A multicentre randomised controlled trial of the use of continuous positive airway pressure and non-invasive positive pressure ventilation in the early treatment of patients presenting to the emergency department with severe acute cardiogenic pulmonary oedema: the 3CPO trial

Abstract

To determine whether non-invasive ventilation reduces mortality and whether there are important differences in outcome by treatment modality. Multicentre open prospective randomised controlled trial. Patients presenting with severe acute cardiogenic pulmonary oedema in 26 emergency departments in the UK. Inclusion criteria were age > 16 years, clinical diagnosis of acute cardiogenic pulmonary oedema, pulmonary oedema on chest radiograph, respiratory rate > 20 breaths per minute, and arterial hydrogen ion concentration > 45 nmol/l (pH < 7.35). Patients were randomised to standard oxygen therapy, continuous positive airway pressure (CPAP) (5-15 cmH2O) or non-invasive positive pressure ventilation (NIPPV) (inspiratory pressure 8-20 cmH2O, expiratory pressure 4-10 cmH2O) on a 1:1:1 basis for a minimum of 2 hours. The primary end point for the comparison between NIPPV or CPAP and standard therapy was 7-day mortality. The composite primary end point for the comparison of NIPPV and CPAP was 7-day mortality and tracheal intubation rate. Secondary end points were breathlessness, physiological variables, intubation rate, length of hospital stay and critical care admission rate. Economic evaluation took the form of a cost-utility analysis, taken from an NHS (and personal social services) perspective. In total, 1069 patients [mean age 78 (SD 10) years; 43% male] were recruited to standard therapy (n = 367), CPAP [n = 346; mean 10 (SD 4) cmH2O] or NIPPV [n = 356; mean 14 (SD 5)/7 (SD 2) cmH2O]. There was no difference in 7-day mortality for standard oxygen therapy (9.8%) and non-invasive ventilation (9.5%; p = 0.87). The combined end point of 7-day death and intubation rate was similar, irrespective of non-invasive ventilation modality (CPAP 11.7% versus NIPPV 11.1%; p = 0.81). Compared with standard therapy, non-invasive ventilation was associated with greater reductions (treatment difference, 95% confidence intervals) in breathlessness (visual analogue scale score 0.7, 0.2-1.3; p = 0.008) and heart rate (4/min, 1-6; p = 0.004) and improvement in acidosis (pH 0.03, 0.02-0.04; p < 0.001) and hypercapnia (0.7 kPa, 0.4-0.9; p < 0.001) at 1 hour. There were no treatment-related adverse events or differences in other secondary outcomes such as myocardial infarction rate, length of hospital stay, critical care admission rate and requirement for endotracheal intubation. Economic evaluation showed that mean costs and QALYs up to 6 months were 3023 pounds and 0.202 for standard therapy, 3224 pounds and 0.213 for CPAP, and 3208 pounds and 0.210 for NIPPV. Modelling of lifetime costs and QALYs produced values of 15,764 pounds and 1.597 for standard therapy, 17,525 pounds and 1.841 for CPAP, and 17,021 pounds and 1.707 for NIPPV. These results suggest that both CPAP and NIPPV accrue more QALYs but at higher cost than standard therapy. However, these estimates are subject to substantial uncertainty. Non-invasive ventilatory support delivered by either CPAP or NIPPV safely provides earlier improvement and resolution of breathlessness, respiratory distress and metabolic abnormality. However, this does not translate into improved short- or longer-term survival. We recommend that CPAP or NIPPV should be considered as adjunctive therapy in patients with severe acute cardiogenic pulmonary oedema in the presence of severe respiratory distress or when there is a failure to improve with pharmacological therapy. Current Controlled Trials ISRCTN07448447.