A comparison of hospital episode statistics and traditional methods to identify outcomes in a randomized trial; a sub-study of HEAT-PPCI.

BACKGROUND: This study aims to compare information from hospital episode statistics (HES) and traditional direct patient contact to identify readmission and clinical events in the follow-up of a randomized controlled trial (RCT). METHODS: The study followed 1812 patients for 28 days using direct contact (DC). In addition, we obtained HES for this period. We examined medical records for all suspected readmissions and determined confirmed events by adjudication. We compared the ability of the individual DC and HES methods to determine readmission and the occurrence of trial-specific events, confirmed at adjudication. RESULTS: In the ascertainment of readmission, compared to DC, HES demonstrated a trend towards better sensitivity (identifying 153/166 = 92.2% versus 144/166 = 86.7%; difference = 5.4%, 95% CI: 0.1-11.5%) and better specificity (1492/1492 = 100% versus 1426/1492 = 95.5%; difference = 4.4%, 95% CI: 4.2-5.6%).An examination of HES coding does not identify rates for specific events that match those from adjudication, with limitations in both sensitivity and specificity. CONCLUSION: HES is effective in the ascertainment of readmission and is a useful tool in follow-up. Information from HES provides a reflection of a patient's course and associated cost, as perceived by the healthcare system. Future studies could modify outcome definitions to reflect episode coding.

Unfractionated heparin versus bivalirudin in primary percutaneous coronary intervention (HEAT-PPCI): an open-label, single centre, randomised controlled trial.

BACKGROUND: Bivalirudin, with selective use of glycoprotein (GP) IIb/IIIa inhibitor agents, is an accepted standard of care in primary percutaneous coronary intervention (PPCI). We aimed to compare antithrombotic therapy with bivalirudin or unfractionated heparin during this procedure. METHODS: In our open-label, randomised controlled trial, we enrolled consecutive adults scheduled for angiography in the context of a PPCI presentation at Liverpool Heart and Chest Hospital (Liverpool, UK) with a strategy of delayed consent. Before angiography, we randomly allocated patients (1:1; stratified by age [<75 years vs ≥75 years] and presence of cardiogenic shock [yes vs no]) to heparin (70 U/kg) or bivalirudin (bolus 0·75 mg/kg; infusion 1·75 mg/kg per h). Patients were followed up for 28 days. The primary efficacy outcome was a composite of all-cause mortality, cerebrovascular accident, reinfarction, or unplanned target lesion revascularisation. The primary safety outcome was incidence of major bleeding (type 3-5 as per Bleeding Academic Research Consortium definitions). This study is registered with ClinicalTrials.gov, number NCT01519518. FINDINGS: Between Feb 7, 2012, and Nov 20, 2013, 1829 of 1917 patients undergoing emergency angiography at our centre (representing 97% of trial-naive presentations) were randomly allocated treatment, with 1812 included in the final analyses. 751 (83%) of 905 patients in the bivalirudin group and 740 (82%) of 907 patients in the heparin group had a percutaneous coronary intervention. The rate of GP IIb/IIIa inhibitor use was much the same between groups (122 patients [13%] in the bivalirudin group and 140 patients [15%] in the heparin group). The primary efficacy outcome occurred in 79 (8·7%) of 905 patients in the bivalirudin group and 52 (5·7%) of 907 patients in the heparin group (absolute risk difference 3·0%; relative risk [RR] 1·52, 95% CI 1·09-2·13, p=0·01). The primary safety outcome occurred in 32 (3·5%) of 905 patients in the bivalirudin group and 28 (3·1%) of 907 patients in the heparin group (0·4%; 1·15, 0·70-1·89, p=0·59). INTERPRETATION: Compared with bivalirudin, heparin reduces the incidence of major adverse ischaemic events in the setting of PPCI, with no increase in bleeding complications. Systematic use of heparin rather than bivalirudin would reduce drug costs substantially. FUNDING: Liverpool Heart and Chest Hospital, UK National Institute of Health Research, The Medicines Company, AstraZeneca, The Bentley Drivers Club (UK).

Twelve-month mortality from the "How Effective are Antithrombotic Therapies in Primary Percutaneous Coronary Intervention (HEAT-PPCI) Trial".

