Louise Choo

Intrapleural Use of Tissue Plasminogen Activator and DNase in Pleural Infection

BACKGROUND More than 30% of patients with pleural infection either die or require surgery. Drainage of infected fluid is key to successful treatment, but intrapleural fibrinolytic therapy did not improve outcomes in an earlier, large, randomized trial. METHODS We conducted a blinded, 2-by-2 factorial trial in which 210 patients with pleural infection were randomly assigned to receive one of four study treatments for 3 days: double placebo, intrapleural tissue plasminogen activator (t-PA) and DNase, t-PA and placebo, or DNase and placebo. The primary outcome was the change in pleural opacity, measured as the percentage of the hemithorax occupied by effusion, on chest radiography on day 7 as compared with day 1. Secondary outcomes included referral for surgery, duration of hospital stay, and adverse events. RESULTS The mean (±SD) change in pleural opacity was greater in the t-PA-DNase group than in the placebo group (-29.5±23.3% vs. -17.2±19.6%; difference, -7.9%; 95% confidence interval [CI], -13.4 to -2.4; P=0.005); the change observed with t-PA alone and with DNase alone (-17.2±24.3 and -14.7±16.4%, respectively) was not significantly different from that observed with placebo. The frequency of surgical referral at 3 months was lower in the t-PA-DNase group than in the placebo group (2 of 48 patients [4%] vs. 8 of 51 patients [16%]; odds ratio for surgical referral, 0.17; 95% CI, 0.03 to 0.87; P=0.03) but was greater in the DNase group (18 of 46 patients [39%]) than in the placebo group (odds ratio, 3.56; 95% CI, 1.30 to 9.75; P=0.01). Combined t-PA-DNase therapy was associated with a reduction in the hospital stay, as compared with placebo (difference, -6.7 days; 95% CI, -12.0 to -1.9; P=0.006); the hospital stay with either agent alone was not significantly different from that with placebo. The frequency of adverse events did not differ significantly among the groups. CONCLUSIONS Intrapleural t-PA-DNase therapy improved fluid drainage in patients with pleural infection and reduced the frequency of surgical referral and the duration of the hospital stay. Treatment with DNase alone or t-PA alone was ineffective. (Funded by an unrestricted educational grant to the University of Oxford from Roche UK and by others; Current Controlled Trials number, ISRCTN57454527.).

A no-prophylaxis platelet-transfusion strategy for hematologic cancers.

BACKGROUND The effectiveness of platelet transfusions to prevent bleeding in patients with hematologic cancers remains unclear. This trial assessed whether a policy of not giving prophylactic platelet transfusions was as effective and safe as a policy of providing prophylaxis. METHODS We conducted this randomized, open-label, noninferiority trial at 14 centers in the United Kingdom and Australia. Patients were randomly assigned to receive, or not to receive, prophylactic platelet transfusions when morning platelet counts were less than 10×10(9) per liter. Eligible patients were persons 16 years of age or older who were receiving chemotherapy or undergoing stem-cell transplantation and who had or were expected to have thrombocytopenia. The primary end point was bleeding of World Health Organization (WHO) grade 2, 3, or 4 up to 30 days after randomization. RESULTS A total of 600 patients (301 in the no-prophylaxis group and 299 in the prophylaxis group) underwent randomization between 2006 and 2011. Bleeding of WHO grade 2, 3, or 4 occurred in 151 of 300 patients (50%) in the no-prophylaxis group, as compared with 128 of 298 (43%) in the prophylaxis group (adjusted difference in proportions, 8.4 percentage points; 90% confidence interval, 1.7 to 15.2; P=0.06 for noninferiority). Patients in the no-prophylaxis group had more days with bleeding and a shorter time to the first bleeding episode than did patients in the prophylaxis group. Platelet use was markedly reduced in the no-prophylaxis group. A prespecified subgroup analysis identified similar rates of bleeding in the two study groups among patients undergoing autologous stem-cell transplantation. CONCLUSIONS The results of our study support the need for the continued use of prophylaxis with platelet transfusion and show the benefit of such prophylaxis for reducing bleeding, as compared with no prophylaxis. A significant number of patients had bleeding despite prophylaxis. (Funded by the National Health Service Blood and Transplant Research and Development Committee and the Australian Red Cross Blood Service; TOPPS Controlled-Trials.com number, ISRCTN08758735.).

