Electrocardiographic assessments and cardiac events after fingolimod first dose - a comprehensive monitoring study.
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ABSTRACT:
SUBMITTER: Limmroth V
PROVIDER: S-EPMC5241949 | biostudies-literature | 2017 Jan
REPOSITORIES: biostudies-literature
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Electrocardiographic assessments and cardiac events after fingolimod first dose - a comprehensive monitoring study.
Limmroth Volker V Ziemssen Tjalf T Lang Michael M Richter Stephan S Wagner Bert B Haas Judith J Schmidt Stephan S Gerbershagen Kathrin K Lassek Christoph C Klotz Luisa L Hoffmann Olaf O Albert Christian C Schuh Katrin K Baier-Ebert Monika M Wendt Guillaume G Schieb Heinke H Hoyer Susanne S Dechend Ralf R Haverkamp Wilhelm W
BMC neurology 20170118 1
<h4>Background</h4>First dose observation for cardiac effects is required for fingolimod, but recommendations on the extent vary. This study aims to assess cardiac safety of fingolimod first dose. Individual bradyarrhythmic episodes were evaluated to assess the relevance of continuous electrocardiogram (ECG) monitoring.<h4>Methods</h4>START is an ongoing open-label, multi-center study. At the time of analysis 3951 patients were enrolled. The primary endpoints are the incidence of bradycardia (he ...[more]
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Project description:Background: First dose observation for cardiac effects is required for fingolimod. Previous results in patients with relapsing remitting multiple sclerosis (RRMS) suggest that transient bradycardia and conduction abnormalities during the observation phase are rare, benign and reversible. Prior analyses corroborate these findings. The present large scale dataset allows subgroup analyses for differences in the incidence of cardiac findings depending on patient characteristics. Methods: START was an open-label, multi-center study that enrolled 6,998 RRMS patients. Primary endpoints were incidence of bradycardia (heart rate < 45 bpm) and second-/third-degree atrioventricular (AV) block during treatment initiation. Subgroup analyses were performed according to age, gender, body mass index (BMI), baseline expanded disability status scale (EDSS), and concomitant medication to determine the impact of these variables on cardiac outcomes parameters. Results: 63 patients (0.9%) developed bradycardia (<45 bpm), 120 patients (1.7%) had a second-degree Mobitz I (Wenkebach) block and/or 2:1 AV block. One case of an asymptomatic third-degree AV block occurred. No Mobitz II AV block was observed. After 1 week, no second-/third-degree AV block was observed. The incidence of second- or third-degree AV blocks was significantly higher in older patients (≥50 years; p = 0.014 vs. patients 35-49 years). Second- or third-degree AV blocks were more frequent in females (87.5% of all patients with a second- or third-degree AV block; p < 0.001), while bradycardia occurred more often in males (58.7% of all bradycardia events; p < 0.001). Furthermore, patients with a BMI below 25 had a higher incidence of second- or third-degree AV block. Conclusions: In summary, transient bradycardia and AV conduction abnormalities after the first dose of fingolimod were rare and asymptomatic. When compared to females, male patients might have a higher risk for bradycardia during treatment initiation, presumably due to a lower resting heart rate. Furthermore, a low heart rate before treatment initiation, low body weight, or low BMI possibly increases the risk for bradycardia. Second- or third-degree AV blocks were more frequent in females, older patients and patients with a low BMI. Nevertheless, these cardiac events remained rare and benign, confirming the favorable cardiac safety profile of fingolimod upon treatment initiation in MS patients without cardiovascular comorbidities.
