Combined TPA/DNase Benefits Pleural Infection Patients

Intrapleural therapy with combined recombinant tissue plasminogen activator (TPA) and DNase improved fluid drainage in patients with pleural infection, led to fewer surgical referrals and reduced the length of hospital stays, according to results of the second Multicenter Intrapleural Sepsis Trial (MIST 2) reported in the Aug. 11, 2011, issue of the New England Journal of Medicine. However, neither agent when used alone was more effective than placebo.

Pleural infection affects more than 65,000 patients annually in the United States and United Kingdom, with a mortality rate between 10% and 20%. Standard therapy typically consists of antibiotics and tube drainage of the infected fluid and surgery when sepsis and infected fluid are not effectively controlled; more than 30% of patients either die or require surgery.

Although the large first Multicenter Intrapleural Sepsis Trial (MIST1) showed no benefit of intrapleural streptokinase, the strong clinical and observational support for the use of fibrinolytic agents inspired the MIST2 trial using a different direct-acting fibrinolytic agent – recombinant TPA – coupled to the use of recombinant DNase (used in order to decrease viscosity due to extracellular bacterial DNA and to inhibit biofilm formation), which has shown use in animal studies.

In order to test these purported benefits, Dr. Najib M. Rahiman of the University of Oxford, and colleagues, conducted a double-blind, double-dummy factorial randomized trial of 210 patients with pleural infection at 11 centers in the United Kingdom between December 2005 and November 2008 (N. Engl. J. Med. 2011;365:518-26). They randomized patients to receive one of four treatments: TPA plus DNase, DNase plus placebo, TPA plus placebo, and double placebo. The primary analysis included 193 patients, with 51 receiving double placebo, 48 receiving TPA only, 46 receiving DNase only and 48 receiving both agents.

The dose of DNase (Pulmozyme, Roche) was 5 mg and the dose of TPA (Actilyse, Boehringer Ingelheim) was 10 mg. Intrapleural medications were given twice daily for 3 days and each administration was followed by drain-clamping to permit the study drug to remain in the pleural space for 1 hr. Pulmozyme is approved by the U.S. Food and Drug Administration for the treatment of cystic fibrosis. Actilyse (marketed as Activase in the United States) is FDA-approved for use in acute ischemic stroke.

Baseline characteristics, including age, sex, percent of hemothorax occupied with pleural fluid, and characteristics of the infection and physiological status of the pleural fluid were not significantly different between the four groups.

The mean decrease in pleural opacity, the primary endpoint, was 29.5% in the TPA-DNase group between days 1 and 7. This was clinically and statistically significant, compared with 17.2% in the placebo group. There was no significant improvement in the primary outcome compared with the placebo when using TPA alone (17.2% decrease) or DNase alone (14.7%).

Researchers also looked at several secondary endpoints and found that:

• The frequency of referral for surgery at 3 months was 2 out of 48 patients (4%) in the TPA-DNase group vs. 8 out of 51 patients (16%) in the placebo group, 18 of 46 patients (39%) in the DNase only group and 3 out of 48 patients (6%) in the TPA group. All referrals were due to clinical evidence of worsening infection.

• Hospital stays on average were 11.8 days for the TPA-DNase group vs. 16.5 days, 28.2 days and 24.8 days for the TPA, DNase and placebo groups, respectively.

• Mortality rates were not significantly different for all four study groups at 3 months and 12 months. At 3 months , mortality rates were 2 out of 50 patients (4%) in the placebo group, 4 out of 48 patients (8%) in the TPA-DNase group, 4 out of 48 patients (8%) in the TPA group and 6 out of 46 (13%) in the DNase group. At 12 months, mortality rates were 4 out of 48 (8%) patients in the placebo group, 5 out of 47 patients (11%) in the combination group, 5 out of 46 patients (11%) in the TPA group and 9 out of 45 patients (20%) in the DNase groups alone.

• By day 7, average C-reactive protein levels were nonsignificantly lower in the combination group than the placebo group, but were nonsignificantly greater in the TPA and DNase groups.

• By day 7, The average white cell count was nonsignificantly higher with TPA alone and nonsignificantly lower with DNase alone versus the placebo group, while the average count was significantly lower in the placebo group (a difference of 3.4x109 per liter).

• Thoracic surgery and deaths due to pleural infection were evenly distributed across all four groups.