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\begin{document}

\title{Evaluation of the QT Interval in Patients with Drug-induced QT
Prolongation and Torsades de Pointes}



\author[1]{Philipp Krisai}%
\author[2]{Konstantinos Vlachos}%
\author[3]{F. Daniel Ramirez}%
\author[4]{Yosuke Nakatani}%
\author[5]{Takashi Nakashima }%
\author[6]{Takamitsu Takagi}%
\author[7]{Tsukasa Kamakura}%
\author[1]{Elodie Surget}%
\author[8]{Clémentine André}%
\author[9]{Ghassen Cheniti}%
\author[10]{Nicolas Welte}%
\author[10]{Remi Chauvel}%
\author[1]{Romain Tixier}%
\author[11]{Josselin Duchateau}%
\author[12]{Thomas Pambrun}%
\author[1]{Nicolas Derval}%
\author[13]{Mélèze Hocini}%
\author[1]{Pierre Jais}%
\author[14]{Michel Haissaguerre}%
\author[15]{Frederic Sacher}%
\affil[1]{Centre Hospitalier Universitaire de Bordeaux}%
\affil[2]{Evangelismos General Hospital of Athens}%
\affil[3]{Centre Hospitalier Universitaire de Bordeaux Hopital Cardiologique}%
\affil[4]{University of Toyama}%
\affil[5]{1.	Electrophysiology and Ablation Unit and L’Institut de rythmologie et modélisation cardiaque (LIRYC)}%
\affil[6]{Yokosuka Kyosai Hospital}%
\affil[7]{National Cerebral and Cardiovascular Center}%
\affil[8]{CHU Trousseau}%
\affil[9]{Hôpital Cardiologique du Haut Lévêque}%
\affil[10]{CHU Bordeaux, Hopital Haut Leveque}%
\affil[11]{IHU Liryc, Electrophysiology and Heart Modeling Institute, Fondation Bordeaux Université, F-/ Bordeaux University Hospital (CHU), Electrophysiology and Ablation Unit / Univ. Bordeaux, Centre de recherche Cardio-Thoracique de Bordeaux, U1045}%
\affil[12]{Hôpital Cardiologique du Haut-Lévêque}%
\affil[13]{Hôpital Cardiologique du Haut-Lévèque}%
\affil[14]{Hopital Cardiologique du Haut-Leveque}%
\affil[15]{Bordeaux University Hospital}%


\vspace{-1em}



  
  \date{May 04, 2024}


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\selectlanguage{english}
\begin{abstract}
Background Data on the optimal location of the ECG leads for the
diagnosis of drug-induced long QT syndrome (diLQTS) with Torsades de
Pointes (TdP) are lacking. Methods We systematically reviewed the
literature for ECGs of patients with diLQTS and subsequent TdP. We
assessed T-wave morphology in each lead and measured the longest QT
interval in the limb and chest leads in a standardized fashion. Results
Of 84 patients, 61.9\% were female and mean age was 58.8 years. QTc was
significantly longer in chest versus limb leads (mean (standard
deviation) 671 (102) vs 655 (97) ms, p=0.02). Using only limb leads for
QT interpretation, 18 (21.4\%) ECGs were non-interpretable: 10 (11.9\%)
due to too flat T-waves, 7 (8.3\%) due to frequent, early PVCs and 1
(1.2\%) due to too low ECG recording quality. In the chest leads, ECGs
were non-interpretable in 9 (10.7\%) patients: 6 (7.1\%) due to
frequent, early PVCs, 1 (1.2\%) due to insufficient ECG quality, 2
(2.4\%) due to missing chest leads but none due to too flat T-waves. The
most common T-wave morphologies in the limb leads were flat (51.0\%),
broad (14.3\%) and late peaking (12.6\%) T-waves. Corresponding chest
lead morphologies were inverted (35.5\%), flat (19.6\%) and biphasic
(15.2\%) T-waves. Conclusions Our results indicate that QT evaluation by
limb leads only underestimates the incidence of diLQTS experiencing TdP
and favors the screening using both limb and chest lead ECG.%
\end{abstract}%



