Differential impact of fentanyl and morphine doses on ticagrelor-induced platelet inhibition in ST-segment elevation myocardial infarction: a subgroup analysis from the PERSEUS randomized trial.

Introduction: Among patients with ST-segment elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (PCI), intravenous fentanyl does not enhance ticagrelor-induced platelet inhibition within 2 h compared to morphine. The impact of the total dose of fentanyl and morphine received on ticagrelor pharmacodynamic and pharmacokinetic responses in patients with STEMI remains however undetermined. Materials and methods: We performed a post-hoc subanalysis of the prospective, open-label, single-center, randomized PERSEUS trial (NCT02531165) that compared treatment with intravenous fentanyl vs. morphine among symptomatic patients with STEMI treated with primary PCI after ticagrelor pretreatment. Patients from the same population as PERSEUS were further stratified according to the total dose of intravenous opioids received. The primary outcome was platelet reactivity using P2Y12 reaction units (PRU) at 2 h following administration of a loading dose (LD) of ticagrelor. Secondary outcomes were platelet reactivity and peak plasma levels of ticagrelor and AR-C124910XX, its active metabolite, at up to 12 h after ticagrelor LD administration. Generalized linear models for repeated measures were built to determine the relationship between raw and weight-weighted doses of fentanyl and morphine. Results: 38 patients with STEMI were included between December 18, 2015, and June 22, 2017. Baseline clinical and procedural characteristics were similar between low- and high-dose opioid subgroups. At 2 h, there was a significant correlation between PRU and both raw [regression coefficient (B), 0.51; 95% confidence interval (CI), 0.02-0.99; p = 0.043] and weight-weighted (B, 0.54; 95% CI, 0.49-0.59; p < 0.001) doses of fentanyl, but not morphine. Median PRU at 2 h was significantly lower in patients receiving low, as compared to high, doses of fentanyl [147; interquartile range (IQR), 63-202; vs. 255; IQR, 183-274; p = 0.028], whereas no significant difference was found in those receiving morphine (217; IQR, 165-266; vs. 237; IQR, 165-269; p = 0.09). At 2 h, weight-weighted doses of fentanyl and morphine were significantly correlated to plasma levels of ticagrelor and AR-C124910XX. Conclusion: In symptomatic patients with STEMI who underwent primary PCI after ticagrelor pretreatment and who received intravenous opioids, we found a dose-dependent relationship between the administration of intravenous fentanyl, but not morphine, and ticagrelor-induced platelet inhibition.

Comparative effects of fentanyl versus morphine on platelet inhibition induced by ticagrelor in patients with ST-segment elevation myocardial infarction: Full results of the PERSEUS randomized trial.

BACKGROUND: Morphine reduces absorption and delays action onset of potent oral P2Y12 receptor inhibitors in patients with ST-segment elevation myocardial infarction (STEMI). We sought to determine the differential effects of fentanyl compared to morphine on the pharmacodynamics and pharmacokinetics of ticagrelor in STEMI patients undergoing primary percutaneous coronary intervention (PCI). METHODS: PERSEUS (NCT02531165) was a prospective, single-center, open-label, randomized controlled study. Patients with STEMI who required analgesia were randomly assigned in a 1:1 ratio to treatment with intravenous fentanyl or morphine after ticagrelor loading dose (LD) administration. The primary endpoint was platelet reactivity at 2 hours after ticagrelor LD assessed by P2Y12 reaction units (PRU). RESULTS: The study was prematurely stopped in June 2017 after enrolment of 38 out of 56 planned patients. PRU at 2 hours following ticagrelor LD was 173.3 ± 89.7 in the fentanyl group and 210.3 ± 76.4 in the morphine group (p = 0.179). At 4 hours, PRU was significantly lower among patients treated with fentanyl as compared to those treated with morphine (90.1 ± 97.4 vs. 168.0 ± 72.2; p = 0.011). Maximal plasma concentrations of ticagrelor and its active metabolite AR-C124910XX tended to be delayed and numerically lower among patients treated with morphine compared to fentanyl. Total exposures to ticagrelor and AR-C124910XX within 6 hours after ticagrelor LD were numerically greater among patients treated with fentanyl compared to those treated with morphine. CONCLUSIONS: In patients with STEMI undergoing primary PCI, fentanyl did not improve platelet inhibition at 2 hours after ticagrelor pre-treatment compared with morphine. Fentanyl may, however, accelerate ticagrelor absorption and increase platelet inhibition at 4 hours compared to morphine.

