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

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.

scholarly journals QT Interval Prolongation in Patients Treated for COVID-19

2020 ◽  
Author(s):  
Parham Habibzadeh ◽  
Abdollah Sarami ◽  
Mahboobeh Yadollahie ◽  
Kourosh Hashemiasl ◽  
Arezoo Salahi ◽  
...  
Keyword(s):  
Serum Potassium ◽  
Cardiac Arrhythmias ◽  
Qt Interval ◽  
Serum Magnesium ◽  
Qtc Interval ◽  
Interval Prolongation ◽  
Qtc Prolongation ◽  
Effective Measure ◽  
Qt Interval Prolongation ◽  
Life Threatening

AbstractBackgroundMany of the drugs commonly used for the treatment of COVID-19 cause QT interval prolongation and increase the risk of life-threatening cardiac arrhythmias. It has been shown that maintaining serum potassium and magnesium levels above 4 and 3 mg/dL, respectively, would prevent the QTc prolongation.ObjectiveTo determine if keeping only the serum magnesium level above 3 mg/dL could be considered an effective measure to prevent QTc prolongation in patients with COVID-19 receiving these drugs.MethodsIn a retrograde observational study, QTc interval was measured in 14 patients diagnosed with COVID-19 before and 3 days after initiation of treatment with either hydroxychloroquine or lopinavir-ritonavir, while their serum magnesium levels were kept ≥3 mg/dL.ResultsThe baseline QTc interval of 412 (SD 36) ms significantly increased by an average of 34 (95% CI 13 to 55) ms after 3 days of treatment. 5 patients, mostly those with lower serum potassium levels, had QTc prolongation ≥60 ms.ConclusionAlthough it seems that the risk of fatal cardiac arrhythmias in this setting is not high, it is prudent to monitor the serum electrolytes, particularly potassium, in patients with COVID-19 who are treated with either hydroxychloroquine or lopinavir-ritonavir.

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

2020 ◽  
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.

scholarly journals Risk of QT Prolongation through Drug-drug Interactions between Hydroxychloroquine and Concomitant Drugs Prescribed in Real-world Practice

2020 ◽  
Author(s):  
Byung Jin Choi ◽  
Yeryung Koo ◽  
Tae Young Kim ◽  
Wou Young Chung ◽  
Yun Jung Jung ◽  
...  
Keyword(s):  
Drug Interactions ◽  
Real World ◽  
Qt Interval ◽  
Qt Prolongation ◽  
Qtc Interval ◽  
Interval Prolongation ◽  
Qt Interval Prolongation ◽  
Life Threatening ◽  
Alternative Drugs

Abstract Background: Hydroxychloroquine has recently received attention as a treatment for COVID-19. However, hydroxychloroquine may prolong the QTc interval, thus increasing the risk of life-threatening arrhythmia. Many patients with COVID-19 have comorbidities, necessitating the use of several drugs simultaneously with hydroxychloroquine. However, the risk of QT prolongation due to drug-drug interactions (DDIs) between hydroxychloroquine and these co-medications has not been identified. Therefore, it is necessary to investigate the risk of QT interval prolongation due to DDIs between hydroxychloroquine and frequently used concurrent drugs.Methods and Results: Using 447,632 patients and 1,040,752 electrocardiograms, we investigated the risk of QT prolongation due to DDIs between hydroxychloroquine and 118 concurrent drugs frequently used in real-world practice. In the analysis, we observed that 11 drugs (trimebutine, tacrolimus, tramadol, rosuvastatin, ciclosporin, sulfasalazine, rofecoxib, diltiazem, piperacillin/tazobactam, and isoniazid) show DDIs with hydroxychloroquine in the direction of QT prolongation.Conclusions: We found 11 drugs that show significant (p <0.05) DDIs with hydroxychloroquine, thereby increasing the risk of QT prolongation in patients. It is necessary to consider prescribing alternative drugs that have less DDI when these drugs are concurrently administered with hydroxychloroquine. Further investigation is needed to assess more profoundly the risk of QT prolongation due to DDI with hydroxychloroquine of each drug that we found in this analysis.