\sloppy


\textbf{Evaluation of the QT Interval in Patients with Drug-induced QT
Prolongation and Torsades de Pointes}

Philipp Krisai MD\textsuperscript{1}, Konstantinos Vlachos
MD\textsuperscript{1}, F. Daniel Ramirez MD MSc\textsuperscript{1},
Yosuke Nakatani MD\textsuperscript{1}, Takashi Nakashima
MD\textsuperscript{1}, Takamitsu Takagi MD\textsuperscript{1}, Tsukasa
Kamakura MD\textsuperscript{1}, Elodie Surget MD\textsuperscript{1},
Cl\selectlanguage{ngerman}émentine André MD\textsuperscript{1}, Ghassen Cheniti
MD\textsuperscript{1}, Nicolas Welte MD\textsuperscript{1}, Rémi Chauvel
MD\textsuperscript{1}, Romain Tixier MD MSc\textsuperscript{1}, Josselin
Duchateau MD PhD\textsuperscript{1}, Thomas Pambrun
MD\textsuperscript{1}, Nicolas Derval MD\textsuperscript{1}, Mélèze
Hocini MD\textsuperscript{1}, Jaïs Pierre MD\textsuperscript{1},
Haïssaguerre Michel MD\textsuperscript{1}, Frédéric Sacher MD
PhD\textsuperscript{1}

Electrophysiology and Ablation Unit and L'Institut de rythmologie et
modélisation cardiaque (LIRYC), Centre hospitalier universitaire de
Bordeaux, Bordeaux-Pessac, France

Brief title: QT Interval in Drug-induced QT Prolongation

Word count (Text): 1632

\emph{Address for correspondence:} Philipp Krisai MD Electrophysiology
and Ablation Unit

Hospital Haut-Lévêque, Centre hospitalier universitaire de Bordeaux

Av. Magellan, 33600 Pessac, France Phone: +43~699 17227228 E-mail:
p.krisai@gmail.com

\textbf{Funding and disclosures}

Philipp Krisai is supported by the University of Basel, the
Mach-Gaensslen foundation and the Bangerter-Rhyner foundation. All other
authors have nothing to disclose.



\textbf{Abstract}

\textbf{Background}

Data on the optimal location of the ECG leads for the diagnosis of
drug-induced long QT syndrome (diLQTS) with Torsades de Pointes (TdP)
are lacking.

\textbf{Methods}

We systematically reviewed the literature for ECGs of patients with
diLQTS and subsequent TdP. We assessed T-wave morphology in each lead
and measured the longest QT interval in the limb and chest leads in a
standardized fashion.

\textbf{Results}

Of 84 patients, 61.9\% were female and mean age was 58.8 years. QTc was
significantly longer in chest versus limb leads (mean (standard
deviation) 671 (102) vs 655 (97) ms, p=0.02). Using only limb leads for
QT interpretation, 18 (21.4\%) ECGs were non-interpretable: 10 (11.9\%)
due to too flat T-waves, 7 (8.3\%) due to frequent, early PVCs and 1
(1.2\%) due to too low ECG recording quality. In the chest leads, ECGs
were non-interpretable in 9 (10.7\%) patients: 6 (7.1\%) due to
frequent, early PVCs, 1 (1.2\%) due to insufficient ECG quality, 2
(2.4\%) due to missing chest leads but none due to too flat T-waves. The
most common T-wave morphologies in the limb leads were flat (51.0\%),
broad (14.3\%) and late peaking (12.6\%) T-waves. Corresponding chest
lead morphologies were inverted (35.5\%), flat (19.6\%) and biphasic
(15.2\%) T-waves.

\textbf{Conclusions}

Our results indicate that QT evaluation by limb leads only
underestimates the incidence of diLQTS experiencing TdP and favors the
screening using both limb and chest lead ECG.

