QT prolongation associated with azithromycin/hydroxychloroquine combination in treatment of COVID-19: a single centre study

Background: The long QT syndrome is characterized by prolongation of QT interval, which may lead to life-threatening cardiac arrhythmias. Objectives were to assess prevalence, quantity and severity of QTc prolongation with combined drugs (azithromycin and hydroxychloroquine) in adults COVID-19 patients treated on these agents at KFSHRC. And to characterize cardiac complications of QTc prolongation with combined drugs.Methods: A retrospective cohort study at KFSH&RC, in Riyadh, Saudi Arabia. Baseline and daily ECG was done until completion of duration as per KFSH&RC guidelines for management of Covid-19, QTc prolongation>500 or increase of at least 60 ms compared with the pre-drug baseline value, or presence of cardiac conductive complications (torsades de pointes). The QTc prolongation was defined as>470 for male and >480 for female as per American Heart Association. A risk score that has been validated by Tisdale et al, for prediction of QT prolongation drug-related in admitted patients in cardiac care unit. The study duration was specified as one month after study approval by Research Ethics committee.Results: A total of 74 patients were included in the study. The patients were distributed according to their risk score for prediction of QT prolongation as the following: low (67/74), medium (6/74), high (1/74). Two patients with medium risk were started on both azithromycin and hydroxychloroquine. one of them his baseline QT was 490, Azithromycin was stopped as QT reached 502. The second patient has QT baseline 471, after starting treatment; QT range was 472-475, hydroxychloroquine was stopped on day 4. None of them had torsades de pointes. Only one patient with low risk, no baseline QT was recorded, but QT was 499 on day three, so hydroxychloroquine was stopped. Repeated ECG showed: QT decreased to 478, no torsades de pointes. Conclusions: In this single centered-retrospective cohort, we noticed that a small percentage of patients developed QT prolongation with the use of this combination. With the increasing the risk of developing QT prolongation the number of the patient who developed the condition increased. We used Tisdale score which is a scoring system Identifying hospitalized patients at risk for QT interval prolongation could lead to interventions to reduce the risk of torsades de pointes validated in May 2013.5 None of our population developed significant cardiac complications of QTc prolongation with combined drugs.

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What is the role of QTc prolongation assessment in new drugs development phase I oncology trials?

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.2006 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 2006-2006

Author(s):

G. Curigliano ◽

C. Cipolla ◽

C. Sessa ◽

C. Noberasco ◽

T. De Pas ◽

...

Keyword(s):

Phase I ◽

Qt Interval ◽

Phase I Study ◽

Qt Prolongation ◽

New Drugs ◽

Accurate Information ◽

Investigational Drug ◽

Qtc Interval ◽

Qtc Prolongation ◽

Qt Interval Prolongation

2006 Background: QT interval prolongation associated with “torsades de pointes” (TdP) has been a common cause of withdrawal from the market for several promising drugs. We determined the degree of QT prolongation in patients treated within a phase I study with a thioxanthone derivative known to have arrhythmogenic potential. Methods: Clinical data and serial ECGs from 31 patients with advanced tumors who received 86 courses of investigational drug were prospectively reviewed. The drug has been administered intravenously over 24 hours every 3 weeks. Patients have been on a 24 hour Holter monitor until 24 hours after infusion was complete. Three baseline ECGs were done and compared to those every 6 hours during therapy and once 6 hours after the infusion was complete. ECGs were read at a central lab according to a standard protocol. All QT measurements were then corrected for heart rate (QTc) using Bazett’s formula (QTc = QT interval divided by the square root of the R-R interval). Results: Overall,843 ECG tracings were obtained, all evaluable for analysis. No basal ECG showed significant abnormalities. Prolonged QT intervals developed in 2 patients without clinical symptoms (1 patient had intervals 500 milliseconds).In both cases it was associated with the maximum concentration of the drug. Compared with baseline, the QTc interval was prolonged by 30 to 60 milliseconds in 20% of total tracings, and by more than 60 milliseconds in 2% of ECGs. In patients receiving multiple courses, QTc intervals returned to pretreatment levels before the second course. Conclusions: The assessment of QTc prolongation was a major effort in this study but produced an accurate information about such event. In phase I study such an effort is justified when arrhythmogenicity is suspected. The timing of collection of ECGs should be guided by the available preclinical information about the pharmacokinetic profile of the drug. Nevertheless uncertainty remains regarding the specific relationship between the degree of QT prolongation and the risk of life-threatening arrhythmias. The decision to use the drug ultimately has to be based on an estimation of the perceived risk relative to expected benefits for patients. No significant financial relationships to disclose.

