Safety signals for QT prolongation or Torsades de Pointes associated with azithromycin with or without chloroquine or hydroxychloroquine.

Background: Combinations of hydroxychloroquine (HCQ) and azithromycin have been promoted as treatments for COVID-19 based on small, uncontrolled clinical trials that have not assessed potential risks. Risks of treatment include QT segment prolongation, Torsades de Pointes (TdP), and death. This comparative pharmacovigilance analysis evaluated the risk of these events. Methods: Data from the U.S. Food and Drug Administration's Adverse Event Reporting System (FAERS) (>13 million total reports) were used. Queries extracted reports based on exposures of HCQ/chloroquine (CQ) alone, azithromycin alone, HCQ/CQ + azithromycin, amoxicillin alone, HCQ/CQ + amoxicillin alone. Amoxicillin served as a control. Events of interest included death and TdP/QT prolongation as well as accidents/injuries and depression as control events. Proportional Reporting Ratios (PRR) and 95% confidence intervals (CI) were calculated where a lower limit of the of 95% CI (Lower95CI) value of ≥2.0 is interpreted as a potential safety signal. Results: Lower95CIs for HCQ/CQ alone showed no potential safety signals for TdP/QT prolongation, death, or any of the control events included. The PRRs and 95% CIs for TdP/QT prolongation was 1.43 (1.29-2.59) with HCQ/CQ use alone and 4.10 (3.80-4.42) for azithromycin alone. For the combined HCQ/CQ + azithromycin group, the PRR and 95% CI was 3.77 (1.80-7.87). For the control of amoxicillin, there were no safety signals when used alone or in combination with HCQ/CQ. Conclusions: HCQ/CQ use was not associated with a safety signal in this analysis of FAERS data. However, azithromycin used alone was associated with TdP/QT prolongation events and should be used with caution.

Use of QT Prolonging Medications by Hemodialysis Patients and Individuals Without End-Stage Kidney Disease.

Background The rate of sudden cardiac death in the hemodialysis population exceeds that of the general population by >20-fold. Hemodialysis patients may be particularly susceptible to sudden cardiac death provoked by drug-induced QT prolongation because of their substantial cardiovascular disease burden, exposure to electrolyte shifts during dialysis, and extensive polypharmacy. However, population-specific data regarding the frequency and patterns of QT prolonging medication use are limited. Methods and Results We conducted a descriptive drug utilization study using 3 administrative databases, the United States Renal Data System, MarketScan, and Medicare claims. We characterized the extent and patterns of QT prolonging medication use by adult hemodialysis patients and individuals without end-stage kidney disease annually from 2012 to 2016. We also identified instances of high-risk QT prolonging medication use among hemodialysis patients. In total, 338 515 hemodialysis patients and 40.7 million individuals without end-stage kidney disease were studied. Annual utilization rates of QT prolonging medications with known torsades de pointes risk in hemodialysis patients were ~1.4 to ~2.5 times higher than utilization rates in individuals without end-stage kidney disease. Hemodialysis patients with demographic and clinical risk factors for drug-induced QT prolongation were exposed to medications with known torsades de pointes risk more often than patients without risk factors. Conclusions Hemodialysis patients use QT prolonging medications with known torsades de pointes risk more extensively than individuals without end-stage kidney disease. Given the widespread use and instances of high-risk prescribing, future studies evaluating the cardiac safety of these drugs in the hemodialysis population are needed.

Urgent Guidance for Navigating and Circumventing the QTc-Prolonging and Torsadogenic Potential of Possible Pharmacotherapies for Coronavirus Disease 19 (COVID-19).

As the coronavirus disease 19 (COVID-19) global pandemic rages across the globe, the race to prevent and treat this deadly disease has led to the "off-label" repurposing of drugs such as hydroxychloroquine and lopinavir/ritonavir, which have the potential for unwanted QT-interval prolongation and a risk of drug-induced sudden cardiac death. With the possibility that a considerable proportion of the world's population soon could receive COVID-19 pharmacotherapies with torsadogenic potential for therapy or postexposure prophylaxis, this document serves to help health care professionals mitigate the risk of drug-induced ventricular arrhythmias while minimizing risk of COVID-19 exposure to personnel and conserving the limited supply of personal protective equipment.

