QT-prolonging Medications Research Articles

136-78: PROLONGATION OF THE QTc INTERVAL IN HIV INFECTED INDIVIDUALS COMPARED TO THE GENERAL POPULATION

Background: A prolongation of the QT interval is a well known marker for the risk for polymorphous ventricular tachycardia such as torsade de pointes and sudden arrhythmic cardiac death (SCD). An increased prevalence and correlation of QT interval prolongation in human immunodeficiency virus infected (HIV) subjects was previously described in various occasions, when compared with HIV-uninfected subjects. The impact of different medications and HIV-infection itself on the electrical activity of the heart is rarely investigated in large HIV+ cohorts. Methods: We compared QTc measurement in 496 HIV-infected patients of the HIV-HEART study (HIVH) and 992 sex- and age-matched controls of the population-based Heinz Nixdorf Recall study, both recruited from the German Ruhr area since 2000. A 12-lead ECG was performed in all participants. ECG were interpreted automatically using the integrated 12SL-Code. The QT was corrected for heart rate using Bazett's formula (QTc = QT/√RR). Data were analysed by use of gender-specific QTc categories (men: abnormal > 440 ms and women: abnormal > 460 ms). Current medication was determined by personal interview and manually coded into Anatomical Therapeutic Chemical (ATC) codes. Based on the literature we defined QT prolonging medication (QT-PM) Results: We observed longer QTc in HIVH subjects compared with HNR controls: 424 ± 23 ms vs. 411 ± 15 ms for male and 435 ± 20 ms vs. 416 ± 17 ms for female subjects (p < 0.0001 for both sexes). HIVH males used QT-PM more often (22.3% vs 17.6% for HNR) than HIVH females (13.3% vs 24.7% for HNR). However, adjusting for QT-PM the mean differences in QTc remained significant with 13 ms (95%CI: 11;15) for male and 19 ms (95%CI: 14;24) for female subjects. Prolongation of QTc was pathologic in 22.8% vs. 3.9% of HIVH and HNR males and in 12.1% vs. 1.8% of the females (OR of 7.9 (5.0;12.6) and OR of 6.7 (1.8;24.2), respectively). We analysed the possible role of HIV status and HIV medication on QTc prolongation in the subgroup of the cohort with HIV infection. There was no significant correlation between the clinical or immunological status and QTc interval for patients infected with HIV. No class of HIV medications was significantly associated with QTc prolongation, nor was the overall number of prescribed medications per patient. Conclusions: Our study established that HIV+ patients have slightly but significantly longer QTc intervals compared to the general population. This translates into a higher proportion of patients with a pathologic QTc interval in our study. When prescribing drugs other than antiretroviral therapy to HIV-infected patients clinicans should thoroughly consider possible QT prolonging effects of these drugs. However, whether the increased QTc interval in HIV-infected patients leads to a higher proportion of arrhythmias and cardiac events in HIV+ compared to the general population remains unclear. Therefore, further prospective studies are needed.

Drug-induced torsades de pointes in an underserved urban population. Methadone: is there therapeutic equipoise?