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Project description:IntroductionFingolimod was the first oral therapy approved for the treatment of relapsing-remitting multiple sclerosis (RRMS). Due to its action on cardiac sphingosine 1-phosphate receptors, fingolimod is leading to a transient decrease in heart rate (HR) and the occurrence of rare and asymptomatic self-limited atrioventricular (AV) blocks. This German non-interventional clinical study aimed to assess the cardiac safety profile in RRMS patients during at least 6 h after the initial treatment or restart after interruption of fingolimod in real-world settings.MethodsThe GoCARD study (German National Health Authorities, BfArM, CFTY720DDE18, NIS334) was a prospective, multi-center non-interventional study which was conducted in neurological and other medical practices or hospitals, qualified to routinely assess electrocardiogram (ECG) findings. Data were collected through interviews, clinical evaluations (notably ECGs), and laboratory tests. Medical history, vital signs, and a 12-lead ECG were assessed before fingolimod administration. After the first dose, a 6 h ECG was performed and vital signs (blood pressure and HR) were measured hourly. The occurrence of bradycardia (HR ≤45 beats per minute [BPM]), AV blocks (2nd degree Mobitz type I or higher), and corrected QT interval (QTc) intervals was also documented.ResultsMore than 95% of physicians adhered to the cardiac monitoring recommendations. The observation of 217 patients in 42 study centers showed that while 35.9% of the patients had any cardiac risk profile, none of them experienced a bradycardia during the 6 h post-dose observation. Overall, only 1.8% of all patients displayed bradycardia (HR ≤45 BPM) during 6 h after treatment initiation. Moreover, in this cohort, none of the patients showed a new or persistent onset AV block (2nd degree Mobitz type I or higher) or QTc ≥500 ms.ConclusionAltogether, these data confirm that the first-dose observation after fingolimod initiation is usually uneventful (even in patients with pre-existing cardiovascular risk factors of this cohort) and that the rarely observed events remained asymptomatic and self-limited.FundingNovartis Pharma GmbH, Nürnberg, Germany.
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Project description:Survival from in-hospital cardiac arrest (IHCA) due to pulseless electrical activity/asystole remains poor. We aimed to evaluate whether electrocardiographic changes provide predictive information for risk of IHCA from pulseless electrical activity/asystole. We conducted a retrospective case-control study, utilizing continuous electrocardiographic data from case and control patients. We selected 3 consecutive 3-hour blocks (block 3, 2, and 1 in that order); block 1 immediately preceded cardiac arrest in cases, whereas block 1 was chosen at random in controls. In each block, we measured dominant positive and negative trends in electrocardiographic parameters, evaluated for arrhythmias, and compared these between consecutive blocks. We created random forest and logistic regression models, and tested them on differentiating case versus control patients (case block 1 vs control block 1), and temporal relation to cardiac arrest (case block 2 vs case block 1). Ninety-one cases (age 63.0 ± 17.6, 58% male) and 1,783 control patients (age 63.5 ± 14.8, 67% male) were evaluated. We found significant differences in electrocardiographic trends between case and control block 1, particularly in QRS duration, QTc, RR, and ST. New episodes of atrial fibrillation and bradyarrhythmias were more common before IHCA. The optimal model was the random forest, achieving an area under the curve of 0.829, 63.2% sensitivity, 94.6% specificity at differentiating case versus control block 1 on a validation set, and area under the curve 0.954, 91.2% sensitivity, 83.5% specificity at differentiating case block 1 versus case block 2. In conclusion, trends in electrocardiographic parameters during the 3-hour window immediately preceding IHCA differ significantly from other time periods, and provide robust predictive information.
| S-EPMC6744991 | biostudies-literature
Project description:BackgroundIn patients with relapsing-remitting MS (RRMS) fingolimod prevents disease relapses and delays disability progression. First dose administration of fingolimod is associated with a transient, dose-dependent decrease in heart rate (HR) in the 6 hours after drug intake.The aim of the study is to to assess safety and tolerability of the first dose of fingolimod in a cohort of Italian patients with RRMS without alternative therapeutic options.MethodsOpen-label, single arm, multicentre study. After the first dose of fingolimod, patients were observed for 6 hours and had their vital signs monitored hourly. Extended on-site monitoring was provided when required.ResultsOf the 906 patients enrolled in the study, most (95.2%) did not experience any adverse event (AE) following fingolimod administration. Cardiovascular AEs occurred in 18 patients and included bradycardia (1.3%), first-and second-degree atrioventricular block (0.1% and 0.2%), palpitations (0.1%), sinus arrhythmia (0.1%) and ventricular premature beats (0.1%). All events were self-limiting and did not require any intervention. Extended monitoring was required in 34 patients.ConclusionsThese results, in a population who better resembled real-world clinical practice in terms of concomitant diseases and medications, are consistent with previous clinical trials and confirmed that the first dose administration of fingolimod is generally safe and well tolerated.Trial registrationEudraCT 2011-000770-60.