The relationship between atypical antipsychotics drugs, QT interval prolongation, and torsades de pointes: implications for clinical use.

Introduction: Increased mortality has been observed in patients with mental health disorders. Specifically, exposure to antipsychotic medications conveys a greater than 2 fold risk of sudden death, thought to be mediated through effects on QT prolongation and risk of torsades de pointes.Areas covered: We review the association between antipsychotic drugs and sudden cardiac death, the physiologic basis for these associations, assessment of patients at risk, and strategies to minimize risk of sudden cardiac death.Expert opinion: Despite the prevalence of antipsychotic medication use for many decades, there remain considerable challenges in reducing the associated risk of sudden cardiac death. A structured algorithm that incorporates patient clinical factors and antipsychotic drug factors may improve risk assessment and reduce the risk of adverse cardiac events. Future advancements in genetics and artificial intelligence may allow for enhanced risk stratification and predicting response (efficacy and adverse effects) to therapy.

Clinical characterization of men with long QT syndrome and torsades de pointes associated with hypogonadism: A review and pharmacovigilance study.

BACKGROUND: Long QT syndrome (LQTS) can cause the potentially fatal ventricular tachycardia torsades de pointes (TdP). QT interval corrected for heart rate (QTc) is shorter in men than in women, with testosterone contributing to shorten QTc. We recently described male hypogonadism as a reversible risk factor for acquired LQTS and TdP, but the clinical characteristics of such patients have not been characterized. AIMS: To describe the clinical characteristics of men with acquired LQTS or TdP associated with hypogonadism caused by endocrine conditions or androgen deprivation therapy (ADT), and to evaluate the relationship between testosterone concentrations and electrocardiographic changes. METHODS: We searched MEDLINE (to 04 January 2019) and the French pharmacovigilance database (to 09 August 2018) to identify male cases of acquired LQTS and TdP associated with endocrine hypogonadism or ADT; their narratives were gathered from reporting collaborators. RESULTS: We identified seven cases of TdP (one fatal) with endocrine hypogonadism, abnormally long QTc and morphologically abnormal T-wave notches. After reversion of low testosterone concentrations in the surviving patients (N=6), QTc shortened, T-wave morphology normalized and there was no TdP recurrence. Among these cases, none had mutation in the LQTS genes, three men required testosterone and three had reversible hypogonadism after resolution of a concurrent acute severe illness. We found an additional 27 reports of men with LQTS (N=6), TdP (N=9; 2/9 fatal) or sudden death (N=12; 10/12 fatal) suspected to be induced or favoured by ADT (24/27 for prostate cancer). Generally, after ADT withdrawal, QTc shortened and no TdP recurred. CONCLUSION: We propose seeking for hypogonadism caused by endocrine conditions or ADT in men presenting with TdP. Caution is warranted when ADT is used in situations at risk of TdP. Testosterone may be useful to treat or prevent TdP.

Long-term proarrhythmic pharmacotherapy among patients with congenital long QT syndrome and risk of arrhythmia and mortality.

AIMS: It is Class I recommendation that congenital long QT syndrome (cLQTS) patients should avoid drugs that can cause torsades de pointes (TdP). We determined use of TdP risk drugs after cLQTS diagnosis and associated risk of ventricular arrhythmia and all-cause mortality. METHODS AND RESULTS: Congenital long QT syndrome patients (1995-2015) were identified from four inherited cardiac disease clinics in Denmark. Individual-level linkage of nation-wide registries was performed to determine TdP risk drugs usage (www.crediblemeds.org) and associated risk of ventricular arrhythmias and all-cause mortality. Risk analyses were performed using Cox-hazards analyses. During follow-up, 167/279 (60%) cLQTS patients were treated with a TdP risk drug after diagnosis. Most common TdP risk drugs were antibiotics (34.1%), proton-pump inhibitors (15.0%), antidepressants (12.0%), and antifungals (10.2%). Treatment with a TdP risk drug decreased 1 year after diagnosis compared with 1 year before (28.4% and 23.2%, respectively, P < 0.001). Five years after diagnosis, 33.5% were in treatment (P < 0.001). Risk factors for TdP risk drug treatment were age at diagnosis (5-year increment) [hazard ratio (HR) = 1.07, confidence interval (CI) 1.03-1.11] and previous TdP risk drug treatment (HR = 2.57, CI 1.83-3.61). During follow-up, nine patients were admitted with ventricular arrhythmia (three were in treatment with a TdP risk drug). Eight patients died (four were in treatment with a TdP risk drug). No significant association between TdP risk drug use and ventricular arrhythmias or all-cause mortality was found (P = 0.53 and P = 0.93, respectively), but events were few. CONCLUSION: Torsades de pointes risk drug usage was common among cLQTS patients after time of diagnosis and increased over time. A critical need for more awareness in prescribing patterns for this high-risk patient group is needed.