Although it has been well established that methadone use can result in prolonged QTc/torsades de pointes (TdP) and has been labeled as one of the main drugs that cause TdP, it is still prescribed indiscriminately, and several cases of methadone-associated TdP have been seen in our community. Our objective was to determine the associated factors for prolonged QTc and the development of torsades de pointes (TdP) in our underserved patient population. We found 12,550 ECGs with prolonged QTc between 2002 and 2013. Medical records were reviewed in order to identify precipitating factors for prolonged QTc and to detect incidence of TdP. We identified 2735 patients with prolonged QTc who met the inclusion criteria. Of these, 89 (3%) experienced TdP. There was a greater prevalence of HIV infection in the TdP group (11.2 vs. 3.7%, p < 0.001). Furosemide, hydrochlorothiazide, selective serotonin reuptake inhibitors (SSRIs), amiodarone, ciprofloxacin, methadone, haloperidol, and azithromycin were the drugs most often associated with prolonged QTc (31, 8.2, 7.6, 7.1, 3.9, 3.4 and 3.3%, respectively). However, the agents most commonly associated with TdP were furosemide (39.3%), methadone (27%), SSRIs (19.1%), amiodarone (18%), and dofetilide (9%). The medications with statistical significance in the multivariate analysis for TdP development in descending order were as follows: ranolazine (odds ratios [OR] = 53.61, 95% confidence interval [CI] 5.4-524, p < 0.001), dofetilide (OR = 25, CI 6.47-103.16, p < 0.001), voriconazole (OR = 21.40, CI 3.24-124.25, p < 0.001), verapamil (OR = 10.98, CI 2.62-44.96, p < 0.001), sotalol (OR = 12.72, 1.95-82.81, p = 0.008), methadone (OR = 9.89, CI 4.05-24.15, p < 0.001), and SSRI (OR = 2.26, CI 1.10-5.96, p < 0.001). This multivariate analysis revealed that amiodarone and HIV infection were not implicated in TdP. Methadone was by far the leading medication implicated in the development of TdP and an independent predictor in both univariate and multivariate analyses despite the fact that it was not the most common QT-prolonging medication in our population.

EKG Monitoring and Co-Prescription of QT-Interacting Medications in Patients Treated With Domperidone: Review of a Community-Based Practice and a Post-Marketing Adverse Drug Event Reporting Database

Introduction: Domperidone is a peripheral D2 and D3 dopamine receptor blocker used for nausea, vomiting, dyspepsia, gastroparesis, and gastroesophageal reflux disease. Prolongation of the QT interval, and life-threatening arrhythmias including Torsades de Pointes have been described with its use. Electrocardiogram (EKG) monitoring in patients receiving the drug is advised. Patients receiving domperidone also are at risk for interactions with drugs that prolong the QT interval. We reviewed EKG monitoring of patients on domperidone and the co-prescription of other QT-prolonging medications in a large, multihospital community-based practice and reports of adverse cardiac events to the Food and Drug Administration (FDA).Figure 1Figure 2Methods: The electronic medical records for all patients in the community practice receiving domperidone from January 1, 2008 to December 1, 2013 were reviewed. EKG monitoring before and during domperidone use was noted. Normal values for corrected QT interval (QTc) were The co-administration of QT prolonging medications and inhibitors of cytochrome P450-3A4 was determined (termed QTinteracting medications). The Adverse Event Reporting System (FAERS) database of the FDA was queried for all reports of adverse events (ADRs) with domperidone. Co-administration of QT-interacting medications was noted. Results: 155 patients (115 female, 40 male, average age 56.2) were prescribed domperidone in the community practice. Only 59 (38.1%) underwent a baseline EKG, with 9 having prolonged QTc. Of 40 follow up EKGs, 13 (32.5%) had prolongation of the QTc. All were co-prescribed a QT-prolonging medication. In total, 108 of 155 patients (69.7%) were co-prescribed QT-interacting drugs along with domperidone (Table 1). There were a total of 5000 reports of ADRs with domperidone between January 2008 and June 2014. Of these, 1979 patients were co-prescribed domperidone and QT-interacting medications. There were 221 non-fatal cardiac events reported. Of these, 162 (73%) patients received concomitant QT-interacting medications. There were 151 deaths and 61 cardiac arrests reported, Co-prescription of QT- interacting medications occurred in 53 (35%) of reported deaths (Table 2). Conclusion: Sporadic EKG monitoring and co-prescription of QT-interacting medications commonly occur with domperidone prescription. Correction of these practices will improve safety and quality of care in patients receiving domperidone.

Phenotype of Children with QT Prolongation Identified Using an Institution-Wide QT Alert System.