Key words: Drug-induced long QT syndrome; Torsades de Pointes; ECG;
screening.



\textbf{Introduction}

Drug-induced prolongation of the QT interval (diLQTS) substantially
increases the risk for Torsades de Pointes (TdP) and sudden
death.\textsuperscript{1} Offending agents include widely used drugs
like antibiotics, antimalarials, antifungals, antivirals,
anti-arrhythmic drugs (AAD), psychiatric drugs, and many
others.\textsuperscript{1--3} In the current context of severe acute
respiratory syndrome coronavirus 2 (SARS-CoV2)
infections,\textsuperscript{4} drugs with a risk for diLQTS, like
hydroxychloroquine, azithromycin or antiviral drugs, are used widely
off-label and are investigated in randomized trials in large patient
populations.\textsuperscript{5} Expert consensus statements therefore
recommend ECG screening for QT interval prolongation before treatment
initiation and regularly during treatment with these
drugs.\textsuperscript{6,7} However, repeated ECG screening using
12-lead ECG is clinically unfeasible in the large number of isolated,
hospitalized or ambulatory patients, may increase the risk for virus
transmission and is economically unfeasible in low-income countries.

Mobile ECG devices seem to be able to reconstruct the six ECG limb leads
with good reproducibility of basic ECG intervals compared to
conventional 12-lead ECGs in patients with normal and prolonged QT
interval.\textsuperscript{8--11} They might therefore offer a
lower-cost, clinically more convenient and safer screening modality for
QT prolongation in diLQTS used by the patients themselves. However, as
T-wave morphology in the limb leads may flatten in very long QT
intervals with the highest risk for TdP, the diagnostic accuracy and
interpretability of the QT interval might be low if only limb leads are
used.\textsuperscript{12} Currently, systematic data on the diagnostic
value of the limb versus chest leads for prolonged QT interval and
T-wave morphology in patients with diLQTS and subsequent TdP are
lacking.

We therefore aimed to systematically investigate the diagnostic value
and interpretability of the limb versus the chest ECG leads in patients
with diLQTS, who subsequently experienced TdP.

\textbf{Methods}

\emph{Patient population}

We systematically reviewed the available literature for ECGs of patients
with diLQTS and subsequent TdP. We entered the MeSH term `drug induced
long qt torsades de pointes' into Medline and Embase and identified 1253
reports published until April 19\textsuperscript{th}, 2020. Eligible
articles had to include human subjects with available limb ECG leads
with drug-induced QT interval prolongation and experiencing subsequent
TdP. We also screened the references of eligible papers. After manual
review, we identified 77 ECGs that were included in the current study.
We also reviewed eligible ECGs with the same criteria from the hospital
files of our institution (Hospital Haut-Leveque, University Hospital
Bordeaux, Pessac, France) and furthermore included 7 patients.

\emph{Study variables}

Patient demographics, medical history and medication were extracted as
available. The ECGs were evaluated independently by cardiac
electrophysiologists in a standardized manner. Disagreement was resolved
by consensus. ECG interpretation included identification,
interpretability and measurement of the longest QT interval in limb and
chest leads, respectively, and the evaluation of the T-wave morphology
in each available lead. T-wave morphology was categorized into flat,
broad, late peaking, notched, biphasic or inverted. We then added up all
limb and chest lead morphologies in order to evaluate the respective
dominant morphology. For measurments, we used electronic calipers which
we calibrated individually to each ECG for the QT interval, QRS duration
and RR interval. The corrected QT (QTc) interval was calculated using
Bazett's formula QTc= QT/\selectlanguage{english}[?]RR if heart rate was \selectlanguage{english}[?]90 beats per minute
(bpm) and Fridericia`s formula QTc= QT/(RR\^{}0.33) if heart rate was
\textgreater{}90 bpm.