Increased long QT and torsade de pointes reporting on tamoxifen compared with aromatase inhibitors.

OBJECTIVE: A prolonged QTc (LQT) is a surrogate for the risk of torsade de pointes (TdP). QTc interval duration is influenced by sex hormones: oestradiol prolongs and testosterone shortens QTc. Drugs used in the treatment of breast cancer have divergent effects on hormonal status. METHODS: We performed a disproportionality analysis using the European database of suspected adverse drug reaction (ADR) reports to evaluate the reporting OR (ROR χ2) of LQT, TdP and ventricular arrhythmias associated with selective oestrogen receptor modulators (SERMs: tamoxifen and toremifene) as opposed to aromatase inhibitors (AIs: anastrozole, exemestane and letrozole). When the proportion of an ADR is greater in patients exposed to a drug (SERMs) compared with patients exposed to control drug (AIs), this suggests an association between the specific drug and the reaction and is a potential signal for safety. Clinical and demographic characterisation of patients with SERMs-induced LQT and ventricular arrhythmias was performed. RESULTS: SERMs were associated with higher proportion of LQT reports versus AIs (26/8318 vs 11/14851, ROR: 4.2 (2.11-8.55), p<0.001). SERMs were also associated with higher proportion of TdP and ventricular arrhythmia reports versus AIs (6/8318 vs 2/14851, ROR: 5.4 (1.29-26.15), p:0.02; 16/8318 vs 12/14851, ROR: 2.38 (1.15-4.94), p:0.02, respectively). Mortality was 38% in patients presenting ventricular arrhythmias associated with SERMs. CONCLUSIONS: SERMs are associated with more reports of drug-induced LQT, TdP and ventricular arrhythmias compared with AIs. This finding is consistent with oestradiol-like properties of SERMs on the heart as opposed to effects of oestrogen deprivation and testosterone increase induced by AIs. TRIAL REGISTRATION NUMBER: NCT03259711.

Hypokalemia in women and methadone therapy are the strongest non-cardiologic factors associated with QT prolongation in an emergency department setting.

BACKGROUND: Our primary objective was to determine the adjusted quantitative associations of clinical predictors with QT prolongation, a defining cause of Torsades de Pointes (TdP). METHODS: A retrospective cohort study was performed on consecutive emergency department patients identified by ECG acquisition date, and heart rate corrected QT (QTc) and QRS durations. QTc was modeled as a function of clinical predictors with multiple linear regression. RESULTS: 1010 patients were included. The strongest predictors of QTc and their coefficients were: antidysrhythmic (26.1ms, 95% CI 15.6-36.6) and methadone (43.6ms, 95% CI 28.1-59.2) therapies, and genetic long QT syndrome diagnosis (32.6ms, 95% CI -4.7-70.0). The association of QTc with serum potassium was approximated by a two piecewise linear function that differed by sex. For potassium below 3.9mmol/L, QTc increased by 43.0ms (95% CI 26.2-59.7) and 29.5ms (95% CI 19.1-40.0) for every 1mmol/L decrease in potassium in women and men, respectively. TdP occurred in only 4/686 (0.6%) of patients with QTc≥500 and QRS<120, but mortality during the visit including hospitalization was 8.0%. CONCLUSIONS: QTc duration is highly sensitive to hypokalemia, particularly in women. Methadone prolongs QTc remarkably compared to other non-cardiologic medicines. QTc>500 with normal QRS often signifies profound illness and substantial mortality risk, though not necessarily imminent TdP.