QT prolongation is an independent risk factor for cardiovascular mortality in adults. However, there is little information available on pediatric patients with QT prolongation and their outcomes. Herein, we evaluated the prevalence of QT prolongation in pediatric patients identified by an institution-wide QT alert system, and the spectrum of their phenotype. Patients with documented QT prolongation on an ECG obtained between November 2010 and June 2011 were included. There were 1303 pediatric ECGs, and 68 children had electrographically isolated QT prolongation. Comprehensive review of medical records was performed with particular attention to QT-prolonging clinical, laboratory, and medication data, which were summarized into a pro-QTc score. Overall, 68 (5 %) pediatric patients had isolated QT prolongation. The mean age of this pediatric cohort was 9 ± 6 years, and the average QTc was 494 ± 42 ms. All children had 1 or more QT-prolonging risk factor(s), most commonly QT-prolonging medications. One patient was identified with congenital long QT syndrome (LQTS), which was not previously diagnosed. In one-year follow-up, only one pediatric death (non-cardiac) occurred (1.5 %). Potentially QT-offending/pro-arrhythmic medications were changed in 80 % of pediatric patients after the physician received the QT alert. Children with QT prolongation had very low mortality and minimal polypharmacy. Still, medications and other modifiable conditions were the most common causes of QT prolongation. Children with a prolonged QTc should be evaluated for modifiable QT-prolonging factors. However, if no risk factors are present or the QTc does not attenuate after risk factor modification/removal, the child should be evaluated for congenital LQTS.

Computer-assisted interventions to improve QTc documentation in patients receiving QT-prolonging drugs.

Many medications commonly used in hospitals can cause prolonged corrected QT interval (QTc), putting patients at risk for torsade de pointes (TdP), a potentially fatal arrhythmia. However, documentation of QTc for hospitalized patients receiving QT-prolonging medications is often not consistent with American Heart Association standards. To examine effects of education and computerized documentation enhancements on QTc documentation. A quasi-experimental multisite study among 4011 cardiac-monitored patients receiving QTc-prolonging medications within a 10-hospital health care system was conducted to compare QTc documentation before (n=1517), 3 months after (n = 1301), and 4 to 6 months after (n = 1193) an intervention. The intervention included (1) online education for 3232 nurses, (2) electronic notifications to alert nurses when a patient received at least 2 doses of a QT-prolonging medication, and (3) computerized calculation of QTc in electronic health records after nurses had documented heart rate and QT interval. QTc documentation for inpatients receiving QTc-prolonging drugs increased significantly from baseline (17.3%) to 3 months after the intervention (58.2%; P < .001) within the 10 hospitals and had increased further 4 to 6 months after the intervention (62.1%, P = .75). Patients at larger hospitals were significantly more likely to have their QTc documented (46.4%) than were patients at smaller hospitals (26.2%; P < .001). A 3-step system-wide intervention was associated with an increase in QTc documentation for patients at risk for drug-induced TdP, and improvements persisted over time. Further study is needed to assess whether increased QTc documentation decreases occurrence of drug-induced TdP. (American Journal of Critical Care. 2015;24:e6-e15).

Management of ventricular arrhythmias in suspected channelopathies.

