Therapy U.K. Controlled Trial of Intrapleural Streptokinase for Pleural Infection
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Summary
Posted By:	jon field
E-Mail:	jonathan_field@health.qld.gov.au
Posted Date:	11/05/05
Title:	U.K. Controlled Trial of Intrapleural Streptokinase for Pleural Infection
Authors:	Nicholas A. Maskell, M.R.C.P., Christopher W.H. Davies, M.D., Andrew J. Nunn, M.Sc., Emma L. Hedley, Fergus V. Gleeson, F.R.C.P., Robert Miller, F.R.C.P., Rhian Gabe, M.Phil., Glyn L. Rees, Timothy E.A. Peto, F.R.C.P., Mark A. Woodhead, F.R.C.P., Donald J. Lane, F.R.C.P., Janet H. Darbyshire, M.B., Ch.B., Robert J.O. Davies, D.M., for the First Multicenter Intrapleural Sepsis Trial (MIST1) Group
Reference:	N Engl J Med. 2005 Mar 3;352(9):865-74.
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Abstract:	Background Intrapleural fibrinolytic agents are used in the drainage of infected pleural-fluid collections. This use is based on small trials that did not have the statistical power to evaluate accurately important clinical outcomes, including safety. We conducted a trial to clarify the therapeutic role of intrapleural streptokinase. Methods In this double-blind trial, 454 patients with pleural infection (defined by the presence of purulent pleural fluid or pleural fluid with a pH below 7.2 with signs of infection or by proven bacterial invasion of the pleural space) were randomly assigned to receive either intrapleural streptokinase (250,000 IU twice daily for three days) or placebo. Patients received antibiotics and underwent chest-tube drainage, surgery, and other treatment as part of routine care. The number of patients in the two groups who had died or needed surgical drainage at three months was compared (the primary end point); secondary end points were the rates of death and of surgery (analyzed separately), the radiographic outcome, and the length of the hospital stay. Results The groups were well matched at baseline. Among the 427 patients who received streptokinase or placebo, there was no significant difference between the groups in the proportion of patients who died or needed surgery (with streptokinase: 64 of 206 patients [31 percent]; with placebo: 60 of 221 [27 percent]; relative risk, 1.14 [95 percent confidence interval, 0.85 to 1.54; P=0.43), a result that excluded a clinically significant benefit of streptokinase. There was no benefit to streptokinase in terms of mortality, rate of surgery, radiographic outcomes, or length of the hospital stay. Serious adverse events (chest pain, fever, or allergy) were more common with streptokinase (7 percent, vs. 3 percent with placebo; relative risk, 2.49 [95 percent confidence interval, 0.98 to 6.36]; P=0.08). Conclusions The intrapleural administration of streptokinase does not improve mortality, the rate of surgery, or the length of the hospital stay among patients with pleural infection.
Are the Results Valid?
1. Was the assignment of patients to treatments randomized? ( Was allocation concealment maintained?)
	Yes The randomization code was prepared and held centrally by the trial statistician. After written informed consent was obtained, patients were randomly assigned to treatment groups by means of a telephone call to the study center.
2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?
2a. Was followup complete?
	Yes, almost. Twenty-four patients died, required surgery, or withdrew consent to the trial before receiving the study drug. Technically, inclusion in an intention to treat analysis does not depend on whether the patient actually received the study drug however, because this trial was blinded, it is unlikely that drop-outs prior to receiving study droug could have been biased. Full reporting should include a statement of exactly how many patients died prior to receiving study drug and how long after randomization they died. The main analysis included 430 subjects (208 of whom received streptokinase, and 222 placebo). Follow-up for the primary outcome analysis was complete for 427 of these patients (99 percent). Fifty-four patients did not receive all six doses of the study drug. Most of these patients ceased to receive the assigned treatment because of an adverse event or because the chest tube became displaced at a time when residual pleural fluid was minimal, so that further chest drainage was not necessary. The authors have focused mainly on the 430 pts who completed the trial. In the Discussion they have included an intention to treat analysis of all pts randomised.
2b. Were patients analyzed in the groups to which they were randomized?
	All patients were analysed in the groups to which they were randomised.
3. Were patients, health workers, and study personnel blind to treatment?
	Yes. The study was placebo controlled, so all health workers and study personnell should have been adequately blinded.
4. Were the groups similar at the start of the trial?
	Yes. Table 1 demonstrates good baseline balance.
5. Aside from the experimental intervention, were the groups treated equally?
	There was no standardisation of the other treatments for empyema. (ie antibiotics, technique of chest tube placement or its final position). In addition clinical judgement determined one of the primary outsome measures, referral for surgical drainage.
What are the Results?
1. How large was the treatment effect?
	There was no statistically or clinically significant difference between the groups in the proportion of patients who required surgical drainage or who died in the three months after randomization. In the streptokinase group, 64 of 206 patients (31 percent) had one of these outcomes, as did 60 of 221 patients (27 percent) in the placebo group (P=0.43) at three months. Where were also no differences in these outcomes at 12 months or when analyzed seperately.
2. How precise was the estimate of the treatment effect?
	The authors report Relative Risk for their primary outcome at 3 months(death or surgical drainage required): 1.14 [95 percent confidence interval, 0.85 to 1.54]; P=0.43 Calculation of the Absolute Risk Reduction reveals a 3.9% ARR in favour of placebo, with a 95% CI from -5% to 13%.
Will the Results Help Me In Caring For My Patients?
1. Can the results be applied to my patient care?
	Yes but.... this is a negative trial that was powered at only 80%. It does not rule out a potential benefit from SK.... however.... The study's inclusion criteria led to the enrollment of heterogeneous patients at all stages of empyema formation. Some patients probably had "organized" (fibrous) pleural infections and were unlikely to benefit from fibrinolysis. The absence of computed tomographic or ultrasonographic studies at enrollment and of comprehensive information on intraoperative findings makes it impossible to evaluate this factor. In this study the advanced age of many of the patients (mean [±SD] age 60±18 years) and the large proportion of patients with coexisting conditions (65 percent) most certainly influenced some of the study end points, such as the duration of the hospital stay, more strongly than did the potential benefits of fibrinolytic therapy. It remains possible, pending further studies, that more homogeneous subgroups of patients with fibrinopurulent empyemas may benefit from fibrinolytic therapy.
2. Were all clinically important outcomes considered?
	The 'need for surgery' as a component of the primary outcome measure is a little subjective, altho the clinicians were blinded.
3. Are the likely treatment benefits worth the potential harms and costs?
	There appeared to be no treatment benefit, however there was an increase in adverse events in the intervention group. There was a trend (p=0.08) towards an excess rate of serious adverse events in the streptokinase group. Fourteen patients receiving streptokinase (7 percent) had such events, as compared with six (3 percent) in the placebo group (relative risk, 2.49 [95 percent confidence interval, 0.98 to 6.36]; P=0.08) (Table 2). No patients had more than one adverse event.
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