Antidepressants and antipsychotics classified with torsades de pointes arrhythmia risk and mortality in older adults - a Swedish nationwide study.

AIM: The aim of the study was to examine mortality risk associated with use of antidepressants and antipsychotics classified with torsades de pointes (TdP) risk in elderly. METHODS: A matched case-control register study was conducted in people 65 years and older dying outside hospital from 2008-2013 (n = 286,092) and matched controls (n = 1,430,460). The association between prescription of antidepressants and antipsychotics with various TdP risk according to CredibleMeds (www.crediblemeds.org) and all-cause mortality was studied by multivariate conditional logistic regression adjusted for comorbidity and several other confounders. RESULTS: Use of antidepressants classified with known or possible TdP risk, was associated with higher adjusted risk for mortality (OR 1.53, 95% CI 1.51, 1.56 and OR 1.63, 95% CI 1.61, 1.67, respectively) compared with antidepressants classified with conditional TdP risk (OR 1.25, 95% CI 1.22, 1.28) or without TdP classification (OR 0.99, 95% CI 0.94, 1.05). Antipsychotics classified with known TdP risk were associated with higher risk (OR 4.57, 95% CI 4.37, 4.78) than antipsychotics with possible risk (OR 2.58, 95% CI 2.52, 2.64) or without TdP classification (OR 2.14, 95% CI 2.03, 2.65). The following risk ranking was observed for commonly used antidepressants: mirtazapine > citalopram > sertraline > amitriptyline and for antipsychotics: haloperidol > risperidone >olanzapine > quetiapine. CONCLUSION: The CredibleMeds system predicted drug-associated risk for mortality in the elderly at the risk class level. Among antipsychotics, haloperidol, and among antidepressants, mirtazapine and citalopram, were associated with the highest risks. The results suggest that the TdP risk with antidepressants and antipsychotics should be taken into consideration when prescribing to the elderly.

Azithromycin-induced proarrhythmia and cardiovascular death.

OBJECTIVE: To review the possible association between azithromycin and increased cardiovascular risk. DATA SOURCES: A literature search of MEDLINE (1946-August 2013) was performed using the search terms macrolide, azithromycin, QT prolongation, cardiovascular, and torsade de pointes. Additional references were identified from a review of literature citations. STUDY SELECTION AND DATA EXTRACTION: All English-language observational studies assessing the association between azithromycin and QT prolongation or cardiovascular risk were evaluated. Case reports describing this potential association were also reviewed. DATA SYNTHESIS: A total of 6 case reports have shown a possible association between azithromycin and QT prolongation. In 3 of these cases, proarrhythmic events were reported. In a prospective observational study of 47 individuals with low cardiovascular risk, electrocardiograms were compared before and after 5 days of azithromycin treatment. Mild prolongation of the QTc was noted, but it was statistically insignificant compared with baseline. No arrhythmias were observed. A large observational cohort study found a small increase in cardiovascular deaths after azithromycin therapy, primarily among patients with high baseline cardiovascular risk. Conversely, a second cohort study involving a population of young to middle-aged adults failed to find an association. CONCLUSIONS: An emerging body of evidence suggests that azithromycin therapy may prolong the QT interval and, in rare cases, precipitate the potentially fatal arrhythmia torsade de pointes. Patients with additional risk factors for QT prolongation appear to be at highest risk, including women, elderly individuals; those with existing or prior history of cardiovascular disease, QT interval prolongation, hypokalemia, hypomagnesium, or bradycardia; and those using concomitant drugs associated with QT prolongation. For patients without these additional risk factors, azithromycin appears to be relatively safe.

Does low-dose droperidol increase the risk of polymorphic ventricular tachycardia or death in the surgical patient?