The pre-clinical assessment of QT interval prolongation: a comparison of in vitro and in vivo methods

1998 ◽  
Vol 17 (12) ◽  
pp. 677-680 ◽  
Author(s):  
A Stewart Davis
Keyword(s):  
Clinical Assessment ◽  
Action Potential Duration ◽  
Qt Interval ◽  
Qt Prolongation ◽  
New Drugs ◽  
Interval Prolongation ◽  
In Vitro Methods ◽  
Qt Interval Prolongation

The literature was searched for in vivo dog studies reporting QT prolongation and in vitro studies reporting increased myocardial action potential duration, which indicates the potential to prolong QT interval, for nine non-cardiac drugs that have been reported to produce QT prolongation in man. The drugs were: astemizole; terfenadine; erythromycin; sparfloxacin; cisapride; probucol; terodiline; risperidone and sertindole. 1 There were reports of the appropriate finding with in vitro methods for six of the drugs and with in vivo methods for seven of the drugs. No reports were found concerning the remaining drugs with each method. This indicates that both methods are effective and each method would have correctly identified the drugs in question as having the potential to prolong the QT interval in man in all cases for which studies were reported. 2 This suggests that, if properly conducted, either method alone is sufficient for the pre-clinical assessment of QT interval prolongation. This does not support the routine use of both methods before the administration of new drugs to man.

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

2020 ◽  
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.

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

2021 ◽  
Vol 8 (3) ◽  
pp. 369
Author(s):  
Sami M. Alrasheedi ◽  
Bader Alothman ◽  
Ayman Alharbi ◽  
Ahmad Alkhdairi ◽  
Mohammed Zeitouni ◽  
...  
Keyword(s):  
Risk Score ◽  
Qt Interval ◽  
Retrospective Cohort ◽  
Heart Association ◽  
Torsades De Pointes ◽  
Qt Prolongation ◽  
Cardiac Complications ◽  
Qtc Prolongation ◽  
Qt Interval Prolongation ◽  
Combined Drugs

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.

Changes of QT interval in the acute phase after pulmonary vein isolation for paroxysmal atrial fibrillation

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
A Chikata ◽  
T Kato ◽  
K Ududa ◽  
S Fujita ◽  
K Otowa ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Pulmonary Vein ◽  
Female Patient ◽  
Pulmonary Vein Isolation ◽  
Acute Phase ◽  
Paroxysmal Atrial Fibrillation ◽  
Qt Interval ◽  
Qt Prolongation ◽  
Qtc Interval ◽  
The Impact