\emph{Statistical analysis}

The distribution of continuous variables was checked by visual
inspection of the histogram and by assessing skewness and kurtosis. As
all variables were normally distributed, they were presented as means (+-
standard deviations (SD)) and compared using paired Student's t-tests.
We used Bland Altmann plots to investigate differences in QTc between
limb and chest leads. A two-sided p-value \textless{}0.05 was considered
statistically significant. All statistical analyses were performed using
SAS 9.4 (SAS Corporation, Cary, North Carolina, USA).

\textbf{Results}

84 patients met the eligibility criteria. All patients experienced TdP
and in 49 (58.3\%) patients early PVCs were present. Mean (SD) age was
58.8 (8.8) years and 52 (61.9\%) were female. Prior medical history
included hypertension in 21 (25.0\%), ischemic heart disease in 13
(15.5\%), heart failure in 12 (14.3\%), atrial fibrillation in 8 (9.5\%)
and renal impairment in 11 (13.1\%) patients. Figure 1 shows the
medications that were suspected to cause QT interval prolongation. The
three most common offending drug classes were anti-arrhythmic drugs,
psychiatric drugs and antibiotics. Amiodarone (n=10), Methadone (n=9)
and Dofetilide (n=7) were the most frequent individual drugs. In 26
(31.0\%) cases, patients took a combination of potentially QT interval
prolonging drugs.

Mean (SD) QRS duration was 100 (26) ms and the mean (SD) heart rate was
66 (20) bpm. Figure 2 shows the Bland Altmann plot with a wide variation
in the QTc differences between the limb and chest leads. Comparing the
limb and chest leads, mean (SD) QT durations were 645 (129) and 661
(125) ms (p=0.03) and mean (SD) QTc durations were 655 (97) and 671
(102) ms (p=0.02), respectively. Using only the limb leads for QT
interval interpretation, 18 (21.4\%) ECGs were non-interpretable: 10
(11.9\%) due to too flat T-waves, 7 (8.3\%) due to frequent, early PVCs
and 1 (1.2\%) due to insufficient ECG recording quality. In the chest
leads, it was not possible to interprete the QT interval in 9 (10.7\%)
patients: 6 (7.1\%) due to frequent, early PVCs, 1 (1.2\%) due to
insufficient ECG quality, 2 (2.4\%) due to missing chest leads but none
due to too flat T-waves. Single limb and chest leads that were judged
most often as the best for QT interval interpretation were II and V5,
respectively.

Figure 3 shows detailed data on T-wave morphology for each individual
lead and cumulative for limb and chest leads. The most common,
cumulative T-wave morphologies in the limb leads were flat T-waves in
51.0\%, broad T-waves in 14.3\% and late peaking T-waves in 12.6\%. The
most common, cumulative morphologies in the chest leads were inverted
T-waves in 35.5\%, flat T-waves in 19.6\% and biphasic T-waves in
15.2\%. T-wave alternans was present in 6 (7.1\%) patients. Beside a
high variability in T-wave morphology between patients, there was also
high variability over the individual leads within the same patient as
showcased in Figure 4.

\textbf{Discussion}

The current study in 84 patients with drug-induced QT interval
prolongation and Torsades de Pointes showed lower diagnostic
interpretability and shorter measured QT intervals in the limb leads in
comparison to chest leads due to flattened T-waves. To the best of our
knowledge, this is the largest study in this patient population to date.

We found that the QT interval was not reliably interpretable due to too
flat T-waves in 11.9\% of the patients with diLQTS with subsequent TdP,
if only the limb leads were used. In comparison, the T-wave morphology
in the chest leads was never a reason for non-interpretability of the QT
interval. Therefore, approximately one out of nine patients with diLQTS
and TdP might have been missed if only limb leads were used. Moreover QT
duration was measured shorter in the limb leads compared to the chest
leads though there was a high variability in the differences. Our
results point out a possible limitation of QT interval monitoring in
diLQTS with limb leads only, as for example by mobile ECG devices.