Although structural heart disease remains the predominant substrate for ventricular arrhythmia, channelopathies including long QT syndrome (LQTS), short QT syndrome (SQTS), Brugada syndrome (BrS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and early repolarization syndrome (ERS) are less common but important contributing entities. These etiologies require specific therapies potentially contrary to empirical management of arrhythmias associated with structural heart disease. Conventional therapy including antiarrhythmic drug therapy may not only fail to resolve unstable arrhythmias but worsen them. Additionally, channelopathy patients with implantable cardioverter defibrillators (ICD) and arrhythmic storms represent a major challenge, and the acute care team needs to be cognizant of unique circumstances that require specific acute therapies beyond empirical advanced life support algorithm recommendations.1 Successful and considered acute management of ventricular arrhythmias is contingent on a number of variables, including knowledge of the cardiac substrate or potential substrate; form, mechanism, and precipitants of ventricular arrhythmias; and acute effect of potential therapies. In the longer term, an understanding of the natural history of the channelopathy along with the efficacy of long-term therapy will lead to superior outcomes. This review will present the risk of ventricular arrhythmias associated with these uncommon entities, the evolving understanding of the mechanism of arrhythmia, and the mechanistic basis of therapies along with a clinical approach to summarize the evidence pertaining to acute and long-term management. Patients with a prolonged QT interval are at risk of sudden cardiac death (SCD) due to Torsade de Pointes (TdP; Figure 1). Most patients with congenital LQTS are asymptomatic and diagnosed incidentally on electrocardiogram screening or following family screening. However, syncope, aborted SCD, or SCD may be the first presentation. Most arrhythmic events in congenital LQT1 occur during physical or emotional stress, at rest or in association with sudden auditory stimulation in LQT2, and during sleep or rest in LQT3 …

QTc interval prolongation in HIV-negative versus HIV-positive subjects with or without antiretroviral drugs.

QTc interval prolongation signifies an increased risk of life-threatening arrhythmia and sudden cardiac death. Cardiac manifestations of human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome have become increasingly important causes of morbidity and mortality. We investigated HIV-positive patients to determine the effects of HIV infection, antiretroviral drugs, and identifiable confounders on QTc prolongation. A case-control study was conducted in a rural tertiary health center in Nigeria. Data collected included demographic variables, body mass index, blood pressure, HIV status, antiretroviral treatment (ART), duration of HIV infection and treatment, CD4 T-lymphocyte count, heart rate (HR), and QT interval. QT was corrected for HR using Bazett's formula. The sample frame comprised 89 (42.4%) HIV-negative subjects (39.3% male, 60.7% female; mean age, 36.28 ± 7.03 years); 45 (21.4%) HIV-positive, ART-naïve patients (31.1% male, 68.9% female; mean age, 36.48 ± 9.12 years); and 76 (36.2%) HIV-positive patients on ART (27.6% male, 72.4% female; mean age, 39.00 ± 7.68 years). The QTc interval and resting HR were higher in HIV-positive, drug-naïve patients than in the other two groups (P < 0.001). Female sex was associated with prolonged QTc intervals in all groups. HIV-positive patients may be at higher risk of sudden cardiac death due to fatal arrhythmia secondary to QTc interval-related cardiac events. Healthcare providers should be aware that a prolonged QTc interval is a potential indicator of increased cardiovascular risk and should exercise caution in prescribing potentially QT-prolonging medications to HIV-positive patients.

Impact of clinical decision support preventing the use of QT-prolonging medications for patients at risk for torsade de pointes

We developed and implemented a 'CPOE-QT Alert' system, that is, clinical decision support integrated in the computerized physician order entry system (CPOE), in 2011. The system identifies any attempts to order medications with risk of torsade de pointes (TdP) for patients with a history of significant QT prolongation (QTc ≥500 ms) and alerts the provider entering the order. We assessed its impact by comparing orders and subsequent medication administration before and after activation of the system. We found a significant decrease in the proportion of completed order per ordering attempt after system activation (94% (1293/1379) vs 77% (1888/2453), difference 16.8%; p<0.001). This resulted in a 13.9% reduction in the administration of those medications to patients. A significant decrease was observed across all provider types, educational levels, and specialties. The CPOE-QT Alert system successfully reduced exposure to QT-prolonging medications in high risk patients.

Prescribers' practice of assessing arrhythmia risk with QT-prolonging medications.