[Telephone follow-up of SARS-CoV-2 positive patients at the Oncology Department of Lausanne University Hospital]. / Suivi téléphonique des patients testés positifs au SARS-CoV-2 au Département d'oncologie du CHUV.

Compared with the general population, oncology patients face a higher morbidity and mortality caused by the COVID-19 pandemic. As a result, health systems had to quickly adapt cancer care in order to maintain the best quality and patient safety. From March to May and from October to December 2020, 254 patients diagnosed with cancer and tested positive for SARS-CoV-2 benefited from a tele-health monitoring at the Oncology Department at CHUV. This article describes the key points of the development, implementation and operation of this tele-health monitoring, enabled by an interdisciplinary and inter-professional collaboration between different units and healthcare professionals.

En comparaison de la population générale, les patients oncologiques font face à une augmentation de leur morbimortalité en lien avec la pandémie de Covid-19. Par conséquent, les systèmes de santé ont dû s'adapter rapidement dans ce contexte instable afin de poursuivre des soins de qualité tout en assurant la sécurité des patients. De mars à mai ainsi que d'octobre à décembre 2020, un total de 254 patients oncologiques testés positifs au SARS-CoV-2 ont bénéficié d'un suivi téléphonique au Département d'oncologie du CHUV. Cet article décrit les points clés de l'implantation et du fonctionnement de ce télésuivi, grâce à la collaboration entre différentes unités et une équipe interprofessionnelle.

Quantification of myocardial interstitial fibrosis and extracellular volume for the detection of cardiac allograft vasculopathy.

In search of a non-invasive alternative detection of early-stage cardiac allograft vasculopathy (CAV), in this preliminary study we tested the hypothesis that interstitial fibrosis quantified with cardiac magnetic resonance (CMR) can serve as a biomarker for the detection of CAV. Late-stage CAV was detected with routine X-ray coronary angiography (XRCA), while a coronary intima-media thickness ratio (IMTR) > 1 on optical coherence tomography (OCT) was used to detect early-stage CAV. Interstitial fibrosis was quantified in the endomyocardial biopsy (EMB) and indirectly with CMR as the T1 relaxation time and extracellular volume (ECV). CMR was performed within 48 h of a single invasive procedure with XRCA, OCT, and EMB procurement in stable HTx recipients (n = 27; age 54 ± 13 years, 5.4 ± 3.7 years post-transplant). XRCA-CAV and IMTR > 1 were present in 15% and 75% of study patients, respectively. The T1 relaxation times and ECV were increased in patients with XRCA-CAV (p = 0.03 each), while IMTR and EMB interstitial fibrosis were not significantly different (both p > 0.05). ECV (ρ = 0.46, p = 0.02) and IMTR (ρ = 0.58; p = 0.01) correlated with the histological quantity of interstitial fibrosis, while the T1 relaxation time (p = 0.06) did not. The correlation of the IMTR with the EMB interstitial fibrosis tentatively validates the hypothesis that interstitial fibrosis may serve as an early indicator of CAV. Moreover, the significant association of CMR-based ECV with the magnitude of interstitial fibrosis in the biopsy suggests ECV as a potential biomarker for interstitial fibrosis due to early-stage CAV. The measurement of ECV may therefore have a role for non-invasive detection and follow-up of early-stage CAV.

Influence of intravenous fentanyl compared with morphine on ticagrelor absorption and platelet inhibition in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention: rationale and design of the PERSEUS randomized trial.