Prior studies on QT interval interpretation with mobile devices have
mainly focused on the measurement of the QT interval and not on T-wave
morphology. Garabelli et al. showed good agreement of the QTc interval
between two limb leads by a mobile device compared to a 12-lead ECG in
99 healthy volunteers and patients loaded with dofetilide or sotalol up
to a QT duration of 500ms, but with decreasing agreement above
500ms.\textsuperscript{9} Castelletti et al. investigated 351
measurements in 20 LQTS patients and 16 controls and also found good
overall agreement between a single lead mobile ECG device and a 12-lead
ECG. However, the range of disagreement also increased with increasing
QTc duration.\textsuperscript{8} Moreover, two other studies in 381 and
94 subjects without known QT interval prolongation, respectively, showed
relevant discrepancies in the QT interval between single lead mobile ECG
devices and 12-lead ECGs.\textsuperscript{13,14} Malone et al.
furthermore reported that the QT interval was not measureable in 9\% of
their study subjects due to low T-wave
amplitudes.\textsuperscript{10}Our results expand the current knowledge
and suggest, that the interpretability of the limb leads further
decreases with even longer QT intervals in patients experiencing TdP.

For optimal patient selection for mobile ECG monitoring, a screening
12-lead ECG before treatment initation might already identify some
patients with non-interpretable QT intervals in the limb leads. However,
T-wave morphology might only change with increasing QT interval
prolongation, which would not be recognizable in the screening ECG. Of
note, no patient in the above mentioned studies on mobile ECG QT
monitoring has experienced TdP, therefore their true prognostic utility
in those patients is not known. A possible solution to limited
interpretability of the QT interval in the limb leads generated by
mobile ECG devices could be the placement of the devices in different
chest positions in order to get chest lead-like cardiograms. However,
this promising approach has only been tested in a small patient
population so far.\textsuperscript{11}

Strengths of our study include the systematic assessment of a large
number of patients with diLQTS and TdP. Limitations include the
retrospective nature of our analyses of prior published cases with
possible publication bias. However, due to the overall low occurrence of
TdP in diLQTS, a prospective study would be unfeasible due to a large
amount of participants needed. Furthermore, our study did not include a
control group.

In conclusion, our results point out the limits of QT interval
measurement using only the limb leads in patients with diLQTS
experiencing TdP due to different T-wave morphologies in the limb and
chest leads. Patients with diLQTS and high risk for TdP should probably
undergo limb and chest lead ECG screening.

\textbf{References}

1. Roden DM. Drug-induced prolongation of the QT interval. \emph{N Engl
J Med} . 2004;350:1013--1022.

2. Schwartz PJ, Woosley RL. Predicting the Unpredictable: Drug-Induced
QT Prolongation and Torsades de Pointes. \emph{J Am Coll Cardiol} .
2016;67:1639--1650.

3. Heist E. Kevin, Ruskin Jeremy N. Drug-Induced
Arrhythmia.\emph{Circulation} . 2010;122:1426--1435.

4. Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, Zhao X, Huang B, Shi W,
Lu R, Niu P, Zhan F, Ma X, Wang D, Xu W, Wu G, Gao GF, Tan W, China
Novel Coronavirus Investigating and Research Team. A Novel Coronavirus
from Patients with Pneumonia in China, 2019. \emph{N Engl J Med} .
2020;382:727--733.

5. Sanders JM, Monogue ML, Jodlowski TZ, Cutrell JB. Pharmacologic
Treatments for Coronavirus Disease 2019 (COVID-19): A Review.\emph{JAMA}
{[}Internet{]}. 2020 {[}cited 2020 Apr 21{]};Available from:
https://jamanetwork.com/journals/jama/fullarticle/2764727

6. Roden Dan M., Harrington Robert A., Poppas Athena, Russo Andrea M.
Considerations for Drug Interactions on QTc in Exploratory COVID-19
(Coronavirus Disease 2019) Treatment. \emph{Circulation} {[}Internet{]}.
{[}cited 2020 Apr 17{]};0. Available from:
https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.120.047521