Abstract Introduction Pulmonary vein isolation (PVI) affects ganglionated plexi (GP) around the atrium, leading to a modification of the intrinsic cardiac autonomic system (ANS). In animal models, GP ablation has a potential risk of QT prolongation and ventricular arrhythmias. However, the impact of PVI on QT intervals in humans remains unclear. Purpose This study aims to evaluate the Impact of PVI on QT interval in patients with paroxysmal atrial fibrillation. Methods We analyzed consecutive 117 PAF patients for their first PVI procedures. 12-lead ECG was evaluated at baseline, 4 hr, day 1, 1 month, and 3 months after ablation. Only patients with sinus rhythm on 12-lead ECG at each evaluation point without antiarrhythmic drugs were included. Results Heart rate significantly increased at 4 hr, day 1, and 1 month. Raw QT interval prolonged at 4 hr (417.1±41.6 ms, P&lt;0.001) but shortened at day 1 (376.4±34.1 ms, P&lt;0.001), 1 month (382.2±31.5 ms, P&lt;0.001), and 3 months (385.1±32.8 ms, P&lt;0.001) compared to baseline (391.6±31.4 ms). Bazett- and Fridericia- corrected QTc intervals significantly prolonged at 4hr (Bazett: 430.8±27.9 ms, P&lt;0.001; Fridericia: 425.8±27.4 ms, P&lt;0.001), day1 (Bazett: 434.8±22.3 ms, P&lt;0.001; Fridericia: 414.1±23.7 ms, P&lt;0.001), 1M (Bazett: 434.8±22.3 ms, P&lt;0.001; Fridericia: 408.2±21.0 ms, P&lt;0.05), and 3M (Bazett: 420.1±21.8 ms, P&lt;0.001; Fridericia: 407.8±21.1 ms, P&lt;0.05) compared to baseline (Bazett: 404.9±25.2 ms; Fridericia: 400.0±22.6 ms). On the other hand, Framingham- and Hodges- corrected QTc interval significantly prolonged only at 4hr (Framingham: 424.1±26.6 ms, P&lt;0.001; Hodges: 426.8±28.4 ms, P&lt;0.001) and at day1 (Framingham: 412.3±29.3 ms, P&lt;0.01; Hodges: 410.6±40.2 ms, P&lt;0.05) compared to baseline (Framingham: 399.2±22.7 ms; Hodges: 400.7±22.8 ms). At 4 hr after ablation, raw QT and QTc of all formulas significantly prolonged than baseline. Raw QT and QTc prolongation at 4hr after ablation were more frequently observed in female patients. Multiple regression analysis revealed that female patient is a significant predictor of raw QT and QTc interval prolongation of all formulas 4hr after PVI. Conclusions Raw QT and QTc prolonged after PVI, especially in the acute phase. Female patient is a risk factor for QT prolongation in the acute phase after PVI. Funding Acknowledgement Type of funding source: None

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

Circulation ◽  
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.

scholarly journals Absence of relevant QT interval prolongation in not critically ill COVID-19 patients

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Juan Jiménez-Jáimez ◽  
Rosa Macías-Ruiz ◽  
Francisco Bermúdez-Jiménez ◽  
Ricardo Rubini-Costa ◽  
Jessica Ramírez-Taboada ◽  
...  
Keyword(s):  
Critically Ill ◽  
Qt Interval ◽  
Treatment Initiation ◽  
Qtc Interval ◽  
Risk Markers ◽  
Interval Prolongation ◽  
Qt Interval Prolongation ◽  
Qtc Interval Prolongation ◽  
Ambulatory Patients ◽  
Reported Data

AbstractSARS-CoV-2 is a rapidly evolving pandemic causing great morbimortality. Medical therapy with hydroxicloroquine, azitromycin and protease inhibitors is being empirically used, with reported data of QTc interval prolongation. Our aim is to assess QT interval behaviour in a not critically ill and not monitored cohort of patients. We evaluated admitted and ambulatory patients with COVID-19 patients with 12 lead electrocardiogram at 48 h after treatment initiation. Other clinical and analytical variables were collected. Statistical analysis was performed to assess the magnitude of the QT interval prolongation under treatment and to identify clinical, analytical and electrocardiographic risk markers of QT prolongation independent predictors. We included 219 patients (mean age of 63.6 ± 17.4 years, 48.9% were women and 16.4% were outpatients. The median baseline QTc was 416 ms (IQR 404–433), and after treatment QTc was prolonged to 423 ms (405–438) (P < 0.001), with an average increase of 1.8%. Most of the patients presented a normal QTc under treatment, with only 31 cases (14.1%) showing a QTc interval > 460 ms, and just one case with QTc > 500 ms. Advanced age, longer QTc basal at the basal ECG and lower potassium levels were independent predictors of QTc interval prolongation. Ambulatory and not critically ill patients with COVID-19 treated with hydroxychloroquine, azithromycin and/or antiretrovirals develop a significant, but not relevant, QT interval prolongation.

Sign in / Sign up

Export Citation Format

Share Document