Out-of-hospital cardiac arrest and differential risk of cardiac and non-cardiac QT-prolonging drugs in 37 000 cases.

AIMS: Drugs that prolong the QT interval, either by design (cardiac QT-prolonging drugs: anti-arrhythmics) or as off-target effect (non-cardiac QT-prolonging drugs), may increase the risk of ventricular arrhythmias and out-of-hospital cardiac arrest (OHCA). Risk mitigation measures were instituted, in particular, surrounding prescription of cardiac QT-prolonging drugs. We studied OHCA risk of both drug types in current clinical practice. METHODS: Using data from large population-based OHCA registries in the Netherlands and Denmark, we conducted two independent case-control studies. OHCA cases with presumed cardiac causes were matched on age/sex/index date with up to five non-OHCA controls. We calculated odds ratios (ORs) for the association of cardiac or non-cardiac QT-prolonging drugs with OHCA risk using conditional logistic regression analyses. RESULTS: We identified 2503 OHCA cases and 10 543 non-OHCA controls in the Netherlands, and 35 017 OHCA cases and 175 085 non-OHCA controls in Denmark. Compared to no use of QT-prolonging drugs, use of non-cardiac QT-prolonging drugs (Netherlands: cases: 3.0%, controls: 1.9%; Denmark: cases: 14.9%, controls: 7.5%) was associated with increased OHCA risk (Netherlands: OR 1.37 [95% CI: 1.03-1.81]; Denmark: OR 1.63 [95% CI: 1.57-1.70]). The association between cardiac QT-prolonging drugs (Netherlands: cases: 4.0%, controls: 2.5%; Denmark: cases: 2.1%, controls: 0.9%) and OHCA was weaker (Netherlands: OR 1.17 [95% CI: 0.92-1.50]; Denmark: OR 1.21 [95% CI: 1.09-1.33]), although users of cardiac QT-prolonging drugs had more medication use and comorbidities associated with OHCA risk than users of non-cardiac QT-prolonging drugs. CONCLUSION: In clinical practice, cardiac QT-prolonging drugs confer lower OHCA risk than non-cardiac QT-prolonging drugs, although users of the former have higher a priori risk. This is likely due to risk mitigation measures surrounding prescription of cardiac QT-prolonging drugs.

Multiple categories of non-cardiac QT-prolonging drugs are associated with increased risk of out-of-hospital cardiac arrest: real-world data from a population-based study.

AIM: Drugs causing QT-prolongation as off-target effect [non-cardiac QT-prolonging drugs (QT-drugs)] increase the risk of out-of-hospital cardiac arrest (OHCA). Such drugs are categorized in multiple clinically widely used CredibleMeds.org lists. Category 1 ('known risk of Torsade de Pointes') and category 2 ('possible risk of Torsade de Pointes') are of particular clinical relevance. However, a category-stratified analysis of OHCA-risk is presently unavailable. METHODS AND RESULTS: We conducted a case-control study with OHCA-cases from presumed cardiac causes included from the ARREST registry in the Netherlands (2009-2018) that was specifically designed to study OHCA, and age/sex/OHCA-date matched non-OHCA-controls. Adjusted odds ratios for OHCA (ORadj) of QT-drugs from categories 1 or 2 were calculated, using conditional logistic regression. Stratified analysis was performed according to sex, age, and presence of cardiovascular drugs (proxy for cardiovascular disease). We included 5473 OHCA-cases (68.8 years, 69.9% men) and matched them to 20 866 non-OHCA-controls. Compared with no use of non-cardiac QT-drugs, drugs of both categories were associated with increased OHCA-risk, but seemingly weaker for category 2 {category 1: case 3.2%, control 1.4%, ORadj 1.7 [95% confidence interval (CI): 1.3-2.1]}; [category 2: case 7.3%, control 4.0%, ORadj 1.4 (95% CI: 1.2-1.6)]. The increased risk occurred in men and women, at all ages (highest in patients aged ≤50 years), and both in the presence or absence of cardiovascular drug use. CONCLUSION: Both category 1 and category 2 QT-drugs are associated with increased OHCA-risk in both sexes, at all ages, and in patients taking or not taking cardiovascular drugs.

