3CPO The Study Efficacy of Non-invasive Ventilation in Patients with Acute Cardiogenic Pulmonary Oedema The 3CPO Trial ISRCTN David Newby University of Edinburgh, UK on behalf of the 3CPO Investigators

3CPO The Study Conflicts of Interest - None This project was funded by the NIHR Health Technology Assessment Programme (project number 01/43/01). The views and opinions expressed herein are those of the investigators and do not necessarily reflect those of the Department of Health. Declarations

3CPO The Study Acute Cardiogenic Pulmonary Oedema Common ,000 hospital admissions per annum in UK Deadly % in- hospital mortality Costly million hospital days per annum in USA

3CPO The Study Acute Cardiogenic Pulmonary Oedema Loop Diuretic Therapy Nitrate Therapy Oxygen Therapy (Opiates) Treat Underlying Cause

3CPO The Study Non-invasive Ventilation In Acute Cardiogenic Pulmonary Oedema “When the household vacuum cleaner is employed, the machine should be run for some minutes first of all to get rid of dust” Poulton EP, Oxon DM: Left-sided heart failure with pulmonary oedema: Its treatment with the "pulmonary plus pressure machine." Lancet (1936);231:

3CPO The Study Non-invasive Ventilation In Acute Cardiogenic Pulmonary Oedema Non-invasive Ventilation: Continuous Positive Airway Pressure (CPAP) Ventilation Non-invasive Intermittent Positive Pressure Ventilation (NIPPV)

3CPO The Study Kelly et al. Eur Heart J 2002;23: Physiological Improvement with CPAP in Patients with ACPO Reduced acidosis, respiratory rate and heart rate

3CPO The Study Mortality reduced from 22% to 11% RR 0.53 (95% CI ) (Individual Group Sizes of n = 9 to 46) Masip et al. JAMA 2005;294: Mortality Benefit of CPAP/NIPPV in Patients with ACPO

3CPO The Study Aims and Hypothesis In patients with acute cardiogenic pulmonary oedema: Aims Clinical effectiveness of non-invasive ventilation Comparative effectiveness of CPAP and NIPPV Safety of non-invasive ventilation Hypothesis: Non-invasive ventilation reduces mortality

3CPO The Study Trial Design Multicentre national randomised controlled trial Setting: Emergency Department Prospective ‘open-label’ trial Three treatment interventions in a 1:1:1 randomisation: ‘standard’ oxygen therapy, CPAP or NIPPV

3CPO The Study Inclusion Criteria Patients older than 16 years of age Signs and symptoms consistent with acute cardiogenic pulmonary oedema as the principal clinical complaint: acute dyspnoea and bilateral crackles on chest auscultation Chest radiograph confirming the diagnosis of acute cardiogenic pulmonary oedema: typical features of interstitial oedema present Arterial blood gas analysis with a pH of 45 nmol/L) Respiratory rate of >20 breaths per minute

3CPO The Study Severely altered consciousness (unconscious or responding to pain only) Need for immediate lifesaving intervention Patients requiring thrombolysis or percutaneous coronary intervention for acute ST segment elevation myocardial infarction A clear alternative primary diagnosis An inability to provide informed consent at any time within the trial period Previous inclusion in the 3CPO study Exclusion Criteria

3CPO The Study Written informed consent If unable to give written consent: –witnessed verbal consent –relatives’ assent is obtained. Verbal patient consent is witnessed in writing by a second individual involved in the patient’s clinical care. Subsequent written consent is obtained as soon as possible prior to the patient’s data being used in the trial and normally within one week of recruitment. MREC/02/0/74 Consent

3CPO The Study Intervention Randomised (1:1:1) to: –Standard oxygen therapy (by facial mask) –CPAP (5 cmH 2 O up titrated to a maximum of 15 cmH 2 O) –NIPPV (8/4 cmH 2 O up titrated to a maximum of 20/10 cmH 2 O) Inhaled oxygen of 60% Attending physicians were encouraged to use nitrate and diuretic therapy Opiate therapy was administered at the discretion of the treating physician

3CPO The Study Power Calculation Randomisation of 400 patients per group. Intention-to-treat analysis. Co-primary end-point of mortality between standard oxygen therapy and non-invasive ventilation (CPAP or NIPPV). 80% Power at P<0.05, to detect a difference of 6% in mortality assuming a mortality of 15%. Co-primary end-point of mortality or intubation between CPAP and NIPPV 80% Power at P<0.05, to detect a difference of 7% in mortality and intubation rate assuming an event rate of 18%.