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QT Interval Prolongation and Torsade De Pointes in Patients with COVID-19 treated with Hydroxychloroquine/Azithromycin

10.1101/2020.04.27.20074583 ◽

2020 ◽

Cited By ~ 8

Author(s):

Ehud Chorin ◽

Lalit Wadhwani ◽

Silvia Magnani ◽

Matthew Dai ◽

Eric Shulman ◽

...

Keyword(s):

Retrospective Study ◽

Qt Interval ◽

Potential Benefit ◽

Drug Exposure ◽

Torsade De Pointes ◽

Careful Consideration ◽

Qt Prolongation ◽

Interval Prolongation ◽

Qtc Prolongation ◽

Qt Interval Prolongation

AbstractBackgroundThe emergence of the COVID-19 pandemic has resulted in over two million affected and over 150 thousand deaths to date. There is no known effective therapy for the disease. Initial reports suggesting the potential benefit of Hydroxychloroquine/Azithromycin (HY/AZ) have resulted in massive adoption of this combination worldwide. However, while the true efficacy of this regimen is unknown, initial reports have raised concerns regarding the potential risk of QT prolongation and induction of torsade de pointes (TdP).MethodsThis is a multicenter retrospective study of 251 patients with COVID-19 treated with HY/AZ. We reviewed ECG tracings from baseline and until 3 days after completion of therapy to determine the progression of QTc and incidence of arrhythmia and mortality.ResultsQTc prolonged in parallel with increasing drug exposure and incompletely shortened after its completion. Extreme new QTc prolongation to > 500 ms, a known marker of high risk for TdP had developed in 15.9% of patients. One patient developed TdP requiring emergent cardioversion. Seven patients required premature termination of therapy. The baseline QTc of patients exhibiting QTc prolongation of > 60 ms was normal.ConclusionThe combination of HY/AZ significantly prolongs the QTc in patients with COVID-19. This prolongation may be responsible for life threating arrhythmia in the form of TdP. This risk mandates careful consideration of HY/AZ therapy in lights of its unproven efficacy. Strict QTc monitoring should be performed if the regimen is given.

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Fluconazole-associated QT interval prolongation and Torsades de Pointes in a paediatric patient

Cardiology in the Young ◽

10.1017/s1047951121001992 ◽

2021 ◽

pp. 1-3

Author(s):

Ayşe Ünal Yüksekgönül ◽

İlker Ertuğrul ◽

Tevfik Karagöz

Keyword(s):

Qt Interval ◽

Torsades De Pointes ◽

Qt Prolongation ◽

Polymorphic Ventricular Tachycardia ◽

Interval Prolongation ◽

Qt Interval Prolongation ◽

Life Threatening ◽

Prolonged Qt Interval ◽

Rhythm Disorder ◽

Anti Fungal

Abstract “Torsades de pointes”, a life-threatening rhythm disorder, is a polymorphic ventricular tachycardia that usually develops in association with a prolonged QT interval. Fluconazole, an anti-fungal drug, may also induce QT prolongation, in some cases subsequent torsades de pointes. Herein, we report a 16-year-old female presenting “torsades de pointes” after administration of fluconazole and rapidly improved upon cessation of the drug.

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Approach to initiating QT-prolonging oncology drugs in the ambulatory setting

Journal of Oncology Pharmacy Practice ◽

10.1177/1078155217748735 ◽

2018 ◽

Vol 25 (1) ◽

pp. 198-204

Author(s):

Mário L de Lemos ◽

Carrie Kung ◽

Victoria Kletas ◽

Nadine Badry ◽

Isabell Kang

Keyword(s):

Risk Factors ◽

Cancer Patients ◽

Qt Interval ◽

Torsades De Pointes ◽

Drug Approval ◽

Qt Prolongation ◽

Ambulatory Setting ◽

Interval Prolongation ◽

Qt Interval Prolongation ◽

Oncology Practice

Since the introduction of regulatory drug approval guidance on the evaluation of QT interval prolongation, an increasing number of drug monographs has included cautions on the risk of QT prolongation. For example, QT prolongation is mentioned in the Canadian product monographs of 29 drugs commonly seen in oncology practice. This presents two major challenges. First, most guidelines and risk predictive tools for QT prolongation have been developed for hospitalized patients in acute care settings. In contrast, most QT-prolonging oncology drugs are used in medically stable patients in the ambulatory setting. Second, many oncology drugs are unique for their indications and non-QT prolonging alternative agents are often not available. In this review, we will outline an empiric initial approach to ambulatory cancer patients who are treated with oncology drugs which may prolong QT interval. This includes the predictive value of QT prolongation on torsades de pointes, the risk factors of the patients and the drugs, and the limitations of existing guidance in this area.

