Sebastian Wiberg

Acute Stent Thrombosis After Primary Percutaneous Coronary Intervention : Insights From the EUROMAX Trial (European Ambulance Acute Coronary Syndrome Angiography)

OBJECTIVES This study sought to determine clinical, procedural, and treatment factors associated with acute stent thrombosis (AST) in the EUROMAX (European Ambulance Acute Coronary Syndrome Angiography) trial. BACKGROUND Bivalirudin started during transport for primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction significantly reduced major bleeding compared with heparin with or without glycoprotein IIb/IIIa inhibitors (GPI), but it was associated with an increase in AST. METHODS We compared patients with (n = 12) or without AST (n = 2,184) regarding baseline, clinical, and procedural characteristics and antithrombotic treatment strategies (choice of P2Y12 inhibitor, post-primary PCI bivalirudin infusion dose [0.25 mg/kg/h, or BIV-LOW] vs. [1.75 mg/kg/h, or BIV-PCI] vs. heparin ± GPI). Logistic regression was performed to identify independent correlates of AST. RESULTS The overall AST rate was 0.6% and was higher with bivalirudin than with heparin ± GPI (1.1% vs. 0.2%; p = 0.007). Median time to AST was 2.3 h (interquartile range: 1.9 to 2.8 h). Patients with AST had less hypertension (2 of 14 [14.0%] vs. 961 of 2,182 [44.0%]; p = 0.03), and more frequently received GPI (11 of 14 [78.6%] vs. 880 of 2,183 [40.3%]; p = 0.004). Multivariate analysis using Firth penalized maximum likelihood estimation found hypertension (odds ratio [OR]: 0.24, 95% confidence interval [CI]: 0.07 to 0.92; p = 0.037) and BIV-LOW (OR: 5.8, 95% CI: 1.5 to 22.2; p = 0.010) predictive of AST. Choice of P2Y12 inhibitor had no impact on AST. Compared with heparin ± GPI, AST rates were higher for BIV-LOW (11 of 670 [1.6%] vs. 2 of 947 [0.2%]; p = 0.008), but not different for BIV-PCI (1 of 244 [0.4%]; p = 0.588). CONCLUSIONS In this post-hoc analysis from EUROMAX, AST occurred very early and was not mitigated by the novel P2Y12 inhibitors. Prolonging the bivalirudin infusion at the PCI dose (but not at a lower dose) appeared to mitigate the risk of AST.

Single versus serial measurements of neuron-specific enolase and prediction of poor neurological outcome in persistently unconscious patients after out-of-hospital cardiac arrest - A TTM-trial substudy

Background Prediction of neurological outcome is a crucial part of post cardiac arrest care and prediction in patients remaining unconscious and/or sedated after rewarming from targeted temperature management (TTM) remains difficult. Current guidelines suggest the use of serial measurements of the biomarker neuron-specific enolase (NSE) in combination with other predictors of outcome in patients admitted after out-of-hospital cardiac arrest (OHCA). This study sought to investigate the ability of NSE to predict poor outcome in patients remaining unconscious at day three after OHCA. In addition, this study sought to investigate if serial NSE measurements add incremental prognostic information compared to a single NSE measurement at 48 hours in this population. Methods This study is a post-hoc sub-study of the TTM trial, randomizing OHCA patients to a course of TTM at either 33°C or 36°C. Patients were included from sites participating in the TTM-trial biobank sub study. NSE was measured at 24, 48 and 72 hours after ROSC and follow-up was concluded after 180 days. The primary end point was poor neurological function or death defined by a cerebral performance category score (CPC-score) of 3 to 5. Results A total of 685 (73%) patients participated in the study. At day three after OHCA 63 (9%) patients had died and 473 (69%) patients were not awake. In these patients, a single NSE measurement at 48 hours predicted poor outcome with an area under the receiver operating characteristics curve (AUC) of 0.83. A combination of all three NSE measurements yielded the highest discovered AUC (0.88, p = .0002). Easily applicable combinations of serial NSE measurements did not significantly improve prediction over a single measurement at 48 hours (AUC 0.58–0.84 versus 0.83). Conclusion NSE is a strong predictor of poor outcome after OHCA in persistently unconscious patients undergoing TTM, and NSE is a promising surrogate marker of outcome in clinical trials. While combinations of serial NSE measurements may provide an increase in overall prognostic information, it is unclear whether actual clinical prognostication with low false-positive rates is improved by application of serial measurements in persistently unconscious patients. The findings of this study should be confirmed in another prospective cohort. Trial registration NCT01020916