This study aimed to assess prescribers' monitoring for arrhythmic risk with QT-prolonging medications (LQT drugs). Over a 6-month period, all inpatients under the care of Cardiologists (Cohort A) and General Physicians (Cohort B) at Aberdeen Royal Infirmary who were prescribed drugs with known risk of Torsades de Pointes (TdP) were identified. Admission and repeat electrocardiograms (ECG) after 48h of commencing a LQT drug were examined. Actions taken if QTc was prolonged and drug-drug interactions were examined. A risk estimate on the UK hospital population was calculated. Of the 4133 patients admitted during the study period, 234 (6%) patients were prescribed a LQT drug. There were 100 (43%) patients in Cohort A and 134 (57%) patients in Cohort B. Of those admitted with a pre-existing LQT drug prescription, an ECG was performed in 167 (96%) of patients and QTc prolongation was identified in 59 (34%). Of those who received a new prescription of LQT drug, 23 (38%) had QTc prolongation and more patients in Cohort A than Cohort B had a repeat ECG within 48h (84% vs. 11%, P<0.0001). QTc prolongation was only recognized in 6 (14%) and 2 (5%) patients in cohorts A and B, respectively. Only one patient at risk of drug interaction had QTc prolongation. None of our patients had documented TdP in hospital. Extrapolating these findings to the UK hospital population, at least 204 and <17-175 patients on cardiac and noncardiac LQT drugs, respectively, might be expected to have TdP each year. Recognition of acquired QTc prolongation is poor. Clinician education and an electronic prescribing system may improve this situation.

Randomized, double-blind, placebo-controlled clinical trial of a two-day regimen of dihydroartemisinin-piperaquine for malaria prevention halted for concern over prolonged corrected QT interval.

Dihydroartemisinin-piperaquine, the current first-line drug for uncomplicated malaria caused by Plasmodium falciparum and Plasmodium vivax in Cambodia, was previously shown to be of benefit as malaria chemoprophylaxis when administered as a monthly 3-day regimen. We sought to evaluate the protective efficacy of a compressed monthly 2-day treatment course in the Royal Cambodian Armed Forces. The safety and efficacy of a monthly 2-day dosing regimen of dihydroartemisinin-piperaquine were evaluated in a two-arm, randomized, double-blind, placebo-controlled cohort study with 2:1 treatment allocation. Healthy military volunteers in areas along the Thai-Cambodian border where there is a high risk of malaria were administered two consecutive daily doses of 180 mg dihydroartemisinin and 1,440 mg piperaquine within 30 min to 3 h of a meal once per month for a planned 4-month period with periodic electrocardiographic and pharmacokinetic assessment. The study was halted after only 6 weeks (69 of 231 projected volunteers enrolled) when four volunteers met a prespecified cardiac safety endpoint of QTcF (Fridericia's formula for correct QT interval) prolongation of >500 ms. The pharmacodynamic effect on the surface electrocardiogram (ECG) peaked approximately 4 h after piperaquine dosing and lasted 4 to 8 h. Unblinded review by the data safety monitoring board revealed mean QTcF prolongation of 46 ms over placebo at the maximum concentration of drug in serum (Cmax) on day 2. Given that dihydroartemisinin-piperaquine is one of the few remaining effective antimalarial agents in Cambodia, compressed 2-day treatment courses of dihydroartemisinin-piperaquine are best avoided until the clinical significance of these findings are more thoroughly evaluated. Because ECG monitoring is often unavailable in areas where malaria is endemic, repolarization risk could be mitigated by using conventional 3-day regimens, fasting, and avoidance of repeated dosing or coadministration with other QT-prolonging medications. (This study has been registered at ClinicalTrials.gov under registration no. NCT01624337.).