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Experience with Hydroxychloroquine and Azithromycin in the COVID-19 Pandemic: Implications for QT Interval Monitoring

10.1101/2020.04.22.20075671 ◽

2020 ◽

Cited By ~ 9

Author(s):

Archana Ramireddy ◽

Harpriya Chugh ◽

Kyndaron Reinier ◽

Joseph Ebinger ◽

Eunice Park ◽

...

Keyword(s):

Qt Interval ◽

Case Series ◽

Torsades De Pointes ◽

Qtc Interval ◽

Interval Prolongation ◽

Qtc Prolongation ◽

Qt Interval Prolongation ◽

Significant Prolongation ◽

Risk Indices ◽

Increase Risk

ABSTRACTBackgroundDespite a paucity of clinical evidence, hydroxychloroquine and azithromycin are being administered widely to patients with verified or suspected COVID-19. Both drugs may increase risk of lethal arrhythmias associated with QT interval prolongation.MethodsWe performed a case series of COVID-19 positive/suspected patients admitted between 2/1/2020 and 4/4/2020 who were treated with azithromycin, hydroxychloroquine or a combination. We evaluated baseline and post-medication QT interval (QTc, Bazett’s) using 12-lead ECGs. Critical QTc prolongation was defined as: a) maximum QTc ≥500 ms (if QRS <120 ms) or QTc ≥550 (if QRS ≥120 ms) and b) increased QTc of ≥60 ms. Tisdale score and Elixhauser comorbidity index were calculated.ResultsOf 490 COVID-19 positive/suspected patients, 314 (64%) received either/both drugs, and 98 (73 COVID-19 positive, 25 suspected) met study criteria (age 62±17 yrs, 61% male). Azithromycin was prescribed in 28%, hydroxychloroquine in 10%, and both in 62%. Baseline mean QTc was 448±29 ms and increased to 459±36ms (p=0.005) with medications. Significant prolongation was observed only in men (18±43 ms vs -0.2±28 ms in women, p=0.02). 12% of patients reached critical QTc prolongation. In a multivariable logistic regression, age, sex, Tisdale score, Elixhauser score, and baseline QTc were not associated with critical QTc prolongation (p>0.14). Changes in QTc were highest with the combination compared to either drug, with many-fold greater prolongation with the combination vs. azithromycin alone (17±39 vs. 0.5±40 ms, p=0.07). No patients manifested torsades de pointes.ConclusionsOverall, 12% of patients manifested critical QTc interval prolongation, and traditional risk indices failed to flag these patients. With the drug combination, QTc prolongation was several-fold higher compared to azithromycin alone. The balance between uncertain benefit and potential risk when treating COVID-19 patients with these drugs should be carefully assessed prior to use.

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Safety and effectiveness of drug therapy for the acutely agitated patient (Part I)

Italian Journal of Medicine ◽

10.4081/itjm.2010.127 ◽

2013 ◽

pp. 127-136

Author(s):

Gianluca Airoldi

Keyword(s):

Heart Rate ◽

Qt Interval ◽

Physical Restraint ◽

Safety Data ◽

Surrogate Marker ◽

Diagnostic Procedures ◽

Torsades De Pointes ◽

Long Qt ◽

Drug Induced ◽

Qt Interval Prolongation

Acute agitation occurs in a variety of medical and psychiatric conditions, and the management of agitated, abusive, or violent patients is a common problem in the emergency department. Rapid control of potentially dangerous behaviors by physical restraint and pharmacologic tranquillization is crucial to ensure the safety of the patient and health-care personnel and to allow diagnostic procedures and treatment of the underlying condition. The purpose of this article (the first in a 2-part series) is to review the extensive safety data published on the antipsychotic medications currently available for managing situations of this type, including older neuroleptics like haloperidol, chlorpromazine, and pimozide as well as a number of the newer atypical antipsychotics (olanzapine, risperidone, ziprasidone). Particular attention is focused on the ability of these drugs to lengthen the QT interval in surface electrocardiograms. This adverse effect is of major concern, especially in light of the reported relation between QT interval and the risk of sudden death. In patients with the congenital long-QT syndrome, a long QT interval is associated with a fatal paroxysmal ventricular arrhythmia knownas torsades de pointes. Therefore, careful evaluation of the QT-prolonging properties and arrhythmogenic potential of antipsychotic drugs is urgently needed. Clinical assessment of drug-induced QT-interval prolongation is strictly dependent on the quality of electrocardiographic data and the appropriateness of electrocardiographic analyses. Unfortunately, measurement imprecision and natural variability preclude a simple use of the actually measured QT interval as a surrogate marker of drug-induced proarrhythmia. Because the QT interval changes with heart rate, a rate-corrected QT interval (QTc) is commonly used when evaluating a drug’s effect. In clinical settings, themost widely used formulas for rate-correction are those of Bazett (QTc=QT/RR^0.5) and Fridericia (QTc=QT/RR^0.33), both of which standardize themeasuredQTinterval to an RRinterval of 1 s (heart rate of 60 bpm).However, QT variability can also be influenced by other factors that are more difficult to measure, including body fat, meals, psycho-physical distress, and circadian and seasonal fluctuations.