Neuroprotective Effects of the Glucagon-Like Peptide-1 Analog Exenatide After Out-of-Hospital Cardiac Arrest: A Randomized Controlled Trial

Background: In-hospital mortality in comatose patients resuscitated from out-of-hospital cardiac arrest (OHCA) is ≈50%. In OHCA patients, the leading cause of death is neurological injury secondary to ischemia and reperfusion. Glucagon-like peptide-1 analogs are approved for type 2 diabetes mellitus; preclinical and clinical data have suggested their organ-protective effects in patients with ischemia and reperfusion injury. The aim of this trial was to investigate the neuroprotective effects of the glucagon-like peptide-1 analog exenatide in resuscitated OHCA patients. Methods: We randomly assigned 120 consecutive comatose patients resuscitated from OHCA in a double-blind, 2-center trial. They were administered 17.4 &mgr;g exenatide (Byetta) or placebo over a 6-hour and 15-minute infusion, in addition to standardized intensive care including targeted temperature management. The coprimary end points were feasibility, defined as initiation of the study drug in >90% patients within 240 minutes of return of spontaneous circulation, and efficacy, defined as the geometric area under the neuron-specific enolase curve from 24 to 72 hours after admission. The main secondary end points included a composite end point of death and poor neurological function, defined as a Cerebral Performance Category score of 3 to 5 assessed at 30 and 180 days. Results: The study drug was initiated within 240 minutes of return of spontaneous circulation in 96% patients. The median blood glucose 8 hours after admission in patients receiving exenatide was lower than that in patients receiving placebo (5.8 [5.2–6.7] mmol/L versus 7.3 [6.2–8.7] mmol/L, P<0.0001). However, there were no significant differences in the area under the neuron-specific enolase curve, or a composite end point of death and poor neurological function between groups. Adverse events were rare with no significant difference between groups. Conclusions: Acute administration of exenatide to comatose patients in the intensive care unit after OHCA is feasible and safe. Exenatide did not reduce neuron-specific enolase levels and did not significantly improve a composite end point of death and poor neurological function after 180 days. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02442791.

The effect of TIcagrelor administered through a nasogastric tube to COMAtose patients undergoing acute percutaneous coronary intervention: the TICOMA study

AIMS Patients in a coma after cardiac arrest may have adversely affected drug absorption and metabolism. This study, the first of its kind, aimed to investigate the early pharmacokinetic and pharmacodynamic effects of ticagrelor administered through a nasogastric tube (NGT) to patients resuscitated after an out of hospital cardiac arrest (OHCA) and undergoing primary percutaneous coronary intervention (pPCI). METHODS AND RESULTS Blood samples were drawn at baseline and at two, four, six, eight, 12, and 24 hours and then daily for up to five days after administration of a 180 mg ticagrelor loading dose (LD), followed by 90 mg twice daily in 44 patients. The primary endpoint was the occurrence of high platelet reactivity (HPR) 12 hours after the LD. Assessment by VerifyNow (VFN) showed 96 (15.25-140.5) platelet reactivity units (PRU), and five (12%) patients exhibited HPR. Multiplate analysis showed 19 (12-29) units (U) at twelve hours, and three patients (7%) had HPR. Ticagrelor and its main metabolite AR-C124910XX concentrations were 85.2 (37.2-178.5) and 18.3 (6.4-52.4) ng/mL. Median times to sufficient platelet inhibition below the HPR limit were 3 (2-6) hours (VFN) and 4 (2-8) hours (Multiplate). CONCLUSIONS Ticagrelor, administered as crushed tablets through a nasogastric tube, leads to sufficient platelet inhibition after 12 hours, and in many cases earlier, in the vast majority of patients undergoing pPCI and subsequent intensive care management after an OHCA.