BACKGROUND: The Food and Drug Administration issued a black box warning regarding the use of droperidol and the potential for torsade de pointes. METHODS: The primary objective of this retrospective study was to determine if low-dose (0.625 mg) droperidol administration was associated with episodes of torsade de pointes in the general surgical population during the 3-yr period following the reinstitution of droperidol to our institutional formulary. RESULTS: The authors identified 20,122 surgical patients who received 35,536 doses of droperidol. These patients were cross-matched with an electrocardiogram database and an adverse outcome database. The charts of 858 patients were reviewed, including patients with documentation of prolonged QTc (>440 ms) from March 2007 to February 2011, polymorphic ventricular tachycardia (VT) within 48 h of receiving droperidol, or death within 7 days of receiving droperidol. Twelve surgical patients had VT (n = 4) or death (n = 8) documented within 48 h of droperidol administration. No patients developed polymorphic VT or death due to droperidol administration (n = 0). The eight patients that died were on palliative care. The four patients with documented VT had previous cardiac conditions: two had pre-existing implantable cardiac defibrillators, three had episodes of VT before receiving droperidol, and another had pre-existing hypertrophic obstructive cardiomyopathy. The authors found 523 patients with a documented QTc >440 ms before receiving droperidol. No patients developed VT or death as a direct result of droperidol administration. CONCLUSIONS: Our evidence suggests that low-dose droperidol does not increase the incidence of polymorphic VT or death when used to treat postoperative nausea and vomiting in the surgical population.

Methadone-induced mortality in the treatment of chronic pain: role of QT prolongation.

Methadone is increasingly prescribed for chronic pain, yet the associated mortality appears to be rising disproportionately relative to other opioid analgesics. We review the available evidence on methadone-associated mortality, and explore potential pharmacokinetic and pharmacodynamic explanations for its greater apparent lethality. While methadone shares properties of central nervous system and respiratory depression with other opioids, methadone is unique as a potent blocker of the delayed rectifier potassium ion channel (IKr). This results in QT-prolongation and torsade de pointes (TdP) in susceptible individuals. In some individuals with low serum protein binding of methadone, the extent of blockade is roughly comparable to that of sotalol, a potent QT-prolonging drug. Predicting an individual's propensity for methadone-induced TdP is difficult at present given the inherent limitations of the QT interval as a risk-stratifier combined with the multifactorial nature of the arrhythmia. Consensus recommendations have recently been published to mitigate the risk of TdP until further studies better define the arrhythmia risk factors for methadone. Studies are needed to provide insights into the clinical covariates most likely to result in methadone-associated arrhythmia and to assess the feasibility of current risk mitigation strategies.

[Heart hypertrophy and heart failure--experimental findings for arrhythmogenesis]. / Herzhypertrophie und Herzinsuffizienz - experimentelle Befunde zur Arrhythmogenese.

One major cause of sudden cardiac death in heart failure is the occurrence of life-threatening polymorphic ventricular tachycardia. Especially in the early stages of heart failure half of the deaths are sudden and unexpected. The majority of these are caused by ventricular tachyarrhythmias. Whereas reentry plays a major role in patients after myocardial infarction, triggered activity is responsible for the occurrence of arrhythmic events in non-ischemic heart failure. Action potential prolongation serves as the electrophysiological basis for the formation of triggered activity and the underlying early afterdepolarizations. It has been demonstrated in heart failure and in cardiac hypertrophy that this results from a reduction in outward repolarizing ion currents, especially due to downregulation of potassium channels. The underlying substrate for the maintenance of arrhythmias in chronic heart failure in experimental models and in humans is an increase in dispersion of repolarization. It opens the floodgate to the occurrence of potentially life-threatening polymorphic ventricular arrhythmias and leads to their maintenance. Thus chronic heart failure leads to a reduced repolarization reserve, i.e. a patient-specific response to risk factors that influence repolarization. Additional risk factors in patients with heart failure are hypokalemia (diuretic therapy), bradycardia (AV block) or concomitant therapy with repolarization prolonging drugs (antiarrhythmic drugs, antibiotics etc.) that may add further stress on the repolarization process and set the stage for the occurrence of life-threatening arrhythmias. One promising therapeutic approach to suppress arrhythmias in chronic heart failure may be a selective blocking of the Na+/Ca2+ exchanger. Experimental data have recently demonstrated a reduction of action potential duration, and dispersion of repolarization as well as suppression of early afterdepolarizations and torsade de pointes in an isolated intact heart model of chronic heart failure in a proarrhythmic milieu due to block of the Na+/Ca2+ exchanger.