The Transfusion Alternatives Preoperatively in Sickle Cell Disease (TAPS) study: a randomised, controlled, multicentre clinical trial

BACKGROUND No consensus exists on whether preoperative blood transfusions are beneficial in patients with sickle-cell disease. We assessed whether perioperative complication rates would be altered by preoperative transfusion. METHODS We did a multicentre, randomised trial. Eligible patients were aged at least 1 year, had haemoglobin SS or Sβ(0)thalassaemia sickle-cell-disease subtypes, and were scheduled for low-risk or medium-risk operations. Patients were randomly assigned no transfusion or transfusion no more than 10 days before surgery. The primary outcome was the proportion of clinically important complications between randomisation and 30 days after surgery. Analysis was by intention to treat. FINDINGS 67 (96%) of 70 enrolled patients-33 no preoperative transfusion and 34 preoperative transfusion-were assessed. 65 (97%) of 67 patients had the haemoglobin SS subtype and 54 (81%) were scheduled to undergo medium-risk surgery. 13 (39%) of 33 patients in the no-preoperative-transfusion group had clinically important complications, compared with five (15%) in the preoperative-transfusion group (p=0.023). Of these, 10 (30%) and one (3%), respectively, had serious adverse events. The unadjusted odds ratio of clinically important complications was 3.8 (95% CI 1.2-12.2, p=0.027). 10 (91%) of 11 serious adverse events were acute chest syndrome (nine in the no-preoperative-transfusion group and one in the preoperative-transfusion group). Duration of hospital stay and readmission rates did not differ between study groups. INTERPRETATION Preoperative transfusion was associated with decreased perioperative complications in patients with sickle-cell disease in this trial. This approach could, therefore, be beneficial for patients with the haemoglobin SS subtype who are scheduled to undergo low-risk and medium-risk surgeries. FUNDING NHS Blood and Transplant.

Prospective, Observational Study of Outcomes in Neonates With Severe Thrombocytopenia

OBJECTIVE: A cross-sectional, observational study of outcomes for neonates with severe neonatal thrombocytopenia (SNT; platelet count of <60 × 109 platelets per L) was performed to examine hemorrhage and use of platelet transfusions. METHODS: Neonates who were admitted to 7 NICUs and developed SNT were enrolled for daily data collection. RESULTS: Among 3652 neonatal admissions, 194 neonates (5%) developed SNT. The median gestational age of 169 enrolled neonates was 27 weeks (interquartile range [IQR]: 24–32 weeks), and the median birth weight was 822 g (IQR: 670–1300 g). Platelet count nadirs were <20 × 109, 20 to 39 × 109, and 40 to 59 × 109 platelets per L for 58 (34%), 64 (39%), and 47 (28%) of all enrolled infants, respectively. During the study, 31 infants (18%) had no recorded hemorrhage, 123 (73%) developed minor hemorrhage, and 15 (9%) developed major hemorrhage. Thirteen (87%) of 15 episodes of major hemorrhage occurred in neonates with gestational ages of <28 weeks. Platelet transfusions (n = 415) were administered to 116 infants (69%); for 338 (81%) transfusions, the main recorded reason was low platelet count. Transfusions increased the platelet count from a median of 27 × 109 platelets per L (IQR: 19–36 × 109 platelets per L) to 79 × 109 platelets per L (IQR: 47.5–127 × 109 platelets per L). CONCLUSIONS: Although one third of neonates enrolled in this study developed thrombocytopenia of <20 × 109 platelets per L, 91% did not develop major hemorrhage. Most platelet transfusions were given to neonates with thrombocytopenia with no bleeding or minor bleeding only.

Do All Patients With Hematologic Malignancies and Severe Thrombocytopenia Need Prophylactic Platelet Transfusions?: Background, Rationale, and Design of a Clinical Trial (Trial of Platelet Prophylaxis) to Assess the Effectiveness of Prophylactic Platelet Transfusions

Although considerable advances have been made in many aspects of platelet transfusion therapy in the last 30 years, some areas continue to provoke debate, including the use of prophylactic platelet transfusions for the prevention of thrombocytopenic bleeding in patients with bone marrow failure. We have designed a randomized controlled trial to compare prophylactic platelet use with a threshold of a platelet count of 10 x 10(9)/L with no prophylaxis in adult thrombocytopenic patients with hematologic malignancies. The trial question is whether a no-prophylactic policy for the use of platelet transfusions in patients with hematologic malignancies is not inferior to a threshold prophylactic policy at 10 x 10(9)/L, for bleeding at World Health Organization (WHO) grade 2, 3, or 4, up to 30 days from randomization. The primary outcome measure is the proportion of patients who have a significant clinical bleed, defined as WHO grade 2 or higher up to 30 days from randomization. Subsidiary clinical outcome measures include time to first bleed and a descriptive analysis of all severe bleeds. A bleeding assessment form is completed daily for all study subjects until day 30 from randomization. Minor modifications were made to the definitions at WHO grades 1 and 2 for petechiae and duration of nose bleeds, after piloting of the bleeding assessment forms. This study has been designed as a 2-stage randomized trial with an interim analysis planned after a minimum of 100 patients had been randomized and had completed their period of observation. Patients have initially been enrolled through 3 United Kingdom hematology centers. The interim analysis has been completed, and the results have confirmed a final sample size of 600 patients. Recruitment is now being extended to other centers in United Kingdom and Australia. Local research nurses are not blinded to treatment allocation, but a number of measures to reduce risk of assessment bias include repeated education around standard operating procedures, common definitions, and duplication of assessments. The expected completion date for the 5-year study is December 2011.