Cerebral Lesions in Patients Undergoing Coronary Artery Bypass Grafting in Relation to Asymptomatic Carotid and Vertebral Artery Stenosis

OBJECTIVES Carotid artery stenosis (CAS) and vertebral artery stenosis (VAS) are associated with cerebral infarction after coronary artery bypass graft surgery (CABG). It remains unclear whether this association is causal. We investigated the associations between neurologically asymptomatic CAS and VAS and the occurrence of subclinical cerebral lesions after CABG verified by magnetic resonance imaging. METHODS CABG patients were included and CAS and VAS were identified by magnetic resonance angiography. Cerebral magnetic resonance imaging was performed to identify new post-operative subclinical cerebral lesions. The associations between CAS/VAS post-operative cerebral lesions were investigated. RESULTS Forty-six patients were included in the study. 13% had significant CAS and 11% had significant VAS. Thirty-five percent had new cerebral infarction postoperatively. We found a significant association between the presence of cerebral vessel stenosis and acute cerebral infarction (67% vs. 27%, p = 0.047). However none of the patients with stenosis had isolated cerebral lesions in the ipsilateral vascular territory. CONCLUSION Asymptomatic CAS and VAS is common in CABG patients and is associated with an increased risk of postoperative cerebral infarction. Our study suggests that asymptomatic CAS and VAS primarily are risk markers rather than causal factors for cerebral infarction after CABG.

Osborn waves following out-of-hospital cardiac arrest—Effect of level of temperature management and risk of arrhythmia and death

BACKGROUND The Osborn or J-wave, an upright deflection of the J-point on the electrocardiogram (ECG), is often observed during severe hypothermia. A possible relation between Osborn waves (OW) and increased risk of ventricular arrhythmia has been reported. We sought to determine whether the level of targeted temperature management (TTM) following out-of-hospital cardiac arrest (OHCA) affects the prevalence of OW and to assess the associations between OW and risk of ventricular arrhythmia and death. METHODS AND RESULTS The present study is part of the TTM-trial ECG-substudy (including OHCA-patients randomized to TTM at 33 °C vs. 36 °C from 24 of 36 sites). Serial 12-lead ECGs from 680 (94%) patients were analysed and stratified by OW at predefined time-points (0, 4, 28, 36, 72-h after admission). On admission, the overall prevalence of OW was 16%, increasing to 32% at target temperature, with higher prevalence in the 33 °C-group (40% vs. 23%, p < 0.0001). No difference in prevalence was found between the 33 °C- and 36 °C-groups on admission (18% vs. 14%, p = .11) or after rewarming (13% vs. 10%, p = .44). OW were not associated with increased risk of ventricular arrhythmia (Odds ratio = 0.78 (0.51-1.20), p = .26), but associated with significantly lower 180-day mortality as compared to no OW (38% vs. 52%, plog-rank = 0.001) in univariable analyses only. CONCLUSION OW are frequent during TTM, particularly in patients treated with 33 °C. OW are not associated with increased risk of ventricular arrhythmia, and may be considered a benign physiological phenomenon, associated with lower mortality in univariable analyses.

Response by Wiberg et al to Letter Regarding Article, “Neuroprotective Effects of the Glucagon-Like Peptide-1 Analog Exenatide After Out-of-Hospital Cardiac Arrest: A Randomized Controlled Trial”

We appreciate the interest of Ma and colleagues in our article reporting the neuroprotective effects of the glucagon-like peptide-1 analog exenatide after out-of-hospital cardiac arrest.1 Ma et al suggest that the neutral findings of our trial could be caused by propofol, which was used to sedate the patients during the period of targeted temperature management. To the best of our …

THE EFFECT OF TICAGRELOR ADMINISTRATED THROUGH A NASOGASTRIC TUBE TO COMATOSE PATIENTS UNDERGOING ACUTE PERCUTANEOUS CORONARY INTERVENTION AFTER CARDIAC ARREST: THE TICOMA TRIAL

In patients resuscitated after cardiac arrest (OHCA) and undergoing primary percutaneous coronary intervention (pPCI) studies on clopidogrel have shown that the antiplatelet effect is almost non-existing 24 hours after initial drug administration. This is the first study to investigate very early

