Sub30: Protocol for the Sub30 feasibility study of a pre-hospital Extracorporeal membrane oxygenation (ECMO) capable advanced resuscitation team at achieving blood flow within 30 ​min in patients with refractory out-of-hospital cardiac arrest.

BACKGROUND: Out-of-hospital cardiac arrest carries a poor prognosis with survival less than 10% in many patient cohorts. Survival is inversely associated with duration of resuscitation as external chest compressions do not provide sufficient blood flow to prevent irreversible organ damage during a prolonged resuscitation. Extracorporeal membrane oxygenation (ECMO) instituted during cardiac arrest can provide normal physiological blood flows and is termed Extracorporeal Cardio-Pulmonary Resuscitation (ECPR). ECPR may improve survival when used with in-hospital cardiac arrests. This possible survival benefit has not been replicated in trials of out-of-hospital cardiac arrests, possibly because of the additional time it takes to transport the patient to hospital and initiate ECPR. Pre-hospital ECPR may shorten the time between cardiac arrest and physiological blood flows, potentially improving survival. It may also mitigate some of the neurological injury that many survivors suffer. METHODS: Sub30 is a prospective six patient feasibility study. The primary aim is to test whether it is possible to institute ECPR within 30 ​min of collapse in adult patients with refractory out of hospital cardiac arrest (OHCA). The secondary aims are to gather preliminary data on clinical outcomes, resource utilisation, and health economics associated with rapid ECPR delivery in order to plan any subsequent clinical investigation or clinical service. On study days a dedicated fast-response vehicle with ECPR capability will be tasked to out-of-hospital cardiac arrests in an area of London served by Barts Heart Centre. If patients suffer a cardiac arrest refractory to standard advanced resuscitation and meet eligibility criteria, ECPR will be started in the pre-hospital environment. DISCUSSION: Delivering pre-hospital ECPR within 30 ​min of an out-of-hospital cardiac arrest presents significant ethical, clinical, governance and logistical challenges. Prior to conducting an efficacy study of ECPR the feasibility of timely and safe application must be demonstrated first. Extensive planning, multiple high-fidelity multiagency simulations and a unique collaboration between pre-hospital and in-hospital institutions will allow us to test the feasibility of this intervention in London. The study has been reviewed, refined and endorsed by the International ECMO Network (ECMONet). TRIAL REGISTRATION: Clinicaltrials. gov NCT03700125, prospectively registered October 9, 2018.

A pragmatic pilot phase II randomised controlled trial of prothrombin complex concentrates (PCC) versus fresh frozen plasma (FFP) in adult patients who are undergoing heart surgery (PROPHESY).

BACKGROUND: Fresh frozen plasma (FFP) is the accepted standard treatment for clotting factor replacement in bleeding patients during or immediately after cardiac surgery. In the United Kingdom prothrombin complex concentrate (PCC) is not licensed in this setting, although it is being used in Europe because it has a higher concentration of clotting factor levels, and it can be administered rapidly and in small volume, resulting in less volume overload during cardiac surgery. METHODS: PROPHESY is a pragmatic, single-centre, open-label, randomised, controlled pilot trial that will assess whether it is feasible to perform a large trial in the future that will compare PCC versus FFP in patients who are bleeding (not on warfarin) and who require blood transfusion. Over a 15-month period, 50 patients will be randomised to PCC versus FFP if they develop active bleeding within 24 h of cardiac surgery and for whom the clinician has decided to administer FFP for treatment of bleeding. Standard laboratory and point-of-care assessments will be performed as per routine practice, and additional research blood samples will be taken at three time points to assess haemostasis. Subjects will be assessed daily up to hospital discharge or 30 days or death (whichever occurs first) and will be seen in follow-up for 90 days after surgery to assess for thromboembolic complications and hospital re-admission since discharge. Quality-of-life assessment will be performed pre-surgery and at 90 days post-surgery. We will also perform qualitative research with clinical experts and patients to explore the understanding of and experience with the interventions, as well as adherence to study procedures and protocol. DISCUSSION: There have been no randomised controlled trials that have compared the safety and efficacy of FFP versus PCC in cardiac surgery patients who are bleeding. This pilot study will assess if individual components of a large trial are deliverable to assess the safety and efficacy of the two blood products in the future. TRIAL REGISTRATION: EudraCT, 2018-003041-41; ClinicalTrials.gov, NCT03715348. Registered on 29 July 2018.

Use of a Multidrug Pill In Reducing cardiovascular Events (UMPIRE): rationale and design of a randomised controlled trial of a cardiovascular preventive polypill-based strategy in India and Europe.

The use of preventive medications in people at high risk of cardiovascular disease is conceptually straightforward, yet in practice the adoption of such measures is disappointingly low, plus there is wide international variation in preventive therapies. Several barriers might explain this shortfall and variation, but the simplicity and economy of a polypill-based strategy might overcome some barriers. The 'Use of a Multidrug Pill In Reducing cardiovascular Events' (UMPIRE) trial assesses whether a polypill strategy (by combining aspirin, a statin and two blood pressure lowering agents) would improve adherence to guideline-indicated therapies and would lower both blood pressure and cholesterol, in people with established cardiovascular disease. UMPIRE, running in India and three European countries (England, Ireland and the Netherlands), is an open, randomised, controlled trial designed to include 1000 participants in India and 1000 in Europe, with a followup of 12-24 months. Participants were randomised to one of two versions of the polypill or relegated to usual care. The primary study outcomes were the self-reported use of aspirin, a statin and at least two blood pressure lowering agents; as well as changes in blood pressure and cholesterol. Secondary outcomes included: any cardiovascular events, reasons for stopping medications, serious adverse events and perceived changes in quality of life. Interpretation of the study data will be enhanced by health, economic and process-related evaluations. UMPIRE is registered with the European Clinical Trials database, as EudraCT: 2009-016278-34 and the Clinical Trials Registry, India as CTRI/2010/091/000250. The trial was part of the 'Single Pill Against Cardiovascular Events (SPACE)' collaboration, which encompasses the 'IMProving Adherence using Combination Therapy (IMPACT)' and 'Kanyini Guidelines Adherence with the Polypill (Kanyini-GAP)' trials.