| S-EPMC4005629 | biostudies-literature
Project description:BACKGROUND:Fingolimod (Gilenya®) is approved for relapsing forms of multiple sclerosis in the USA. Owing to transient heart-rate effects when initiating fingolimod, eligible patients undergo precautionary baseline assessment and first-dose observation (FDO) for ≥6 h. Prior to 2014, FDO was undertaken only in clinics. As the FDO period is short, and fingolimod has accumulated evidence of a positive benefit:risk ratio, an in-home treatment-initiation program, Gilenya@Home, was developed to offer a convenient alternative. METHODS:Cardiac parameters and adverse events (AEs) were recorded by healthcare professionals performing fingolimod FDOs in the US Gilenya@Home program or in US Gilenya Assessment Network clinics. Anonymized data were collated retrospectively from the first 34 months in the home setting and from 78 months in clinics; data are reported descriptively. Satisfaction with Gilenya@Home was rated by patients using a 7-item questionnaire that considered aspects such as ease of scheduling, courtesy, and competency. RESULTS:Data were captured as part of standard care from 5573 patients initiating fingolimod in-home (October 2014 to July 2017) and from 15,025 patients initiating in-clinic (July 2010 to December 2016). In the Gilenya@Home questionnaire, 91.7% of 1848 respondents rated their overall satisfaction as "very good," and 7.6% rated their satisfaction as "good." AEs were reported for 30.7 and 32.6% of in-home and in-clinic patients, respectively. In total, 557 in-home (10.0%) and 398 in-clinic (2.6%) patients were monitored for > 6 h; 15 (0.3%) in-home and 129 (0.9%) in-clinic patients were transferred to an emergency room for overnight monitoring. The mean (standard deviation) heart rate (HR; bpm) pre-FDO was 74.8 (12.2) in-home and 74.2 (11.3) in-clinic; reduction in HR at 6 h postdose was 10.6 (12.0) and 6.3 (9.6), respectively. New-onset first-degree atrioventricular block was experienced by 132 (2.4%) in-home and 74 (0.5%) in-clinic patients, and Wenckebach (Mobitz type I) second-degree atrioventricular block by four (0.07%) and nine (0.1%) patients, with no cases of third-degree atrioventricular block. CONCLUSIONS:A substantial number of patients have initiated fingolimod at home, reporting very high levels of satisfaction. Gilenya@Home was as rigorous as the clinic setting in detecting cardiovascular events. Overall, FDO safety outcomes were similar with Gilenya@Home and in-clinic.
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Project description:Machine learning (ML) methods for the analysis of electrocardiography (ECG) data are gaining importance, substantially supported by the release of large public datasets. However, these current datasets miss important derived descriptors such as ECG features that have been devised in the past hundred years and still form the basis of most automatic ECG analysis algorithms and are critical for cardiologists' decision processes. ECG features are available from sophisticated commercial software but are not accessible to the general public. To alleviate this issue, we add ECG features from two leading commercial algorithms and an open-source implementation supplemented by a set of automatic diagnostic statements from a commercial ECG analysis software in preprocessed format. This allows the comparison of ML models trained on clinically versus automatically generated label sets. We provide an extensive technical validation of features and diagnostic statements for ML applications. We believe this release crucially enhances the usability of the PTB-XL dataset as a reference dataset for ML methods in the context of ECG data.
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Project description:BackgroundCardiotoxicity induced by 5-fluorouracil (5-FU) is well known but poorly understood. In this study, we undertook ECG recording (Holter) and analyses of the biomarkers troponin and copeptin in patients receiving 5-FU to increase our understanding of the cardiotoxicity.Subjects, materials, and methodsPatients with colorectal or anal cancer that received first-time treatment with 5-FU-based chemotherapy were prospectively included. Holter recording, clinical evaluation, 12-lead electrocardiogram, and assessment of plasma concentrations of troponin I and copeptin were performed before (control) and during 5-FU treatment (intervention).ResultsA total of 108 patients were included, 82 with colorectal and 26 with anal cancer. The proportion of patients with myocardial ischemia on Holter recording was significantly higher during the first 5-FU infusion (14.1%) than before (3.7%; p = .001). The ischemic burden per day (p = .001), the number of ST depression episodes per day (p = .003), and the total duration of ischemic episodes per day (p = .003) were higher during the first 5-FU infusion than before, as was plasma copeptin (p < .001), whereas plasma troponin I was similar (p > 0.999). Six patients (5.6%) developed acute coronary syndromes and two (1.8%) developed symptomatic arrhythmias during 5-FU treatment.Conclusion5-FU infusion is associated with an increase in the number of patients with myocardial ischemia on Holter recording. According to biomarker analyses, 5-FU is associated with an increase in copeptin, but rarely with increases in cardiac troponin I. However, 5%-6% of the patients developed acute coronary syndromes during treatment with 5-FU.Implications for practiceSymptomatic 5-fluorouracil (5-FU) cardiotoxicity occurs in 0.6%-19% of patients treated with this drug, but a small electrocardiographic (Holter) study has revealed silent myocardial ischemia in asymptomatic patients, suggesting a more prevalent subclinical cardiac influence. This study demonstrated a significant increase in the number of patients with myocardial ischemia on Holter recording during 5-FU treatment and an increase in ischemic burden. Cardiac biomarker analyses suggested that 5-FU infusion results in endogenous stress (increased copeptin) but rarely induces myocyte injury (no change in troponin). These findings suggest a more prevalent cardiac influence from 5-FU and that Holter recording is an important tool in the evaluation of patients with suspected cardiotoxicity from 5-FU.