AIMS: Recent evidence demonstrates that intravenous morphine significantly reduces absorption and delays onset of action of oral P2Y12 receptor inhibitors in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (pPCI). We aimed to assess the influence of intravenous fentanyl compared with morphine on pharmacokinetics and pharmacodynamics of ticagrelor and its active metabolite (AR-C124910XX) in patients undergoing pPCI for STEMI. METHODS AND RESULTS: Single-centre, prospective, open-label, randomized controlled study that will randomly assign in a 1:1 ratio patients with STEMI undergoing pPCI to receive intravenous fentanyl or morphine following a pre-hospital 180-mg loading dose of ticagrelor (ClinicalTrials.gov Identifier: NCT02531165). Pharmacokinetic and pharmacodynamic analyses will be performed at baseline and 1, 2, 4, 6, and 12 h post-loading dose. Pharmacodynamic assessments will include P2Y12 reaction units (PRU) measured by VerifyNow P2Y12. Pharmacokinetic assessments include determination of maximal observed plasma concentrations, time for maximal plasma concentration, and area under the plasma concentration vs. time curve from time 0 to the last measurable concentration (AUC0-t) for ticagrelor and AR-C124910XX. The primary endpoint is platelet reactivity assessed by PRU at 2 h post ticagrelor loading dose. CONCLUSION: PERSEUS will provide randomized data regarding the impact of fentanyl administration, in patients with STEMI undergoing pPCI, on platelet inhibition and ticagrelor absorption and total exposure.

Circadian variation of ticagrelor-induced platelet inhibition in healthy adulty.

Aims: The circadian variation of platelet aggregation is well demonstrated. However, whether this has an impact on antiplatelet inhibition therapy is poorly documented. We aimed to observe whether ticagrelor-induced platelet inhibition follows a circadian rhythm. Methods and results: The study included 25 healthy volunteers (11 female; 14 male). Blood samples were collected every 4 h. Ticagrelor was added in vitro at a concentration that provided 50% inhibition of the maximum response using the VerifyNow System Platelet Reactivity Test® thus avoiding any bias induced by circadian gastrointestinal absorption. Platelet aggregation testing was subsequently performed using the VerifyNow. Circadian changes in total platelet count, percentage of platelets inhibition, Von Willebrand activity, and volunteers' physiological parameters were analysed by fitting individuals' data to a sine curve with a 24-h period. Volunteers' physiological parameters [heart rate (b.p.m.), systolic/diastolic blood pressure (mmHg), and body temperature (Celsius)] followed a significant mean circadian pattern of 6 b.p.m. (P < 0.001), 5 mmHg/7 mmHg (P < 0.002), and 0.3°C (P < 0.001), respectively. Ticagrelor-induced platelet inhibition was significantly lower at 13:00 (38.4%) than at any other time (45.2%) (P = 0.018). Percentage of inhibited platelets plotted against time followed a circadian rhythm (P < 0.001), with mean minimum/maximum values at 13:00/02:00, respectively. Von Willebrand activity also followed a circadian pattern (P < 0.001), with an amplitude of 12.24% and a maximum activity at 12:00. Conclusion: Ticagrelor-induced platelet inhibition follows a circadian rhythm, with the lowest mean values achieved at 13:00. These results deserve further studies in patients with coronary artery disease.

Circadian rhythm of blood cardiac troponin T concentration.

INTRODUCTION: High-sensitivity cardiac troponin assays have significantly improved the sensitivity of myocardial infarction detection by using cutoff values and early absolute changes. However, variation in repeated measures also depends on biological variability. This study aimed to assess the potential circadian component of this biological variability. METHODS: 17 healthy volunteers were recruited, and standardized conditions for physical activity, meals, exposure to light and duration of sleep were imposed. Blood samples were collected every 4 h and high-sensitivity troponin T assay with a limit of detection of 3 ng/l and a 99th percentile of 14 ng/l were used. Circadian variations were analyzed using the cosinor method. RESULTS: Statistically significant circadian variations were observed for body temperature, heart rate, and systolic/diastolic arterial blood pressures (p < 0.01 using both a non-adjusted cosinor model and a gender- and BMI-adjusted cosinor model). The amplitudes of the circadian variations were 18.93, 6, 15.35, and 1.92%, respectively. A statistically significant circadian biological variation of troponin blood concentrations was evidenced (p < 0.01 in both the non-adjusted cosinor model and the gender- and BMI-adjusted cosinor), with an amplitude of 20.5% (average: 4.39 ng/l; amplitude: 0.9 ng/l; peak at 06:00 and nadir at 18:00). DISCUSSION: This study demonstrates a circadian biological variation in blood troponin concentration in a healthy population. The amplitude of this variation challenges the cutoff value for instant rule-out of the rapid rule-in/rule-out of the recent European guidelines for the management of acute coronary syndromes. These findings deserve further investigation in a population at risk of myocardial infarction.