Prospective meta-analysis of trials comparing fixed dose combination based care with usual care in individuals at high cardiovascular risk: the SPACE Collaboration.

BACKGROUND: An international collaboration of investigators will assess the benefits and risks of fixed dose combination (FDC) based care compared with usual care in populations at high risk of cardiovascular disease (CVD). Several trials are being conducted, as the effectiveness and economic impact of a FDC-based strategy may vary substantially between countries, given the varying influence of the health-care system within which the intervention is delivered. METHODS: Individual patient data (IPD) will be provided by participating trials for combined IPD meta-analysis. RESULTS: Primary outcomes will include self-reported current use of antiplatelet, statin, and combination (≥ 2) blood pressure lowering therapies at 12 months, and change in systolic blood pressure (SBP) and LDL cholesterol from baseline to 12 months. Non-inferiority margins of 3 mm Hg for SBP and 0.3 mmol/L for LDL cholesterol have been pre-specified. Secondary outcomes will include change in cholesterol fractions, diastolic blood pressure and creatinine from baseline to 12 months, quality of life, new onset diabetes mellitus, mortality (cardiovascular, non-cardiovascular and all cause) and a composite outcome of cardiovascular events (including all coronary heart disease events, heart failure events leading to death or requiring hospital admission, cerebrovascular events and peripheral arterial events). CONCLUSION: The SPACE group of trials will assess, in a variety of healthcare settings, whether a FDC strategy for delivery of preventive medication has the potential to significantly improve prevention of cardiovascular disease in patients at high risk.

Effects of a fixed-dose combination strategy on adherence and risk factors in patients with or at high risk of CVD: the UMPIRE randomized clinical trial.

IMPORTANCE: Most patients with cardiovascular disease (CVD) do not take recommended medications long-term. The use of fixed-dose combinations (FDCs) improves adherence in several clinical areas. Previous trials of cardiovascular FDCs have assessed short-term effects compared with placebo or no treatment. OBJECTIVE: To assess whether FDC delivery of aspirin, statin, and 2 blood pressure-lowering agents vs usual care improves long-term adherence to indicated therapy and 2 major CVD risk factors, systolic blood pressure (SBP) and low-density lipoprotein cholesterol (LDL-C). DESIGN, SETTING, AND PARTICIPANTS: The UMPIRE trial, a randomized, open-label, blinded-end-point trial among 2004 participants with established CVD or at risk of CVD enrolled July 2010-July 2011 in India and Europe. The trial follow-up concluded in July 2012. INTERVENTIONS: Participants were randomly assigned (1:1) to an FDC-based strategy (n=1002) containing either (1) 75 mg aspirin, 40 mg simvastatin, 10 mg lisinopril, and 50 mg atenolol or (2) 75 mg aspirin, 40 mg simvastatin, 10 mg lisinopril, and 12.5 mg hydrochlorothiazide or to usual care (n=1002). MAIN OUTCOMES AND MEASURES: Adherence to medication (defined as self-reported use of antiplatelet, statin, and ≥2 BP-lowering medications) and changes in SBP and LDL-C from baseline. RESULTS: At baseline, mean BP was 137/78 mm Hg, LDL-C was 91.5 mg/dL, and 1233 (61.5%) of 2004 participants reported use of antiplatelet, statin, and 2 or more BP-lowering medications. Median follow-up was 15 months (interquartile range, 12-18 months). The FDC group had improved adherence vs usual care (86% vs 65%; relative risk [RR] of being adherent, 1.33; 95% CI, 1.26-1.41; P < .001) with concurrent reductions in SBP (-2.6 mm Hg; 95% CI, -4.0 to -1.1 mm Hg; P < .001) and LDL-C (-4.2 mg/dL; 95% CI, -6.6 to -1.9 mg/dL; P < .001) at the end of the study. Although there was consistency of effects across predefined subgroups, evidence existed of larger benefits in patients with lower adherence at baseline. In this subgroup of 727 participants (36%), adherence at the end of study was 77% vs 23% (RR, 3.35; 95% CI, 2.74-4.09; P < .001 for interaction), SBP was reduced by 4.9 mm Hg (95% CI 7.3-2.6 mm Hg; P = .01 for interaction), and LDL-C was reduced by 6.7 mg/dL (95% CI, 10.5-2.8 mg/dL; P = .11 for interaction). There were no significant differences in serious adverse events or cardiovascular events (50 [5%] in the FDC group and 35 [3.5%] in the usual care group; RR, 1.45; 95% CI, 0.94-2.24; P=.09) between the groups. CONCLUSIONS AND RELEVANCE: Among patients with or at high risk of CVD, use of an FDC strategy for blood pressure, cholesterol, and platelet control vs usual care resulted in significantly improved medication adherence at 15 months and statistically significant but small improvements in SBP and LDL-C. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01057537.