Abstract MP09: Deep Terminal Negativity of the P Wave in V1 is Associated with Sudden Cardiac Death in the Community: The Atherosclerosis Risk in Communities Study

Background: Deep terminal negativity of the P wave in V1 (P prime in V1, PPV1) defined as PPV1 ≤ -0.1mV in amplitude and ≥40 ms in duration (one small box on ECG grid) is sign of a left atrium enlargement, and a component in the Romhilt-Estes score of left ventricular hypertrophy (LVH). LVH is known to be associated with the risk of sudden cardiac death (SCD). Deep PPV1 negativity is also associated with atrial fibrillation (AF) and stroke; both have been linked to SCD as well. However, it is unknown whether or not PPV1 negativity is independently associated with SCD. Method: Baseline resting digital 12-lead ECGs of 13232 ARIC cohort participants (mean age 53.9±5.7 y; 5760 [43.5%] men; 9747 [73.7%] white) were analyzed. Individuals with prevalent baseline coronary heart disease (CHD), heart failure (HF), or QRS ≥ 120 ms were excluded. The ECGs were analyzed using a 12SL TM algorithm (GE Healthcare, Wauwatosa, WI, USA). Amplitude and duration of PPV1 was automatically measured. Results: Deep PPV1 negativity was observed in 97 (0.73%) participants. During a median follow-up of 14 years, 182 participants had SCD. In multivariable competing risks regression analysis, deep PPV1 negativity was significantly associated with SCD after adjustment for baseline risk factors of CHD and SCD (age, sex, race, diabetes, smoking, alcohol consumption, cholesterol, triglycerides, body mass index, serum creatinine, albumin, systolic blood pressure, use of antihypertensive, QT-prolonging medications, level of physical activity, mean heart rate, QTc, QRS duration, ECG-LVH by Cornell product), and incident HF, AF, stroke [subHR 3.8 (95%CI 1.88-7.69); P&lt;0.0001]. Deep PPV1 negativity showed 7% sensitivity and 99% specificity for SCD prediction. Conclusion: In apparently CV healthy, middle-aged individuals, deep terminal negativity of P-wave in V1 is associated with about 4-times higher risk of SCD during 14 years of follow-up. Further studies should explore the cardiac substrate underlying presence of this marker and its use for risk stratification.

Ondansetron and the Risk of Cardiac Arrhythmias: A Systematic Review and Postmarketing Analysis

To explore the risk of cardiac arrhythmias associated with ondansetron administration in the context ofrecent recommendations for identification of high-risk individuals. We conducted a postmarketing analysis and systematically reviewed the published literature, grey literature, manufacturer's database, Food and Drug Administration Adverse Events Reporting System, and the WorldHealth Organization Individual Safety Case Reports Database (VigiBase). Eligible cases described a documented (or perceived) arrhythmia within 24 hours of ondansetron administration. The primary outcome was arrhythmia occurrence temporally associated with the administration of a single, oral ondansetron dose. Secondary objectives included identifying all cases associating ondansetron administration (any dose, frequency, or route) to an arrhythmia. Primary: No reports describing an arrhythmia associated with single oral ondansetron dose administration were identified. Secondary: Sixty unique reports were identified. Route of administration was predominantly intravenous (80%). Asignificant medical history (67%) or concomitant use of a QT-prolonging medication (67%) wasidentified in 83%of reports. Approximately one third occurred in patients receiving chemotherapeutic agents, many of whichare known toprolong the QT interval. An additional third involved administration to prevent postoperative vomiting. Current evidence does not support routine ECG and electrolyte screening before single oral ondansetron dose administration to individuals without known risk factors. Screening should be targeted to high-risk patients and those receiving ondansetron intravenously.

Changes in Domperidone Prescribing Practices after a “Black Box” Warning: Are We Exposing Inpatients to Unnecessary Cardiac Risk?