Performance of highly sensitive cardiac troponin T assay to detect ischaemia at PET-CT in low-risk patients with acute coronary syndrome: a prospective observational study.

BACKGROUND: Highly sensitive troponin T (hs-TnT) assay has improved clinical decision-making for patients admitted with chest pain. However, this assay's performance in detecting myocardial ischaemia in a lowrisk population has been poorly documented. PURPOSE: To assess hs-TnT assay's performance to detect myocardial ischaemia at positron emission tomography/CT (PET-CT) in low-risk patients admitted with chest pain. METHODS: Patients admitted for chest pain with a nonconclusive ECG and negative standard cardiac troponin T results at admission and after 6 hours were prospectively enrolled. Their hs-TnT samples were at T0, T2 and T6. Physicians were blinded to hs-TnT results. All patients underwent a PET-CT at rest and during adenosine-induced stress. All patients with a positive PET-CT result underwent a coronary angiography. RESULTS: Forty-eight patients were included. Six had ischaemia at PET-CT. All of them had ≥1 significant stenosis at coronary angiography. Areas under the curve (95% CI) for predicting significant ischaemia at PET-CT using hs-TnT were 0.764 (0.515 to 1.000) at T0, 0.812(0.616 to 1.000) at T2 and 0.813(0.638 to 0.989) at T6. The receiver operating characteristicbased optimal cut-off value for hs-TnT at T0, T2 and T6 needed to exclude significant ischaemia at PET-CT was <4 ng/L. Using this value, sensitivity, specificity, positive and negative predictive values of hs-TnT to predict significant ischaemia were 83%/38%/16%/94% at T0, 100%/40%/19%/100% at T2 and 100%/43%/20%/100% at T6, respectively. CONCLUSIONS: Our findings suggest that in low-risk patients, using the hs-TnT assay with a cut-off value of 4 ng/L demonstrates excellent negative predictive value to exclude myocardial ischaemia detection at PET-CT, at the expense of weak specificity and positive predictive value. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT01374607.

Assessment of quality performance measures for primary percutaneous coronary intervention: A report from a tertiary referral centre in Switzerland.

AIMS: The present study aimed to document a local pattern of care in consecutive patients undergoing primary percutaneous coronary intervention for ST-elevation myocardial infarction (STEMI) in a tertiary centre in Switzerland. METHODS: A retrospective study was conducted at the University Hospital of Lausanne, Switzerland. A total of 389 consecutive patients undergoing primary percutaneous coronary intervention for STEMI between 2009 and 2010 were studied. The audit focused on 14 items derived from the American College of Cardiology/American Heart Association 2008 quality performance measures position paper on STEMI management. These indicators all corresponded to a class 1 recommendation at the time of the study period. RESULTS: All patients received aspirin and anticoagulation within 24 hours after admission. Only 31.3% of patients received beta-blocking agents within 24 hours of admission. Left ventricular function was evaluated in 89.2% of cases and referral for cardiac rehabilitation was achieved in 78.5% of eligible patients. Patients subsequently transferred to another facility for further inpatient care had significantly less evaluation of left ventricular function (82.0% vs. 97.5%, P<0.0001). Global adherence to all performance measures was significantly higher among younger patients (45.9% vs. 31.4%, P<0.0075). CONCLUSIONS: The present study, which provides a snapshot on quality performance between 2009 and 2010 in a referral centre for primary percutaneous coronary intervention, demonstrates a suboptimal application of the global guidelines on STEMI management. This observation is mainly driven by a low prescription of beta-blocking agents, a class IA indication at that time. This observation should be put in perspective to current practice.