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Project description:BackgroundPrevious studies with the majority of breast cancer (BC) patients treated up to 2000 provided evidence that radiation dose to the heart from radiotherapy (RT) was linearly associated with increasing risk for long-term cardiac disease. RT techniques changed substantially over time. This study aimed to investigate the dose-dependent cardiac risk in German BC patients treated with more contemporary RT.MethodsIn a cohort of 11,982 BC patients diagnosed in 1998-2008, we identified 494 women treated with 3D-conformal RT who subsequently developed a cardiac event. Within a nested case-control approach, these cases were matched to 988 controls. Controls were patients without a cardiac event after RT until the index date of the corresponding case. Separate multivariable conditional logistic regression models were used to assess the association of radiation to the complete heart and to the left anterior heart wall (LAHW) with cardiac events.ResultsMean dose to the heart for cases with left-sided BC was 4.27 Gy and 1.64 Gy for cases with right-sided BC. For controls, corresponding values were 4.31 Gy and 1.66 Gy, respectively. The odds ratio (OR) per 1 Gy increase in dose to the complete heart was 0.99 (95% confidence interval (CI): 0.94-1.05, P = .72). The OR per 1 Gy increase in LAHW dose was 1.00 (95% CI: 0.98-1.01, P = .68).ConclusionsContrary to previous studies, our study provided no evidence that radiation dose to the heart from 3D-conformal RT for BC patients treated between 1998 and 2008 was associated with risk of cardiac events.
| S-EPMC9207715 | biostudies-literature
Project description:Background:Many of the drugs being used in the treatment of the ongoing pandemic coronavirus disease 2019 (COVID-19) are associated with QT prolongation. Expert guidance supports electrocardiographic (ECG) monitoring to optimize patient safety. Objective:The purpose of this study was to establish an enhanced process for ECG monitoring of patients being treated for COVID-19. Methods:We created a Situation Background Assessment Recommendation tool identifying the indication for ECGs in patients with COVID-19 and tagged these ECGs to ensure prompt over reading and identification of those with QT prolongation (corrected QT interval > 470 ms for QRS duration ? 120 ms; corrected QT interval > 500 ms for QRS duration > 120 ms). This triggered a phone call from the electrophysiology service to the primary team to provide management guidance and a formal consultation if requested. Results:During a 2-week period, we reviewed 2006 ECGs, corresponding to 524 unique patients, of whom 103 (19.7%) met the Situation Background Assessment Recommendation tool-defined criteria for QT prolongation. Compared with those without QT prolongation, these patients were more often in the intensive care unit (60 [58.3%] vs 149 [35.4%]) and more likely to be intubated (32 [31.1%] vs 76 [18.1%]). Fifty patients with QT prolongation (48.5%) had electrolyte abnormalities, 98 (95.1%) were on COVID-19-related QT-prolonging medications, and 62 (60.2%) were on 1-4 additional non-COVID-19-related QT-prolonging drugs. Electrophysiology recommendations were given to limit modifiable risk factors. No patient developed torsades de pointes. Conclusion:This process functioned efficiently, identified a high percentage of patients with QT prolongation, and led to relevant interventions. Arrhythmias were rare. No patient developed torsades de pointes.
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