Patch monitors for arrhythmia monitoring in patients for suspected inherited arrhythmia syndrome.

INTRODUCTION: Patients undergoing evaluation for an inherited arrhythmia syndrome undertake a series of ambulatory investigations including 24-h Holter monitor, exercise treadmill testing (ETT), and others. Patch monitors may simplify the evaluation, providing accurate arrhythmia evaluation and QT assessment. METHODS AND RESULTS: Patients referred for evaluation of an inherited arrhythmia syndrome underwent standard investigations, including 12-lead electrocardiography (ECG), 24-h Holter monitoring, ETT, along with supplemental monitoring using a 7-day ECG patch monitor. Heart rates (HR), corrected QT intervals (QTc), and ectopic burden were compared across monitoring modalities. Among 35 patients that wore the patch monitor, the median age was 39 years (54% male). There was intermediate correlation between resting HR across modalities (r = .58-.66) and poor correlation of peak HR (r = .27-.39). There was intermediate correlation between resting QTc intervals across modalities (r = .72-.77) but negligible correlation between QTc intervals at peak HR across modalities (r = -.01 to -.06). There was good correlation in PAC and PVC ectopic burden across the Holter and patch monitor. CONCLUSION: Patch monitors may simplify the evaluation of patients for an inherited arrhythmia syndrome and provide resting QT assessment over time. However, QTc interval comparison at peak HRs remains variable, and may be limited by the single-lead ECG vector when using the patch monitor. Apart from QTc intervals at peak HR, patch monitors demonstrated good correlation with the ECG and Holter monitor for other parameters.

Death of a young woman with cyclic vomiting: a case report.

We report the death of a 22-year-old woman, with a 3½ year history of cyclic vomiting and cannabis use since age 14, who developed torsades de pointes cardiac arrythmia while being treated in the emergency room for nausea and vomiting. Resuscitation restored spontaneous cardiac circulation, however, due to post-cardiac arrest anoxic brain injury, she never regained consciousness and was declared brain dead 4 days later. Postmortem examination confirmed hypoxic-ischemic encephalopathy, in keeping with the in-hospital diagnosis of brain death. The heart was anatomically normal but showed signs of acute post-cardiopulmonary arrest reperfusion injury. As a consequence of limited survival in hospital in a neuro-vegetative state, early bronchopneumonia and isolated pulmonary thromboemboli were seen. Toxicological studies confirmed cannabis use, in addition to the presence of haloperidol and ondansetron. Genetic studies were performed to rule out a possible channelopathy and revealed a mutation in the MYBPC3 and RYR2 genes. Death in this woman with cannabinoid hyperemesis syndrome was attributed to a fatal cardiac arrhythmia complicating vomiting-induced hypokalemia and treatment with QT interval prolonging and potentially arrhythmogenic medications, with the identified cardiac genetic mutations listed as contributing factors. The emphasis of this report is a) to raise awareness that death can occur due to cyclic vomiting, b) provide a brief but practical overview of cannabinoid hyperemesis syndrome, c) describe the findings from our postmortem examination and come to the most reasonable cause and mechanism of death, d) comment on the risk factors associated with torsades de pointes cardiac arrythmia, and e) conclude that a complete postmortem examination is needed to exclude an anatomical or toxicological cause of death in cannabinoid hyperemesis syndrome, a disabling but preventable disorder.

Prevalence of the risk factors for QT prolongation and associated drug-drug interactions in a cohort of medical inpatients.