Purpose: Domperidone is used in Canada as a motility and antiemetic agent. Inappropriate use is of particular concern because of its associated risks of life-threatening ventricular arrhythmias and sudden cardiac death. This study aimed to assess the impact of a Health Canada advisory in 2012 on domperidone prescription patterns. Methods: A retrospective chart review was conducted for consecutive patients at two tertiary care sites prescribed domperidone before and after the Health Canada advisory during quarters in 2005 and 2012, respectively. Study patients included those prescribed domperidone during hospital and those with preexisting prescriptions. The main outcome assessed was appropriateness of domperidone prescription based on: 1) Health Canada-approved indications, 2) dosing regimens, and 3) pre-treatment assessment, including measurement of serum potassium (K+), magnesium (Mg+) and calcium (Ca2+) levels, performance of baseline ECG, monitoring of QTc intervals and left ventricular (LV) dysfunction, and co-prescription of other QT-prolonging medications. Differences in outcomes between 2005 and 2012 were evaluated by univariable and multivariable analyses. Results: A total of 577 patients were included: 290 in 2005 (mean age 62.4) and 287 in 2012 (mean age 67.9). Compared to 2005 (prior to the Health Canada advisory), significantly less domperidone was initiated in hospital (71.4% vs. 39.4%, p<0.0001), or was prescribed for non-approved indications (84.8% vs. 58.2%, p<0.0001) or at inappropriate doses >30 mg/day (65.5% vs. 47.4%, P<0.0001) in 2012 (after the Health Canada advisory). In a multivariable model, in-hospital initiation (OR 7.01, 95% CI 4.52-10.87, p<0.0001) and domperidone use as a sole GI drug (OR 2.51, 95% CI 1.38-4.55, p=0.002) predicted prescription with non-approved indications. Basic cardiac risk assessment and the performance of baseline laboratory tests were not routinely done prior to initiation of domperidone, although there was improvement in 2012 compared to 2005 (Table 1).Table 1: Assessment prior to domperidone initiation during hospitalization—2005 vs. 2012Conclusion: There has been more appropriate use of domperidone following the Health Canada warning. Yet, inappropriate utilization and inadequate pre-treatment assessment remain common. Increased awareness of domperidone's indications and adverse effects could serve to reduce inappropriate prescription and thereby improve patient safety and reduce cost.

Fish oil for prevention of sudden death in hemodialysis patients?

Friedman et al. report that hemodialysis patients with the highest levels of n-3 fatty acids had impressively low odds of sudden cardiac death. The study is limited by a small sample size, and the analysis relies on only a single baseline measurement of blood levels. Recent randomized evidence indeed fails to support that n-3 fatty acids may prevent sudden death in nonrenal patients. More evidence is needed to advocate fish oil in this setting.

Use of QT‐prolonging medications in US emergency departments, 1995–2009

Emergency department (ED) patients receive medications that place them at risk for adverse events, including drug-induced prolongation of the QT interval, which can lead to Torsade de Pointes and sudden cardiac death. We report the frequency of prescription and co-prescription of QT-prolonging medications in US EDs and factors associated with high-risk prescribing practices. We analyzed the ED component of the National Hospital Ambulatory Medical Care Survey for 1995 through 2009. Yearly rates of visits involving the prescription of QT-prolonging medications were determined. Multivariate regression analyses identified factors associated with the prescription of two or more QT-prolonging medications. Approximately 16.5 million visits annually (15.0%) involved prescription of a QT-prolonging drug, with 1.7 million (1.6%) involving multiple prescriptions. Visits associated with QT-prolonging drugs more than doubled over the study period (10.4% to 22.2%). Diphenhydramine, azithromycin, and ondansetron were most frequently implicated (46.1% of cases). The most commonly prescribed combination was diphenhydramine and famotidine, both QT-prolonging medications available over-the-counter. Female gender and older age were associated with co-prescription of QT-prolonging medications. The rate of EKG screening among visits associated with QT-prolonging drug combinations was low (20.9%), but more common than among visits without a QT-prolonging drug (OR 1.3; 95% CI 1.2-1.5). Use of QT-prolonging medications is increasing in EDs nationally. A small number of agents account for a large proportion of these visits and may represent an area for targeted screening or monitoring interventions in the ED.