Influence of socioeconomic factors on delays, management and outcome amongst patients with acute myocardial infarction undergoing primary percutaneous coronary intervention.

AIMS: The outcome after primary percutaneous coronary intervention (pPCI) for ST-elevation myocardial infarction (STEMI) is strongly affected by time delays. In this study, we sought to identify the impact of specific socioeconomic factors on time delays, subsequent STEMI management and outcomes in STEMI patients undergoing pPCI, who came from a well-defined region of the French part of Switzerland. METHOD AND RESULTS: A total of 402 consecutive patients undergoing pPCI for STEMI in a large tertiary hospital were retrospectively studied. Symptom-to-first-medical-contact time was analysed for the following socioeconomic factors: level of education, origin and marital status. Main exclusion criteria were: time delay beyond 12 hours, previous treatment with fibrinolytic agents or patients immediately referred for coronary artery bypass graft surgery. Therefore, 222 patients were finally included. At 1 year, there was no difference in mortality between the different socioeconomic groups. Furthermore, there was no difference in management characteristics between them. Symptom-to-first-medical-contact time was significantly longer for patients with a low level of education, Swiss citizens and unmarried patients, with median differences of 23 minutes, 18 minutes and 13 minutes, respectively (p <0.05). Nevertheless, no difference was found regarding in-hospital management and clinical outcome. CONCLUSION: This study demonstrates that symptom-to-first-medical-contact time is longer amongst people with a lower educational level, Swiss citizens and unmarried people. Because of the low mortality rate in general, these differences in delays did not affect clinical outcomes. Still, tertiary prevention measures should particularly focus on these vulnerable populations.

Quality assessment of cardiovascular magnetic resonance in the setting of the European CMR registry: description and validation of standardized criteria.

BACKGROUND: Cardiovascular magnetic resonance (CMR) has become an important diagnostic imaging modality in cardiovascular medicine. However, insufficient image quality may compromise its diagnostic accuracy. We aimed to describe and validate standardized criteria to evaluate a) cine steady-state free precession (SSFP), b) late gadolinium enhancement (LGE), and c) stress first-pass perfusion images. These criteria will serve for quality assessment in the setting of the Euro-CMR registry. METHODS: Thirty-five qualitative criteria were defined (scores 0-3) with lower scores indicating better image quality. In addition, quantitative parameters were measured yielding 2 additional quality criteria, i.e. signal-to-noise ratio (SNR) of non-infarcted myocardium (as a measure of correct signal nulling of healthy myocardium) for LGE and % signal increase during contrast medium first-pass for perfusion images. These qualitative and quantitative criteria were assessed in a total of 90 patients (60 patients scanned at our own institution at 1.5T (n=30) and 3T (n=30) and in 30 patients randomly chosen from the Euro-CMR registry examined at 1.5T). Analyses were performed by 2 SCMR level-3 experts, 1 trained study nurse, and 1 trained medical student. RESULTS: The global quality score was 6.7±4.6 (n=90, mean of 4 observers, maximum possible score 64), range 6.4-6.9 (p=0.76 between observers). It ranged from 4.0-4.3 for 1.5T (p=0.96 between observers), from 5.9-6.9 for 3T (p=0.33 between observers), and from 8.6-10.3 for the Euro-CMR cases (p=0.40 between observers). The inter- (n=4) and intra-observer (n=2) agreement for the global quality score, i.e. the percentage of assignments to the same quality tertile ranged from 80% to 88% and from 90% to 98%, respectively. The agreement for the quantitative assessment for LGE images (scores 0-2 for SNR <2, 2-5, >5, respectively) ranged from 78-84% for the entire population, and 70-93% at 1.5T, 64-88% at 3T, and 72-90% for the Euro-CMR cases. The agreement for perfusion images (scores 0-2 for %SI increase >200%, 100%-200%,<100%, respectively) ranged from 81-91% for the entire population, and 76-100% at 1.5T, 67-96% at 3T, and 62-90% for the Euro-CMR registry cases. The intra-class correlation coefficient for the global quality score was 0.83. CONCLUSIONS: The described criteria for the assessment of CMR image quality are robust with a good inter- and intra-observer agreement. Further research is needed to define the impact of image quality on the diagnostic and prognostic yield of CMR studies.