BACKGROUND/PURPOSE: Medical inpatients are at increased risk of QT interval prolongation due to multiple risk actors and QT prolonging drugs. This study aimed to identify the prevalence of risk factors for QT prolongation; QT prolonging medications; associated drug-drug interactions (QT-DDIs); their predictors; and TdP (torsades de pointes) risks of drugs. METHODS: This cohort study was carried out in medical wards of two tertiary hospitals in Khyber Pakhtunkhwa, Pakistan. The QT-DDIs were identified using Micromedex DrugReax® and AZCERT (Arizona Center for Education and Research on Therapeutics) QT drugs lists. AZCERT QT drugs lists were used to identify TdP risks. Logistic regression analysis was performed to identify predictors of QT-DDIs. RESULTS: Total 400 patients were included in this study. The most frequent QT prolonging risk factors included use of ≥1 QT prolonging drugs (74.5%), female gender (55%) and diabetes mellitus (36.3%). Total 487 QT prolonging drugs were identified. According to AZCERT classification, 33.8% of the interacting drugs were included in list-1 (known risk of TdP), 0.9% in list-2 (possible risk of TdP) and 58.8% in list-3 (conditional risk of TdP). The occurrence of QT-DDIs was significantly associated with ≥10 prescribed medications (p = 0.01), chronic liver disease (p = 0.05), chronic obstructive pulmonary disease (p = 0.03), gastroenteritis (p = 0.02), antimicrobials (p < 0.001), antiemetics (p < 0.001) and antinausea (p < 0.001). CONCLUSION: A substantial number of patients were exposed to risk factors for QT prolongation; and QT prolonging drugs such as proton pump inhibitors, antimicrobials and diuretics which may lead to serious outcomes.

QT interval prolongation in hospitalized patients on cardiology wards: a prospective observational study.

PURPOSE: Prolonged QT interval may lead to a lethal form of arrhythmia, torsades de pointes (TdP), which is associated with cardiovascular mortality. Therefore, we aimed to identify prevalence of QT interval prolongation, compare clinical characteristics of patients with normal and prolonged QT interval, and identify predictors of QT interval prolongation. METHODS: A prospective observational study was conducted in cardiology wards of two teaching hospitals in Pakistan. Bazett's correction formula was used for the calculation of QTc interval. Prevalence of QT prolongation and pro-QTc scores were calculated. Comparative analysis was performed with respect to various clinical characteristics by applying t test and chi-square test. Odds ratios were calculated using regression analysis. RESULTS: Among 417 patients, 44.6% were found having prolonged QT interval, of which, 17.3% presented with an abnormally high QTc interval (> 500 ms). Significant difference was recorded between the groups (normal vs. prolonged) with respect to age, all prescribed medications, QT drugs, number of risk factors, QT-DDIs (QT-prolonging drug-drug interactions), gender, and diuretics use. Multivariate logistic regression analysis showed significant results for various predictors such as male gender (p = 0.03), various age categories 41-50 years (p = 0.04), 51-60 years (p = 0.01), and > 60 years (p < 0.001), and diuretics (p = 0.008). CONCLUSION: A substantial number of patients in cardiology wards presented with QT prolongation. Proper considerations are needed in order to minimize the associated risk particularly in patients with abnormally high QT prolongation, old age, polypharmacy, one or more QT-prolonging drugs, and high pro-QTc scores.

Drugs and ventricular repolarization in a general population: the Rotterdam Study.