BACKGROUND: There is ongoing uncertainty regarding the safety and efficacy of unfractionated heparin and bivalirudin when used for systemic anticoagulation in patients undergoing primary percutaneous coronary intervention (PPCI). This paper reports 12-month mortality from the HEAT-PPCI randomised trial. METHODS: In this open-label, randomised controlled trial (RCT) we enrolled consecutive adults with suspected ST-elevation myocardial infarction (STEMI). Patients were randomised to heparin (bolus 70 U/kg) or bivalirudin (bolus 0.75 mg/kg followed by an infusion 1.75 mg/kg/h for the duration of the procedure). We report the pre-specified secondary outcome of all-cause mortality at 12 months. Mortality was classified as cardiovascular or not, blinded to treatment allocation. Deaths in the first 28 days were classified by formal event adjudication and later events classified from death certificates. RESULTS: Mortality status at 12 months was obtained for 1805/1812 = 99.6% of participants. Overall mortality was 160/1812 = 8.9%. There were more deaths in those randomised to bivalirudin (95/902 = 10.5% vs 65/903 = 7.2%; HR 1.48; 95% CI 1.08 to 2.03; p = 0.015). Most deaths were classified as cardiovascular (71/902 = 7.9% in the bivalirudin group and 53/904 = 5.9% in the heparin group). The difference between the rates of cardiovascular deaths in each treatment group did not reach statistical significance: HR 1.35; 95% CI 0.95 to 1.93; p = 0.095. CONCLUSIONS: At 12 months, treatment with bivalirudin, rather than heparin, was associated with a higher rate of all-cause mortality. Cardiovascular mortality was higher with bivalirudin although this difference was not statistically significant.

A randomised controlled trial to compare two coronary pressure wires using simultaneous measurements in human coronary arteries: the COMET trial.

AIMS: We aimed to examine the relative performance of the new COMET wire from Boston Scientific (BS), and the established technology from St. Jude/Abbott Vascular (SJ). METHODS AND RESULTS: We compared simultaneous readings from pairs of wires. Patients were randomised to one of three groups: BS/BS, SJ/SJ, or SJ/BS. The last group was sub-randomised to specify the type of wire that would be passed first. After pressure equalisation at the guide catheter, we recorded paired observations in sequence: (a) distal to proximal pressure ratio at baseline, (b) FFR at maximum hyperaemia, and (c) pressure on withdrawal into the guide catheter to quantify "drift". We randomised 106 patients, yielding 288 sets of paired recordings (BS/BS=90; SJ/SJ=90; SJ/BS=108). Drift was recorded from 208 vessels (BS=105; SJ=103). All wires were successfully advanced to their desired positions in the coronary vasculature. The mean (±SD) differences for the randomised pairs were similar: BS/BS=0.0016 (0.023); SJ/SJ=0.002 (0.03); SJ/BS=0.0013 (0.028). The primary outcome tested the hypothesis that the absolute magnitude of the difference (irrespective of sign) observed in the SJ/BS pairing would be similar to that in the SJ/SJ group. The median (IQR) values were SJ/BS=0.015 (0.01-0.03); SJ/SJ=0.01 (0.00-0.03); p=0.61. The drift, expressed as the median (IQR) difference in Pd/Pa from 1.0 (irrespective of sign), was similar: BS=0.02 (0.01-0.05); SJ=0.02 (0.01-0.04); p=0.14. CONCLUSIONS: We found no significant difference between these wires in terms of safety and performance.

Comparison of the effects of P2Y12 receptor antagonists on platelet function and clinical outcomes in patients undergoing Primary PCI: A substudy of the HEAT-PPCI trial.

AIMS: The HEAT-PPCI trial compared bivalirudin and unfractionated heparin in patients undergoing primary percutaneous coronary intervention (PPCI). The aim of this study was to report pre-specified, secondary analyses comparing the effects of P2Y12 inhibiting agents on platelet reactivity and clinical events. METHODS AND RESULTS: All patients received preprocedural oral antiplatelet therapy. During the early stages of the trial, the P2Y12 inhibitor of choice was prasugrel with some use of clopidogrel. Later, routine therapy switched to ticagrelor. For cases performed during working hours, multiple electrode aggregometry (MEA) was used to assess ADP-induced platelet aggregation at the end of the index procedure. The effect of P2Y12 inhibitors on the primary efficacy (major adverse cardiac events [MACE]) and safety (major bleeding) outcomes was assessed in all patients. Multiple logistic regression was used to adjust for differences in baseline characteristics. With MEA data from 469 patients, prasugrel therapy resulted in significantly greater suppression of ADP-induced platelet aggregation at 40 U (23, 78) (median; interquartile range [IQR]) when compared against ticagrelor 75 U (41, 100.75); p<0.001 or clopidogrel 79 U (56, 96); p<0.001. In the entire study population (N=1,803), prasugrel therapy was associated with significantly fewer MACE (26/497; 5.2%) in comparison to ticagrelor (83/1,123; 7.4%) or clopidogrel (18/183; 9.8%); odds ratio (OR) 0.64, confidence interval (CI): 0.41-0.99, p=0.045. For major bleeding, there were no significant differences among the three groups - clopidogrel (3/183; 1.6%), prasugrel (13/497; 2.6%) and ticagrelor (43/1,123; 3.8%); OR 0.73, CI: 0.39-1.35, p=0.31. Patients treated with clopidogrel had more high-risk features and clopidogrel use was more common as an alternative to prasugrel. After adjustment, there were no significant differences in the rates of MACE (OR 0.70, CI: 0.41-1.21, p=0.20) or major bleeding (OR 0.80, CI: 0.41-1.60, p=0.53). CONCLUSIONS: In HEAT-PPCI, patients who received prasugrel (rather than clopidogrel or ticagrelor) had significantly greater suppression of ADP-induced platelet aggregation at the end of the procedure. After adjustment for differences in baseline characteristics, there were no significant differences in ischaemic or bleeding outcomes among the antiplatelet therapies.