3CPO The Study Consort Diagram Recruited n = 1156 O 2 Only n = 391 Protocol Violations n = 14 Duplicates n =10 Treated n = 367 Patient Withdrawal n =0 7 Day n = Day n = 348 Patient Withdrawal n = 1 Refused Retrospective Consent n = 18 CPAP n = 382 Protocol Violations n = 18 Duplicates n =18 Treated n = 346 Patient Withdrawal n =3 7 Day n = Day n = 325 Patient Withdrawal n = 4 Refused Retrospective Consent n = 14 NIPPV n = 383 Protocol Violations n = 10 Duplicates n =17 Treated n = 356 Patient Withdrawal n =4 7 Day n = Day n = 344 Patient Withdrawal n = 1 Refused Retrospective Consent n = 17

3CPO The Study StandardCPAPNIPPVAll Number Age (years) Sex (male)42%45%43% Sx of MI at Presentation22% Ischemic heart disease63%65%60%63% Congestive heart failure45%42%47%44% Valvular heart disease12%11%9%11% COPD19%15%21%18% Hypertension56%55%57%56% Diabetes Mellitus30% 33%31% Hypercholesterolemia30%33%31%32% Current Smoker16%19% 18% PVD10%11%10% Cerebrovascular disease18%17%16%17% Baseline Characteristics Mean±SD or % (n)No significant differences (P>0.05)

3CPO The Study Baseline Characteristics Medications StandardCPAPNIPPVAll Anti-platelet Therapy62%65%63% Anti-coagulant Therapy14%11%13% ACE Inhibitor/ARB38%41%43%41% Aldosterone Antagonist3%4%6%4% Diuretic63%61%64%63% Beta-Blocker31%36%38%35% Calcium Antagonist19%18%23%20% Nitrate22%26% 24% Nicorandil7%9%8% Theophyllines2%1% Oral Steroids7%5% 6% Inhaled Steroids16%11%10%12% Bronchodilator Inhalers19%13%17%16% % (n)No significant differences (P>0.05)

3CPO The Study Immediate Therapeutic Interventions StandardCPAPNIPPVAll Nitrate Therapy93%88%91%90% Diuretic Therapy90%89% Opiate Therapy3%5%4% Inspired Oxygen (L/min)12±413±412±4 Ventilation Pressure (cmH 2 O) -10±414±5/7±2- No significant differences (P>0.05) except ventilation pressuresMean±SD or %

3CPO The Study Trial treatment StandardCPAPNIPPVP-value Treatment allocated Started allocated treatment 365 (100%)336 (98.2%)341 (97.2%)0.07 Completed allocated treatment 298 (83.2%)284 (84.5%)265 (77.7%)0.016 Not tolerated1 (0.3%)18 (5.4%)30 (8.8%)<0.001 Worsening ABGs26 (7.1%)10 (3.0%)15 (4.4%)0.027 Respiratory distress31 (8.5%)5 (1.5%)12 (3.5%)<0.001 Other reason17 (4.6%)24 (7.1%)25 (7.3%)0.152 Changed to standard3 (0.8%)32 (9.5%)51 (15.0%) Changed to CPAP43 (11.8%)1 (0.3%)12 (3.5%) N (%)