Free-breathing 3 T magnetic resonance T2-mapping of the heart.

OBJECTIVES: This study sought to establish an accurate and reproducible T(2)-mapping cardiac magnetic resonance (CMR) methodology at 3 T and to evaluate it in healthy volunteers and patients with myocardial infarct. BACKGROUND: Myocardial edema affects the T(2) relaxation time on CMR. Therefore, T(2)-mapping has been established to characterize edema at 1.5 T. A 3 T implementation designed for longitudinal studies and aimed at guiding and monitoring therapy remains to be implemented, thoroughly characterized, and evaluated in vivo. METHODS: A free-breathing navigator-gated radial CMR pulse sequence with an adiabatic T(2) preparation module and an empirical fitting equation for T(2) quantification was optimized using numerical simulations and was validated at 3 T in a phantom study. Its reproducibility for myocardial T(2) quantification was then ascertained in healthy volunteers and improved using an external reference phantom with known T(2). In a small cohort of patients with established myocardial infarction, the local T(2) value and extent of the edematous region were determined and compared with conventional T(2)-weighted CMR and x-ray coronary angiography, where available. RESULTS: The numerical simulations and phantom study demonstrated that the empirical fitting equation is significantly more accurate for T(2) quantification than that for the more conventional exponential decay. The volunteer study consistently demonstrated a reproducibility error as low as 2 ± 1% using the external reference phantom and an average myocardial T(2) of 38.5 ± 4.5 ms. Intraobserver and interobserver variability in the volunteers were -0.04 ± 0.89 ms (p = 0.86) and -0.23 ± 0.91 ms (p = 0.87), respectively. In the infarction patients, the T(2) in edema was 62.4 ± 9.2 ms and was consistent with the x-ray angiographic findings. Simultaneously, the extent of the edematous region by T(2)-mapping correlated well with that from the T(2)-weighted images (r = 0.91). CONCLUSIONS: The new, well-characterized 3 T methodology enables robust and accurate cardiac T(2)-mapping at 3 T with high spatial resolution, while the addition of a reference phantom improves reproducibility. This technique may be well suited for longitudinal studies in patients with suspected or established heart disease.

Circadian variations of ischemic burden among patients with myocardial infarction undergoing primary percutaneous coronary intervention.

BACKGROUND: Several parameters of cardiovascular physiology and pathophysiology exhibit circadian rhythms. Recently, a relation between infarct size and the time of day at which it occurs has been suggested in experimental models of myocardial infarction. The aim of this study is to investigate whether circadian rhythms could cause differences in ischemic burden in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). METHODS: In 353 consecutive patients with STEMI treated by PPCI, time of symptom onset, peak creatine kinase (CK), and follow-up at 30 days were obtained. We divided 24 hours into 4 time groups based on time of symptom onset (00:00-05:59, 06:00-11:59, 12:00-17:59, and 18:00-23:59). RESULTS: There was no difference between the groups regarding baseline patients and management's characteristics. At multivariable analysis, there was a statistically significant difference between peak CK levels among patients with symptom onset between 00:00 and 05:59 when compared with peak CK levels of patients with symptom onset in any other time group (mean increase 38.4%, P < .05). Thirty-day mortality for STEMI patients with symptom onset occurring between 00:00 and 05:59 was significantly higher than any other time group (P < .05). CONCLUSION: This study demonstrates an independent correlation between the infarct size of STEMI patients treated by PPCI and the time of the day at which symptoms occurred. These results suggest that time of the day should be a critical issue to look at when assessing prognosis of patients with myocardial infarction.