Comparison of the antiplatelet and antithrombotic effects of bivalirudin versus unfractionated heparin: A platelet substudy of the HEAT PPCI trial.

In randomised trials, bivalirudin has been associated with higher rates of acute stent thrombosis (AST) compared to unfractionated heparin (UFH), without mechanistic explanation. Furthermore, data are discrepant regards the antiplatelet effects of bivalirudin. This prespecified study, part of a larger HEAT-PPCI Platelet Substudy, aimed to compare the antiplatelet and antithrombotic effects of bivalirudin and UFH using short thrombelastography (s-TEG), an ex vivo whole blood platelet function assay. In HEAT-PPCI, patients were randomised to receive UFH or bivalirudin before angiography. Assay with s-TEG was performed in 184 patients (10.2%) at end of procedure (EOP) and repeated at 24 h. In addition to adenosine diphosphate- (ADP) and arachidonic acid- (AA) mediated platelet aggregation, thrombin-mediated clotting (TMC) was assessed using kaolin with and without heparinase. There were no significant differences between UFH and bivalirudin in ADP- and AA-mediated platelet aggregation at EOP or 24 h. Whilst UFH obliterated TMC at EOP, bivalirudin prolonged R time (19.7 min [15.9-25.4] vs. 8.4 min [7.5-10]; P < 0.0001), K time (2.4 min [1.9-3.4] vs. 2.2 min [1.8-2.7]; P = 0.007) and significantly increased maximum clot strength (MA 62.7 mm [58.7-67.4] vs. 58.6 [55-63]; P = 0.0005), compared to control. In conclusion, there were no significant differences in the antiplatelet effects of UFH and bivalirudin. However, whilst UFH obliterated TMC, bivalirudin prolonged clot initiation but potentiated maximum clot strength. As AST is likely multifactorial in aetiology, in patients treated with bivalirudin, increased clot strength may contribute to this hazard in some individuals and this observation warrants further investigation.

Describing Activity in Primary Percutaneous Coronary Intervention: An Exploration of Denominators. From the HEAT Trial - A Systematic Evaluation of PPCI Activations in Liverpool, Explaining Denominators (HEAT-SEALED).

BACKGROUND: The provision of primary percutaneous coronary intervention (PPCI) in the emergency management of ST-elevation myocardial infarction (STEMI) is expensive and resource intensive. Accurate data collection is essential not only for outcomes analysis but also to characterize activity and performance for regions, centers, and operators. Inconsistency in the use of denominators currently creates problems in data interpretation. OBJECTIVE: To establish a system of denominator groupings, seeking to better describe the range of clinical activity resulting from an unselected series of PPCI activations. METHODS: The HEAT-SEALED pathway designates a key denominator group (n1-n9) to each phase of PPCI activity and identifies a final "destination category" for each patient leaving the pathway. HEAT-PPCI (How Effective are Antithrombotic Therapies in Primary Percutaneous Coronary Intervention) is a true "all-comers" trial and provides an ideal platform to collect data for prospective validation of the pathway. We report data from all PPCI activation events for the HEAT-PPCI trial. RESULTS: Our findings demonstrate important differences between the sizes of key PPCI denominator groups and hence the potential for variation in reported outcomes depending on the denominator category selected. The main figures are: all activations (n1 = 2490); all suspected MI cases (n4 = 1940; 77.91%); patients in whom angiography was performed (n5 = 1904; 76.46%); cases in which diagnosis was confirmed with a probable culprit lesion (n6 = 1657; 66.54%), and cases with complete PCI success (n9 = 1441; 57.87%). CONCLUSION: The HEAT-SEALED pathway offers a practical and comprehensive solution to the problem of describing denominators in STEMI and PPCI. Routine application would facilitate a more consistent and precise description of activity and outcome.