3CPO The Study Tolerability and Side-effects StandardCPAPNIPPVP-value Vomiting6 (1.7%)6 (1.8%)8 (2.3%)0.808 Aspiration001 (0.3%)0.367 Hypotension46 (13.1%)36 (10.9%)37 (10.8%)0.554 Arrhythmia23 (6.6%)12 (3.6%)25 (7.3%)0.097 Pneumothorax001 (0.3%)0.367 Increasing Respiratory Distress 35 (9.9%)17 (5.1%)20 (5.8%)0.028 Cardiac Arrest16 (4.5%)6 (1.8%)10 (2.9%)0.118 Other23 (6.6%)18 (5.5%)17 (5.0%)0.661 % (n)

3CPO The Study Tolerability and Side-effects of Non-Invasive Ventilation CPAPNIPPV Facial skin necrosis001.0 Facial discomfort14 (4.7%)15 (4.9%)0.929 Increased breathing discomfort 11 (3.7%)16 (5.2%)0.370 Other side effect16 (5.4%)19 (6.2%)0.659 % (n)

3CPO The Study StandardCPAPNIPPVAll Pulse rate (/min)114±24113±21112±22113±22 Systolic BP (mmHg)161±38162±35161±37162±37 Diastolic BP (mmHg)87±2589±2387±2488±24 Respiratory Rate (/min)33±732±7 Oxygen Saturation (%)91±890±8 Arterial pH7.22± ± ±0.09 Arterial pO 2 (kPa)13.1± ± ± ±8.0 Arterial pCO 2 (kPa)7.6±2.57.5±1.97.7±2.37.6±2.2 Bicarbonate (mmol/L)21±4 21±521±4 GCS verbal=590%88%91%89% GCS eye opening=491%86%90%89% GCS motor=696%97%98%97% Baseline Characteristics Physiological Variables Mean±SDNo significant differences (P>0.05)

3CPO The Study Physiological Response to Intervention One Hour Physiology StandardCPAP or NIPPV P Value (t-test) Pulse rate (/min)102±2396±22<0.001 Systolic BP (mmHg)128±30124± Diastolic BP (mmHg)65±2066± Respiratory Rate (/min)26±625± Oxygen Saturation (%)94±693± Arterial pH7.30± ±0.08<0.001 Arterial pO 2 (kPa)14.1± ± Arterial pCO 2 (kPa)6.7±2.56.2±1.9<0.001 Bicarbonate (mmol/L)22±822± Mean±SD

3CPO The Study Physiological Response to Intervention One Hour Physiology CPAPNIPPVP Value (t-test) Pulse rate (/min)96±2097± Systolic BP (mmHg)124±27124± Diastolic BP (mmHg)66±1966± Respiratory Rate (/min)25±724± Oxygen Saturation (%)94±693± Arterial pH7.33± ± Arterial pO 2 (kPa)12.4± ± Arterial pCO 2 (kPa)6.0±1.66.3± Bicarbonate (mmol/L)23±722± Mean±SD

3CPO The Study Primary Outcome Any NIV v standard Mortality Standard Therapy Non- Invasive Ventilation Odds Ratio95% Confidence Intervals P Value 7-Day9.8%9.5% to Day16.7%15.4% to

3CPO The Study Primary Outcome: Mortality Standard Oxygen Therapy versus Non-invasive Ventilation

3CPO The Study Primary Outcome CPAP v NIPPV Mortality CPAPNIPPVOdds Ratio95% Confidence Intervals P Value 7-Day Mortality 9.6%9.4% to Day Mortality/ Intubation 11.7%11.1% to Day Mortality 15.4% to

3CPO The Study Hospital stay StandardCPAPNIPPVP-value Admitted to intensive Care 8.8%9.1%6.6%0.411 Admitted to high- dependency Care 7.7%10.3%10.9%0.301 Admitted to coronary Care 38.1%43.7%40.9%0.337 Median length of hospital stay in days ( IQR) 8 (5-13)9 (5-16) No significant differences (P>0.05)

3CPO The Study In patients with acute cardiogenic pulmonary oedema, non-invasive ventilation: Produces more rapid resolution of metabolic abnormalities and respiratory distress Has no major effect on 7-day or 30-day mortality Is beneficial irrespective of the mode (CPAP or NIPPV) of delivery CONCLUSIONS