7. Sacher F, Fauchier L, Boveda S, de Chillou C, Defaye P, Deharo JC,
Gandjbakhch E, Probst V, Cohen A, Leclercq C, Working Group of Pacing,
Electrophysiology of the French Society of Cardiology, the Board of the
French Society of Cardiology. Use of drugs with potential cardiac effect
in the setting of SARS-CoV-2 infection. \emph{Arch Cardiovasc Dis} .
2020;

8. Castelletti S, Dagradi F, Goulene K, Danza AI, Baldi E,
Stramba-Badiale M, Schwartz PJ. A wearable remote monitoring system for
the identification of subjects with a prolonged QT interval or at risk
for drug-induced long QT syndrome. \emph{Int J Cardiol} .
2018;266:89--94.

9. Garabelli P, Stavrakis S, Albert M, Koomson E, Parwani P, Chohan J,
Smith L, Albert D, Xie R, Xie Q, Reynolds D, Po S. Comparison of QT
Interval Readings in Normal Sinus Rhythm Between a Smartphone Heart
Monitor and a 12-Lead ECG for Healthy Volunteers and Inpatients
Receiving Sotalol or Dofetilide. \emph{J Cardiovasc Electrophysiol} .
2016;27:827--832.

10. Malone D, Gallo T, Beck J, Clark D. Feasibility of measuring QT
intervals with a portable device. \emph{Am J Health-Syst Pharm AJHP Off
J Am Soc Health-Syst Pharm} . 2017;74:1850--1851.

11. Cheung CC, Davies B, Gibbs K, Laksman ZW, Krahn AD. Multi-lead QT
Screening is Necessary for QT Measurement: Implications for Management
of Patients in the COVID-19 Era. \emph{JACC Clin
Electrophysiol}{[}Internet{]}. 2020 {[}cited 2020 Apr 21{]};Available
from:
http://electrophysiology.onlinejacc.org/content/early/2020/04/06/j.jacep.2020.04.001

12. Vicente Jose, Johannesen Lars, Mason Jay W., Crumb William J., Pueyo
Esther, Stockbridge Norman, Strauss David G. Comprehensive T wave
Morphology Assessment in a Randomized Clinical Study of Dofetilide,
Quinidine, Ranolazine, and Verapamil. \emph{J Am Heart Assoc} .
4:e001615.

13. Haberman ZC, Jahn RT, Bose R, Tun H, Shinbane JS, Doshi RN, Chang
PM, Saxon LA. Wireless Smartphone ECG Enables Large-Scale Screening in
Diverse Populations. \emph{J Cardiovasc Electrophysiol} .
2015;26:520--526.

14. Haverkamp HT, Fosse SO, Schuster P. Accuracy and usability of
single-lead ECG from smartphones - A clinical study. \emph{Indian Pacing
Electrophysiol J} . 2019;19:145--149.

\textbf{Figure legends}

\textbf{Figure} \textbf{1} Reported drugs with potential for QT interval
prolongation that patients were taking stratified by drug class. Number
in the brackets denotes number of individual drugs. AAD =
anti-arrhythmic drugs; DPM = diphenhydramine; MCP = metoclopramide.

\textbf{Figure} \textbf{2} Bland Altman plots comparing mean QTc
intervals of the limb and chest leads. Horizontal line indicates mean
difference.

\textbf{Figure 3} T-wave morphologies in each individual lead and
cumulative for limb and chest leads. Number In the brackets denotes
percentages.

\textbf{Figure 4} 12-lead ECG showing different T-wave morphologies over
individual leads in the same patient.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

\textbf{Figure 1}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

\textbf{Figure 2}

\textbf{Figure 3}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image3/image3}

\end{center}
\end{figure}

\textbf{Figure 4}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image4/image4}

\end{center}
\end{figure}

\selectlanguage{english}
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