PURPOSE: Prolonged ventricular repolarization (measured as heart-rate corrected QT (QTc) prolongation or JT-interval prolongation) is a risk factor for ventricular arrhythmias and can be drug-induced. Drugs can be classified as having known or possible QTc-prolonging properties. Regulatory agencies recommend avoiding concomitant use of multiple QTc-prolonging drugs, but evidence is lacking to what degree ventricular repolarization is influenced by concomitant use of these drugs. METHODS: Within a population-based cohort of persons aged 45 years and older, with up to five electrocardiograms recorded per participant between 1991 and 2010, we used generalised estimating equations to study the association between concomitant use of multiple QTc-prolonging drugs and repolarization duration. RESULTS: The study population consisted of 13 009 participants with 26 908 electrocardiograms. With the addition of a second or third QTc-prolonging drug there was no substantial increase in QTc and JT interval and no increased risk of a prolonged QTc interval, compared to use of one QTc-prolonging drug. There was a large difference between the effect of one known or one possible QTc-prolonging drugs on QTc interval: 15 ms for known, and 3 ms for possible QTc-prolonging drugs. CONCLUSIONS: In this study, the added prolongation in users of two or three QTc-prolonging drugs on QTc was small. There was a large difference in QTc prolongation between known and possible QTc-prolonging drugs. Further research in larger or high-risk populations is needed to establish whether it is safe to use multiple QTc-prolonging drugs concomitantly to prevent that the current advice might unnecessarily withhold beneficial drugs from patients.

Developing a Model for Quantifying QTc-Prolongation Risk to Enhance Medication Safety Assessment: A Retrospective Analysis.

There are currently no established methods to predict quantitatively whether the start of a drug with the potential to prolong the QTc interval poses patients at risk for relevant QTc prolongation. Therefore, this retrospective study aimed to pave the way for the development of models for estimating QTc prolongation in patients newly exposed to medications with QTc-prolonging potential. Data of patients with a documented QTc prolongation after initiation of a QTc-prolonging drug were extracted from hospital charts. Using a standard model-building approach, general linear mixed models were identified as the best models for predicting both the extent of QTc prolongation and its absolute value after the start of a QTc-time-prolonging drug. The cohort consisted of 107 adults with a mean age of 64.2 years. Patients were taking an average of 2.4 drugs associated with QTc prolongation, with amiodarone, propofol, pipamperone, ondansetron, and mirtazapine being the most frequently involved. There was a significant but weak correlation between measured and predicted absolute QTc values under medication (r2 = 0.262, p < 0.05), as well as for QTc prolongation (r2 = 0.238, p < 0.05). As the developed models are based on a relatively small number of subjects, further research is necessary to ensure their applicability and reliability in real-world scenarios. Overall, this research contributes to the understanding of QTc prolongation and its association with medications, providing insight into the development of predictive models. With improvements, these models could potentially aid healthcare professionals in assessing the risk of QTc prolongation before adding a new drug and in making informed decisions in clinical settings.

Association of QT interval-prolonging drugs with clinical trial eligibility in patients with advanced cancer.

Introduction: Drug-induced prolongation of the heart rate-corrected QT interval (QTc) is associated with increased risk for the potentially fatal arrhythmia torsades de pointes. Due to arrhythmia risk, clinical trials with cancer therapeutics often exclude patients based on thresholds for QTc prolongation. Our objective was to assess associations between prescriptions for QT-prolonging drugs and the odds of meeting cancer trial exclusionary QTc thresholds in a cohort of adults with advanced cancer. Methods: Electronic health records were retrospectively reviewed for 271 patients seen at our institutional molecular solid tumor clinic. Collected data included demographics, QTc measurements, ventricular arrhythmia-related diagnoses, and all inpatient and outpatient prescriptions. Potential associations were assessed between demographic and clinical variables, including prescriptions for QT-prolonging drugs, and QTc measurements. Results: Women had longer median QTc measurements than men (p = 0.030) and were prescribed more QT-prolonging drugs during the study (p = 0.010). In all patients, prescriptions for QT-prolonging drugs were associated with longer median and maximum QTc measurements at multiple assessed time points (i.e., for QT-prolonging drugs prescribed within 10, 30, 60, and 90 days of QTc measurements). Similarly, the number of QT-prolonging drugs prescribed was correlated with longer median and maximum QTc measurements at multiple time points. Common QTc-related exclusionary criteria were collected from a review of ClinicalTrials.gov for recent cancer clinical trials. Based on common exclusion criteria, prescriptions for QT-prolonging drugs increased the odds of trial exclusion. Conclusion: This study demonstrates that prescriptions for QT-prolonging drugs were associated with longer QTc measurements and increased odds of being excluded from cancer clinical trials.