Neuroprotective Effects of the Glucagon-Like Peptide-1 Analog Exenatide After Out-of-Hospital Cardiac ArrestClinical Perspective

Background: In-hospital mortality in comatose patients resuscitated from out-of-hospital cardiac arrest (OHCA) is ≈50%. In OHCA patients, the leading cause of death is neurological injury secondary to ischemia and reperfusion. Glucagon-like peptide-1 analogs are approved for type 2 diabetes mellitus; preclinical and clinical data have suggested their organ-protective effects in patients with ischemia and reperfusion injury. The aim of this trial was to investigate the neuroprotective effects of the glucagon-like peptide-1 analog exenatide in resuscitated OHCA patients. Methods: We randomly assigned 120 consecutive comatose patients resuscitated from OHCA in a double-blind, 2-center trial. They were administered 17.4 &mgr;g exenatide (Byetta) or placebo over a 6-hour and 15-minute infusion, in addition to standardized intensive care including targeted temperature management. The coprimary end points were feasibility, defined as initiation of the study drug in >90% patients within 240 minutes of return of spontaneous circulation, and efficacy, defined as the geometric area under the neuron-specific enolase curve from 24 to 72 hours after admission. The main secondary end points included a composite end point of death and poor neurological function, defined as a Cerebral Performance Category score of 3 to 5 assessed at 30 and 180 days. Results: The study drug was initiated within 240 minutes of return of spontaneous circulation in 96% patients. The median blood glucose 8 hours after admission in patients receiving exenatide was lower than that in patients receiving placebo (5.8 [5.2–6.7] mmol/L versus 7.3 [6.2–8.7] mmol/L, P<0.0001). However, there were no significant differences in the area under the neuron-specific enolase curve, or a composite end point of death and poor neurological function between groups. Adverse events were rare with no significant difference between groups. Conclusions: Acute administration of exenatide to comatose patients in the intensive care unit after OHCA is feasible and safe. Exenatide did not reduce neuron-specific enolase levels and did not significantly improve a composite end point of death and poor neurological function after 180 days. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02442791.

Neuroprotective Effects of the Glucagon-Like Peptide-1 Analog Exenatide After Out-of-Hospital Cardiac ArrestClinical Perspective: A Randomized Controlled Trial

Background: In-hospital mortality in comatose patients resuscitated from out-of-hospital cardiac arrest (OHCA) is ≈50%. In OHCA patients, the leading cause of death is neurological injury secondary to ischemia and reperfusion. Glucagon-like peptide-1 analogs are approved for type 2 diabetes mellitus; preclinical and clinical data have suggested their organ-protective effects in patients with ischemia and reperfusion injury. The aim of this trial was to investigate the neuroprotective effects of the glucagon-like peptide-1 analog exenatide in resuscitated OHCA patients. Methods: We randomly assigned 120 consecutive comatose patients resuscitated from OHCA in a double-blind, 2-center trial. They were administered 17.4 &mgr;g exenatide (Byetta) or placebo over a 6-hour and 15-minute infusion, in addition to standardized intensive care including targeted temperature management. The coprimary end points were feasibility, defined as initiation of the study drug in >90% patients within 240 minutes of return of spontaneous circulation, and efficacy, defined as the geometric area under the neuron-specific enolase curve from 24 to 72 hours after admission. The main secondary end points included a composite end point of death and poor neurological function, defined as a Cerebral Performance Category score of 3 to 5 assessed at 30 and 180 days. Results: The study drug was initiated within 240 minutes of return of spontaneous circulation in 96% patients. The median blood glucose 8 hours after admission in patients receiving exenatide was lower than that in patients receiving placebo (5.8 [5.2–6.7] mmol/L versus 7.3 [6.2–8.7] mmol/L, P<0.0001). However, there were no significant differences in the area under the neuron-specific enolase curve, or a composite end point of death and poor neurological function between groups. Adverse events were rare with no significant difference between groups. Conclusions: Acute administration of exenatide to comatose patients in the intensive care unit after OHCA is feasible and safe. Exenatide did not reduce neuron-specific enolase levels and did not significantly improve a composite end point of death and poor neurological function after 180 days. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02442791.