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Novel Approaches to Monitoring QT Intervals in Patients Receiving Chemotherapeutic Agents
EP Lab Digest. 2022;22(12):1,12-15.
Abstract
Oncology patients are a unique subset of the patient population identified as having an increased risk for QT prolongation.1 In addition to their predisposing risk factors at baseline, these patients also receive potentially arrhythmogenic chemotherapy, which further increases their risk. Long-term monitoring of the QT interval in this population is critical to prevent fatal arrhythmias. This study proposes the use of an implantable loop recorder (ILR) device (Reveal LINQ insertable cardiac monitor [ICM], Medtronic) to improve monitoring of the QT interval over the patients’ chemotherapy course. This approach allows for increasing availability of QT data, so that clinicians can make more accurate arrhythmogenic risk calculations and thereby appropriately adjust their chemotherapy course and concomitant drug therapy. In this study, patients with malignancy receiving chemotherapy underwent implantation of a loop recorder device prior to initiation of chemotherapy. At the start of each chemotherapy cycle, electrocardiograms (ECGs) were obtained and loop recorder devices were interrogated to provide a 1:1 comparison of the ECG QTc to the LINQ QTc.
Patients then transmitted daily via a remote home monitoring system (CareLink, Medtronic) in the interval period between cycles. QT intervals were manually measured from the LINQ data, and the QTc was calculated using the Bazett formula. These intervals were compared to the QTc intervals obtained from ECGs for each respective cycle. Our results showed that 100% of the LINQ QTc intervals were within 15% of the ECG QTc intervals. When applying more strict parameters, 93.75% of the LINQ QTc intervals were within 10% of the ECG QTc. The data obtained in this study suggests that the LINQ QTc intervals were not significantly varied from the ECG QTc intervals. Thus, the loop recorder may be a viable way for real-time monitoring of the QT interval. In summary, this study demonstrates noninferiority of the ILR to the gold standard ECG in monitoring QT intervals in oncology patients undergoing arrhythmogenic chemotherapy.
Key words: chemotherapy, insertable cardiac monitor, oncology, QT prolongation
Background
As seen on a 12-lead ECG tracing, the QT interval is defined as the amount of time in milliseconds (msec) from the beginning of the QRS complex to the end of the T wave. Physiologically, it represents depolarization and subsequent repolarization of the ventricles.2 When ventricular repolarization is longer than expected, prolongation of the QT interval results. Based on criteria used in previous drug trials, an interval >500 msec or a change >15% from baseline warrants clinical concern.3 Excessive prolongation of the QT interval is significant as it is known to lead to torsades de pointes, a type of fatal ventricular tachycardia.1,2,4
A variety of risk factors have been identified in predisposing patients to QT prolongation. Some of these contributing factors include age, gender, pre-existing cardiovascular disease, hepatic impairment, renal failure, and electrolyte derangements.2,5,6 However, the use of certain medications is another important risk factor to consider in contributing to QT prolongation. Over the last 20 years, one of the most common reasons medications were removed from the market was secondary to their effects on the QT interval.7,8 Examples of QT-prolonging medications include cardiac drugs such as antiarrhythmics and noncardiac drugs such as antiemetics, antimicrobials, antidepressants, and antipsychotics.5,8,9
Oncology patients are one subset of the patient population that we have identified at an increased risk for QT prolongation. In addition to their predisposing risk factors at baseline, these patients undergo treatment with potentially arrhythmogenic chemotherapeutic agents plus concomitant drugs, such as antiemetics needed for supportive care.1,5 Thus, there is a significant need for improved QT monitoring strategies in this population. This study proposes a new approach to monitoring the QT interval with an ILR device allowing clinicians to assess and reassess patients’ risk over the course of their treatment. Ultimately, improved monitoring strategies could result in more appropriate chemotherapeutic treatment courses for patients as the availability of QT data provides more accurate arrhythmogenic risk calculation.
Methods
Study Population
The population studied included 5 patients with active malignancy undergoing chemotherapy. Inclusion criteria for enrollment required that patients be older than 21, have a projected life expectancy of ≥3 months, and a platelet count >20,000 and white blood cell count >3,000 at the time of device implantation. Informed consent and HIPAA authorization were obtained from all patients prior to enrollment. Specific patient demographic information is included in Table 1.
Methods
Patients underwent implantation of a LINQ ICM device. Baseline ECG and LINQ QTc intervals were recorded at the time of implantation. At the start of each cycle of chemotherapy, an ECG was obtained, and the LINQ devices were interrogated on the same day. Patients then transmitted via CareLink once daily during the time interval between each chemotherapy cycle. If patients were admitted to the hospital with an acute illness at any point during the study, transmission or interrogation of the device was completed on a daily basis in addition to daily ECGs. At the end of the study, the loop recorder devices were explanted and a final ECG was obtained. All ECGs obtained during the study were performed on a MAC 5500 HD (GE Healthcare).
