urokinase) versus placebo or a comparison of two fibrinolytic agents.

Data collection and analysis: 

Two review authors independently extracted data. We contacted study authors for further information. We used odds ratios (OR) for dichotomous data and reported 95% confidence intervals (CIs). We used Cochrane's standard methodological procedures of meta-analysis. We applied the GRADE approach to summarise results and to assess the overall certainty of evidence.

Main results: 

We included in this review a total of 12 RCTs. Ten studies assessed fibrinolytic agents versus placebo (993 participants); one study compared streptokinase with urokinase (50 participants); and one compared alteplase versus urokinase (99 participants). The primary outcomes were death, requirement for surgical intervention, overall treatment failure and serious adverse effects. All studies were in the inpatient setting. Outcomes were measured at varying time points from hospital discharge to three months. Seven trials were at low or unclear risk of bias and two at high risk of bias due to inadequate randomisation and inappropriate study design respectively.

We found no evidence of difference in overall mortality with fibrinolytic versus placebo (OR 1.16, 95% CI 0.71 to 1.91; 8 studies, 867 participants; I² = 0%; moderate certainty of evidence). We found evidence of a reduction in surgical intervention with fibrinolysis in the same studies (OR 0.37, 95% CI 0.21 to 0.68; 8 studies, 897 participants; I² = 51%; low certainty of evidence); and overall treatment failure (OR 0.16, 95% CI 0.05 to 0.58; 7 studies, 769 participants; I² = 88%; very low certainty of evidence, with evidence of significant heterogeneity). We found no clear evidence of an increase in adverse effects with intrapleural fibrinolysis, although this cannot be excluded (OR 1.28, 95% CI 0.36 to 4.57; low certainty of evidence). In a sensitivity analysis, the reduction in referrals for surgery and overall treatment failure with fibrinolysis disappeared when the analysis was confined to studies at low or unclear risk of bias. In a moderate-risk population (baseline 14% risk of death, 20% risk of surgery, 27% risk of treatment failure), intra-pleural fibrinolysis leads to 19 more deaths (36 fewer to 59 more), 115 fewer surgical interventions (150 fewer to 55 fewer) and 214 fewer overall treatment failures (252 fewer to 93 fewer) per 1000 people.

A single study of streptokinase versus urokinase found no clear difference between the treatments for requirement for surgery (OR 1.00, 95% CI 0.13 to 7.72; 50 participants; low-certainty evidence). A single study of alteplase versus urokinase showed no clear difference in requirement for surgery (OR alteplase versus urokinase 0.46, 95% CI 0.04 to 5.24) but an increased rate of adverse effects, primarily bleeding, with alteplase (OR 5.61, 95% CI 1.16 to 27.11; 99 participants; low-certainty evidence). This translated into 154 (6 to 499 more) serious adverse events with alteplase compared with urokinase per 1000 people treated.

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