La muerte de Napoleón: ¿causa natural u homicidio?

Napoleón Bonaparte murió a la edad de 52 años mientras purgaba exilio en la isla de Santa Helena, en el Atlántico Sur, una colonia británica donde fue desterrado luego de su derrota en Waterloo en 1815. Desde 1961 han abundado las teorías de que Napoleón murió envenenado con arsénico, particularmente porque el análisis de sus cabellos mostró elevados niveles del elemento tóxico. Sin embargo, de acuerdo a una nueva investigación sobre la causa de muerte del emperador francés, su muerte tuvo origen en una causa más prosaica de lo que muchos pensarían, sucumbió a un cáncer del estómago más que por envenenamiento arsenical. La autopsia describe un tumor gástrico de 10 cm de extensión. Otras fuentes históricas muestran que el obeso líder francés había perdido cerca de nueve kilogramos de peso en los últimos meses de su vida, otro signo de cáncer gástrico. La cavidad gástrica estaba llena de un líquido en borra de café, un claro signo de importante sangrado en el tracto digestivo. Este sangrado masivo, fue la causa inmediata de su muerte

Napoleon Bonaparte died at age 52 while in exile on the South Atlantic island of Saint Helena, a british colony, where he was banished after his defeat at the battle of Waterloo in 1815. Theories that Napoleon was poisoned with arsenic have abounded since 1961, when an analysis of his hair showed elevated levels of the toxic element. According to new research into what killed the french emperor his death’ cause was more prosaic than some people would like to think, succumbing to stomach cancer rather than arsenic poisoning, The autopsy describes a tumor in his stomach that was 4 inches (10 centimeters) long. Other historical sources indicate that the rotund French leader had lost about 20 pounds (nine kilograms) in the last few months of his life, another sign of stomach cancer. His stomach also contained a dark material similar to coffee grounds, a telltale sign of extensive bleeding in the digestive tract. The massive bleeding was likely the immediate cause of death

Sudden cardiac death secondary to antidepressant and antipsychotic drugs.

A number of antipsychotic and antidepressant drugs are known to increase the risk of ventricular arrhythmias and sudden cardiac death. Based largely on a concern over QT prolongation and the development of life-threatening arrhythmias, a number of antipsychotic drugs have been temporarily or permanently withdrawn from the market or their use restricted. Some antidepressants and antipsychotics have been linked to QT prolongation and the development of Torsade de pointes arrhythmias, whereas others have been associated with a Brugada syndrome phenotype and the development of polymorphic ventricular arrhythmias. This review examines the mechanisms and predisposing factors underlying the development of cardiac arrhythmias, and sudden cardiac death, associated with antidepressant and antipsychotic drugs in clinical use.

[Short coupled variant of torsade de pointes: our experience and review of the literature]. / La torsade de pointes a couplage court: notre expérience et revue de la littérature.

We present three cases of short-coupled variant of torsade de pointes with review of the literature. These women presented with syncope or presyncope due to torsade de pointes initiated by a short-coupled premature ventricular beat and without evidence of prolonged QT. There were no electrolyte disturbances in all cases, no apparent structural heart disease in two cases and a mild interventricular septum hypertrophy in the other case. One patient took spiramycin and metronidazole and another was taking pheniramin and lincomycin without any evidence of cause to effect relationship. One patient responded to verapamil but died suddendly after 44 months of follow-up. The two others recieved implantable cardioverter-defibrillators and verapamil per os. They still alive 46 and 54 months later. Short-coupled variant of torsade de pointes have a high incidence of sudden death, so it is very important for physicians to identify and treat it promptly. Long-term verapamil treatement is effective but still insufficient and patients should be considered for implantable cardioverter-defibrillator therapy.