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Abstract 13215: Gender-affirming Hormones Are Associated With Increased Risk of QT Prolongation in Transgender Females

Circulation ◽

10.1161/circ.142.suppl_3.13215 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Daniel Antwi Amoabeng ◽

Ahmed Hanfy ◽

Munadel Awad ◽

Bryce D Beutler ◽

Amneet Rai ◽

...

Keyword(s):

Qt Interval ◽

Small Sample Size ◽

Qt Prolongation ◽

Small Sample ◽

Rank Test ◽

Qt Interval Prolongation ◽

Northern Nevada ◽

Increased Risk ◽

Before And After ◽

Signed Rank Test

Introduction: Women have a longer QT interval than men. This sex-specific difference is attributed to hormones associated with the biological female sex. Male-to-female transgender individuals often take antiandrogens such as spironolactone or goserelin in addition to estrogens to suppress testosterone effects while increasing feminine features. Effects of gender-affirming hormone therapy (GHT) on the QT interval in these individuals remains to be elucidated. Hypothesis: We assessed the hypothesis that the use of GHT is associated with an increased risk for QT interval prolongation in transgender females. Methods: We identified 46 transgender females through a search of the electronic medical records of a Veterans Administration hospital in Northern Nevada. Patients with a diagnosis of congenital long QT syndrome were excluded. Of these, 13 patients had ECGs before and after initiation of GHT and were included. We adapted the Tisdale score using the auto-calculated corrected QT interval (QTc) to estimate the risk of QT prolongation. Age, QTc, and Tisdale scores before and after GHT initiation were compared using the Wilcoxon signed-rank test. All tests were performed as two-tailed at a 5% level of significance. Results: All 13 study patients were taking estrogens. Of these, 3 (23.1%) were taking goserelin and 9 (69.2%) were taking spironolactone. Mean ± SEM age at ECG acquisition was 45.0 ± 4.4 and 47.7 ± 4.7 years before and after the initiation of GHT respectively. Mean ± SEM QTc after initiation of GHT was significantly higher compared to the baseline (467.5 ± 12.8 ms vs. 428.2 ± 7.1 ms) (Figure 1A). The average baseline Tisdale score was significantly smaller on follow-up (1-point vs. 3 points) (Figure 1B). Conclusions: GHT appears to be associated with increased QTc in transgender women. This needs to be interpreted with caution owing to the very small sample size in this study. Further studies to investigate the strength of this association, if it exists, are warranted.

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Managing drug-induced QT prolongation in clinical practice

Postgraduate Medical Journal ◽

10.1136/postgradmedj-2020-138661 ◽

2020 ◽

pp. postgradmedj-2020-138661

Author(s):

Rani Khatib ◽

Fatima R N Sabir ◽

Caroline Omari ◽

Chris Pepper ◽

Muzahir Hassan Tayebjee

Keyword(s):

Qt Interval ◽

Simple Algorithm ◽

Torsades De Pointes ◽

Daily Practice ◽

Qt Prolongation ◽

Key Factors ◽

Drug Induced ◽

Electrolyte Disturbances ◽

Related Risk ◽

Life Threatening

Many drug therapies are associated with prolongation of the QT interval. This may increase the risk of Torsades de Pointes (TdP), a potentially life-threatening cardiac arrhythmia. As the QT interval varies with a change in heart rate, various formulae can adjust for this, producing a ‘corrected QT’ (QTc) value. Normal QTc intervals are typically <450 ms for men and <460 ms for women. For every 10 ms increase, there is a ~5% increase in the risk of arrhythmic events. When prescribing drugs associated with QT prolongation, three key factors should be considered: patient-related risk factors (eg, female sex, age >65 years, uncorrected electrolyte disturbances); the potential risk and degree of QT prolongation associated with the proposed drug; and co-prescribed medicines that could increase the risk of QT prolongation. To support clinicians, who are likely to prescribe such medicines in their daily practice, we developed a simple algorithm to help guide clinical management in patients who are at risk of QT prolongation/TdP, those exposed to QT-prolonging medication or have QT prolongation.

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