CareLink data was analyzed on a weekly basis to ensure that no critical data (significant bradycardia (heart rate [HR] <40 bpm or pause greater than 3 seconds), tachycardia (HR >200 bpm), harmful arrhythmias, or QT prolongation >15% of a patient’s baseline) was received. If critical data was identified, this information was shared with the patient’s primary oncology team to allow appropriate intervention. During the study, no critical data was noted, and therefore, no intervention from the study team was required.
Data and Results
Data
In this study, the QT interval data from the ECGs served as the gold standard control to which the daily LINQ data was compared. On the ECGs, the corrected QT (QTc) intervals were recorded if the HR was measured as >60 beats per minute (bpm). The MAC 5500 HD uses the Marquette 12SL ECG Analysis Program (GE Healthcare) to calculate the QTc according to the Bazett formula.10 If the HR was <60 bpm, the QT interval was recorded instead. Conversely, the QT intervals from the LINQ devices were obtained from manual measurements. For each day of transmitted data, a random R-R interval was selected and the associated QT interval was manually measured by 3 independent readers, then averaged. Of note, the interval readers in this study had varying degrees of experience and included a practicing electrophysiologist, cardiac device engineer, and medical student. Using the Bazett formula, the QTc was calculated from the average measured QT among the 3 readers and the corresponding LINQ calculated R-R interval. The Bazett formula was chosen for correction of the QT intervals due to its frequent use in clinical practice as well as because it allowed for 1:1 comparison to the QTc intervals obtained from the ECGs. Sample data for patient #1 during their first chemotherapy cycle is illustrated in Table 2.
Results
Statistical analyses of the data were performed to determine how the LINQ QTc readings compared to the gold standard ECG QTc on chemotherapy cycle days. A total of 80 data points were analyzed. No data was missing from chemotherapy cycle days; however, 6.7% of the data obtained from CareLink transmissions in the interim periods were missing due to lack of patient compliance with transmissions. The data revealed that 100% of the absolute differences between the ECG and LINQ QTc on cycle days were within 15% of the gold standard ECG QTc. Even when applying more strict parameters, 93.75% of the absolute differences were within 10% of the ECG QTc. Graph 1 illustrates the 1:1 comparison of the ECG QTc to the LINQ QTc on chemotherapy cycle days for patients 1-5. Graph 2 depicts the percent variance of the ECG and LINQ QTc intervals for all patients throughout their chemotherapy cycle, including both cycle days and interim cycle periods. As seen in Graph 2, there were no variances >15% that occurred during chemotherapy for any patient, further demonstrating no significant difference between the LINQ and ECG measurements of the QT interval.
Additionally, since the LINQ QT intervals were measured manually by 3 independent readers, the differences in their measurements were analyzed (n=939). Inter-reader reliability was found to have a Cronbach alpha of .991.
Discussion
The data obtained in this study suggests that the ILR may be a viable way to monitor QT intervals in patients undergoing arrhythmogenic chemotherapy. On chemotherapy cycle days, the LINQ QTc intervals were not significantly varied from the ECG QTc intervals, demonstrating that the ILR is noninferior to the gold standard ECG. This is clinically significant, because it suggests that the ILR may be used by clinicians for real-time monitoring of the QT interval in patients that are identified at risk for prolongation. The findings may even allow for the monitoring of peak chemotherapy QT toxicities and determination of “vulnerable QTc periods” in these patients. Such data may be useful to clinicians as well as pharmaceutical companies to allow for monitoring of drug toxicity in patients over a prolonged period of time.
The utility of this monitoring approach allows for the extrapolation to multiple fields, beyond just oncology patients, and to multiple drug classes including antiarrhythmics, cardiac drugs, and multiple sclerosis drugs.3,8,11 This technology may also be used to monitor QT prolongation at home while loading certain drugs, such as chemotherapies or antiarrhythmics such as sotalol, resulting in decreased length of hospital stays for patients and reduced medical costs to both hospitals and patients.
The inter-reader reliability in this study was found to be excellent despite the wide range of ECG reading experience between the readers. Thus, with minimal training, oncologists or other health care personnel could be taught to manually read the QT intervals obtained from the LINQ data. This would allow them to receive the cardiac data from the CareLink transmissions, measure the QT intervals, and make clinical decisions regarding the patient’s treatment regimens in real time.
We recognize that the primary limitation of our study was the small number of patients included in our sample. This was primarily due to the extensive amount of time required to collect and measure the data points. Future studies, with increased manpower, would allow for larger sample sizes, and thus, more data points available for analysis. Future development of the Medtronic software to automatically measure these QT intervals from the LINQ devices may contribute to increasing sample sizes. In these larger data sets, interim chemotherapy cycle days may reveal detailed information about drug toxicity and effect.
Conclusion
This study demonstrates noninferiority of the ILR to the gold standard ECG when monitoring QTc intervals in patients receiving arrhythmogenic chemotherapy. We also identified that inter-reader reliability of the QT intervals was exceptionally high despite varying levels of reader experience.
Disclosures: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest, and have no conflicts of interest to report regarding the content herein. Dr Memon reports a grant from Medtronic made to DCH Regional Medical Center.
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