Prevalence, predictors and clinical implications of prolonged corrected QT in elderly patients with dementia and suspected syncope.

BACKGROUND: Long QT and use of QT-prolonging drugs are common among older patients receiving polytherapies, but real-world evidence on their impact in clinical practice is controversial. We investigated prevalence, variables associated and clinical implications of prolonged corrected QT (QTc) among patients from the Syncope and Dementia study. METHODS: Observational, prospective, multicenter study. Patients≥65 years with dementia and fall suspected for syncope in the previous three months were enrolled. Several clinical variables and the complete list of medications were recorded for each patient. A 12­lead ECG was obtained and corrected QT was calculated by the Bazett's formula. One-year followup for death and recurrent syncope was performed. RESULTS: Prolonged QTc was observed in 25% of the 432 enrolled patients (mean age 83.3), and was significantly associated with male gender (OR 2.09; 95% CI 1.34-3.26) and diuretics use (OR 1.85; 95% CI 1.18-2.90). At one-year 23.3% of patients died and 30.4% reported at least one recurrent event. Variables associated with one-year mortality were: age, male gender, atrial fibrillation (AF), use of calcium channel blockers and prolonged QTc (OR 1.80; 95% CI 1.01-3.20). Among patients with prolonged QTc a significant interaction for mortality was found with AF. Recurrent events were associated with the use of antiplatelets, cholinesterase. inhibitors and antipsychotics, but not with prolonged QTc. CONCLUSIONS: We documented a high prevalence of prolonged QTc, that was associated with male gender and diuretics but not with psychoactive medications. Patients with prolonged QTc had higher one-year mortality, that was four-fold increased in those with concomitant AF.

Impact of hospital pharmacist interventions on the combination of citalopram or escitalopram with other QT-prolonging drugs.

Background Citalopram and escitalopram can both induce dose-dependent QT prolongation. The risk of arrhythmia may be increased with concomitant use of other drugs that induce QT prolongation. Objective To evaluate the prevalence and impact of pharmacist interventions on the combination of citalopram or escitalopram with other drugs that induce QT prolongation. Setting A French hospital with 517 computerized beds. Method All cardiac adverse drug reactions (ADRs) related to citalopram or escitalopram reported to the French pharmacovigilance database (FPDB) were analyzed. Then, over a 6-month period, all computerized prescriptions including citalopram or escitalopram and drug-drug interactions (DDI) were analyzed by pharmacists using a computerized provider order entry system (DXCare®, Medasys). Results Only 27 cardiac ADRs related to citalopram or escitalopram were reported in the database. Among the 57,857 prescriptions and 2116 contraindicated DDIs (3.7 %) that were analyzed. 444 DDIs (0.8 %) were considered to be clinically relevant by pharmacists and physicians and 168 (i.e., approximately 30 %) were related to a combination including citalopram or escitalopram. Most of the prescriptions related to DDIs including citalopram or escitalopram were discontinued in response to a pharmacist intervention when initiated during the hospital stay. Conclusion A high number of hospital prescriptions including citalopram or escitalopram with another QT-prolonging drug occurred, highlighting the importance of involvement of clinical pharmacists in prevention of potential ADRs related to such contraindications.

High prevalence of the risk factors for QT interval prolongation and associated drug-drug interactions in coronary care units.