Prevalence of maternal anaemia and its predictors: a multi-centre study

OBJECTIVE To investigate the prevalence, predictors, and management of anaemia in pregnancy. STUDY DESIGN A multi centre study across 11 maternity units in the UK. Data were collected over a two week study period in 2008 on maternal history, haemoglobin (Hb) and ferritin concentrations, iron therapy during pregnancy and in the postpartum period. Logistic regression models were used to explore factors associated with anaemia during pregnancy. Main outcomes included anaemia, defined as Hb<11 g/dl at booking, Hb<10.5 g/dl in subsequent antenatal visits, and Hb<10 g/dl postnatally. RESULTS Completed data were received on 2103 of 2155 women (97% completion rate). Of these, 24.4% (502) (95% CI 22.5-26.2%) were anaemic at some stage during the antenatal period. Predictors for having anaemia by 32 weeks gestation included young maternal age (odds ratio 1.96, 95% CI 1.38-2.79), non-white ethnic origin (odds ratios varied 1.37-2.89 depending on ethnic origin) and increasing parity (odds ratio 1.24, 95% CI 1.08-1.41). Of women who had postnatal Hb levels checked, 30% (309/1031) were anaemic and, depending on centre, 16% to 86% of these received iron therapy. CONCLUSION Anaemia was reported in nearly one in four women in the antenatal period, and nearly one in three of the women who had a postpartum Hb checked. Despite national guidelines, there was considerable variation in administration of iron including low utilisation of parenteral iron therapy. Future research needs to focus on the consequences of iron deficiency anaemia for maternal and infant health outcomes and effectiveness of implementation strategies to reduce anaemia.

Severe thrombocytopenia and patterns of bleeding in neonates: results from a prospective observational study and implications for use of platelet transfusions

To describe patterns of clinical bleeding in neonates with severe thrombocytopenia (ST and platelet count <60 × 109 L−1), and to investigate the factors related to bleeding.

A randomized noninferiority crossover trial of corrected count increments and bleeding in thrombocytopenic hematology patients receiving 2- to 5- versus 6- or 7-day–stored platelets

Bacterial screening offers the possibility of extending platelet (PLT) storage to Day 7. We conducted a noninferiority, crossover trial comparing PLTs stored for 6 or 7 days versus 2 to 5 days.

Transfusion of prion‐filtered red cells does not increase the rate of alloimmunization or transfusion reactions in patients: results of the UK trial of prion‐filtered versus standard red cells in surgical patients (PRISM A)

This study, conducted for the UK Blood Transfusion Services (UKBTS), evaluated the clinical safety of red cells filtered through a CE‐marked prion removal filter (P‐Capt™). Patients requiring blood transfusion for elective procedures in nine UK hospitals were entered into a non‐randomized open trial to assess development of red cell antibodies to standard red cell (RCC) or prion‐filtered red cell concentrates (PF‐RCC) at eight weeks and six months post‐transfusion. Patients who received at least 1 unit of PF‐RCC were compared with a control cohort given RCC only. About 917 PF‐RCC and 1336 RCC units were transfused into 299 and 291 patients respectively. Twenty‐six new red cell antibodies were detected post‐transfusion in 10 patients in each arm, an overall alloimmunization rate of 4·4%. Neither the treatment arm [odds ratio (OR) 0·93, 95% confidence interval (CI) 0·3, 2·5] nor number of units transfused (OR 0·95, 95% CI 0·8, 1·1) had a significant effect on the proportion of patients who developed new alloantibodies. No pan‐reactive antibodies or antibodies specifically against PF‐RCC were detected. There was no difference in transfusion reactions between arms, and no novel transfusion‐related adverse events clearly attributable to PF‐RCC were seen. These data suggest that prion filtration of red cells does not reduce overall transfusion safety. This finding requires confirmation in large populations of transfused patients.

Cost-effectiveness analysis of preoperative transfusion in patients with sickle cell disease using evidence from the TAPS trial

The studys objective was to assess the cost‐effectiveness of preoperative transfusion compared with no preoperative transfusion in patients with sickle cell disease undergoing low‐ or medium‐risk surgery. Seventy patients with sickle cell disease (HbSS/Sß0thal genotypes) undergoing elective surgery participated in a multicentre randomised trial, Transfusion Alternatives Preoperatively in Sickle Cell Disease (TAPS). Here, a cost‐effectiveness analysis based on evidence from that trial is presented. A decision‐analytic model is used to incorporate long‐term consequences of transfusions and acute chest syndrome. Costs and health benefits, expressed as quality‐adjusted life years (QALYs), are reported from the ‘within‐trial’ analysis and for the decision‐analytic model. The probability of cost‐effectiveness for each form of management is calculated taking into account the small sample size and other sources of uncertainty. In the range of scenarios considered in the analysis, preoperative transfusion was more effective, with the mean improvement in QALYs ranging from 0.018 to 0.206 per patient, and also less costly in all but one scenario, with the mean cost difference ranging from −£813 to £26. All scenarios suggested preoperative transfusion had a probability of cost‐effectiveness >0.79 at a cost‐effectiveness threshold of £20 000 per QALY.