OBJECTIVES: Patients admitted in coronary care units are susceptible to QT interval prolongation due to numerous risk factors. The purpose of this study was to identify the prevalence of risk factors for QT interval prolongation; QT prolonging medications; drug-drug interactions; their predictors; and torsades de pointes risks of drugs. METHODS: After obtaining approval, this cross-sectional study was carried out during one-year period in coronary care units of two major tertiary care hospitals of Khyber Pakhtunkhwa, Pakistan. The Arizona Center for Education and Research on Therapeutics QT drugs lists and Micromedex DrugReax® were used to identify the QT prolonging medications and QT prolonging drug-drug interactions. RESULTS: Total 649 patients were included in this study. The most frequent QT prolonging risk factors included use of ≥ 1 QT prolonging drugs (74.9%) and myocardial infarction (61.3%). Total 181 patients were presented with 361 QT prolonging drug-drug interactions. There was significant association of the occurrence of QT prolonging drug-drug interactions with female gender (p = 0.01), 9-10 prescribed medications (p = 0.001), and > 10 prescribed medications (p < 0.001). CONCLUSIONS: The majority of patients presented with multiple risk factors for QT prolongation in coronary care units which may precipitate lethal outcomes.

Frequency, characteristics and risk factors of QT interval prolonging drugs and drug-drug interactions in cancer patients: a multicenter study.

BACKGROUND: Cancer patients may receive a high number of medications with the potential to prolong QT interval and subsequent TdP (torsades de pointes). This study aimed to identify the prevalence of QT prolonging drugs, their TdP risk, QT prolonging drug-drug interactions (QT-DDIs), levels, predictors, and TdP risk of drugs involved in QT-DDIs. METHODS: This multicenter study included cancer patients from three major tertiary care hospitals of Khyber-Pakhtunkhwa, Pakistan. Micromedex DrugReax® was used for identification of QT-DDIs. TdP risks were identified by AZCERT (Arizona Center for Education and Research on Therapeutics) classification. Logistic regression analysis was performed to identify predictors of QT-DDIs. RESULTS: Of 555 patients, 51% were females. Mean age was 46.9 ± 15.7 years. Total 28 distinct QT prolonging drugs were identified in 92.6% of the patients. Overall 21.8% patients were presented with QT-DDIs. Of total 288 identified QT-DDIs, all were of major-severity and fair-documentation. According to AZCERT classification, 59.9% of the interacting drugs were included in list-1 (known risk of TdP), 4.7% in list-2 (possible risk of TdP) and 6.8% in list-3 (conditional risk of TdP). Univariate logistic regression analysis showed significant results for various predictors such as, 8-9 prescribed medications (p < 0.001) and ≥10 medications (p < 0.001), 2 QT drugs (p < 0.001) and ≥3 QT drugs (p < 0.001), breast cancer (p = 0.03), gastrointestinal cancer (p = 0.03), 4-5 supportive care drugs (p < 0.001), 6-8 supportive care drugs (p < 0.001) and >8 supportive care drugs (p < 0.001). CONCLUSIONS: A high prevalence of QT prolonging drugs and QT-DDIs was reported in oncology. Appropriate precautions are needed to prevent harmful consequences of these interactions.

Multi-factorial causes of torsade de pointes in a hospitalised surgical patient.

A 55-year-old chronic alcoholic male known to be positive for human immunodeficiency virus (HIV) was admitted to a surgical ward following perianal abscess drainage. He was noted to have sinus bradycardia, ventricular premature complexes, and mild hypotension. His laboratory investigations revealed mild hypokalaemia. He was intermittently agitated and alcohol withdrawal syndrome (AWS) was diagnosed. Postoperatively, he received intravenous piperacillin/tazobactam and metronidazole infusions along with a small dose of dopamine. Analysis of a 24-hour Holter monitor (ECG) showed a prolonged QT interval with two episodes of self-terminating torsade de pointes. His AWS was treated, hypokalaemia was corrected, and dopamine, along with antibiotics, was withdrawn. There was no recurrence of arrhythmias. This case highlights the importance of avoiding QT-prolonging drugs in hospitalised patients, since hospitalised patients often have multiple risk factors for a proarrhythmic response.