Institution-Wide QT Alert System Identifies Patients With a High Risk of Mortality

ObjectivesTo determine the phenotype and outcome of patients with QTc of at least 500 ms and to create a pro-QTc risk score for mortality. Patients and MethodsAn institution-wide computer-based QT alert system was developed and implemented at Mayo Clinic in Rochester, Minnesota. This system screens all electrocardiograms (ECGs) performed and alerts the physician if the QTc is 500 ms or greater. Between November 10, 2010, and June 30, 2011, 86,107 ECGs were performed in 52,579 patients. Clinical diagnoses, laboratory abnormalities, and medications known to influence the QT interval were collected from the medical records and summarized in a new pro-QTc score. Survival was compared with that of the 51,434 Mayo Clinic patients with a QTc less than 500 ms during the same period. ResultsQT alerts were sent for 1145 patients (2%); of these, 470 (41%) had no other identifiable ECG reason for QT prolongation (eg, pacing). All-cause mortality during a mean ± SD of 224±174 days of follow-up was 19% in those with QTc of 500 ms or greater compared with 5% in patients with QTc less than 500 ms (log-rank P<.001). The pro-QTc score was an age-independent predictor of mortality (pro-QTc score: hazard ratio, 1.18; 95% CI, 1.05-1.32; P=.006; age: hazard ratio, 1.02; 95% CI, 1.01-1.03; P=.004.). QT-prolonging medications accounted for 37% of the pro-QTc score. ConclusionThis novel institution-wide QT alert system identified patients with a high risk of mortality. The pro-QTc score, reflecting patients’ multimorbidity and multipharmacy, was an independent predictor of mortality. The QT alert system may increase a physician’s awareness of a high-risk patient. Potentially lifesaving interventions can be facilitated by reducing the modifiable factors of the pro-QTc score.

Dialysate Calcium Concentration and the Risk of Sudden Cardiac Arrest in Hemodialysis Patients

The optimal dialysate calcium concentration to maintain normal mineralization and reduce risk of cardiovascular events in hemodialysis patients is debated. Guidelines suggest that dialysate Ca concentration should be lowered to avoid vascular calcification, but cardiac arrhythmias may be more likely to occur at lower dialysate Ca. Concurrent use of QT-prolonging medications may also exacerbate arrhythmic risk. This study examined the influence of serum Ca, dialysate Ca, and QT interval-prolonging medications on the risk of sudden cardiac arrest in a cohort of hemodialysis patients. This case-control study among 43,200 hemodialysis patients occurred between 2002 and 2005; 510 patients who experienced a witnessed sudden cardiac arrest were compared with 1560 matched controls. This study examined covariate-adjusted sudden cardiac arrest risk associations with serum Ca, dialysate Ca, serum dialysate Ca gradient, and prescription of QT-prolonging medications using logistic regression techniques. Patients assigned to low Ca dialysate<2.5 mEq/L were more likely to be exposed to larger serum dialysate Ca gradient and had a greater fall in BP during dialysis treatment. After accounting for covariates and baseline differences, low Ca dialysate<2.5 mEq/L (odds ratio=2.00, 95% confidence interval=1.40-2.90), higher corrected serum Ca (odds ratio=1.10, 95% confidence interval=1.00-1.30), and increasing serum dialysate Ca gradient (odds ratio=1.40, 95% confidence interval=1.10-1.80) were associated with increased risk of sudden cardiac arrest, whereas there were no significant risk associations with QT-prolonging medications. Increased risk of sudden cardiac arrest associated with low Ca dialysate and large serum dialysate Ca gradients should be considered in determining the optimal dialysate Ca prescription.

Acquired Long QT Syndrome: Frequency, Onset, and Risk Factors in Intensive Care Patients

Acquired long QT syndrome is a reversible condition that can lead to torsades de pointes and sudden cardiac death. To determine the frequency, onset, frequency of medications, and risk factors for the syndrome in intensive care patients. In a retrospective chart review of 88 subjects, hourly corrected QT intervals calculated by using the Bazett formula were collected. Acquired long QT syndrome was defined as a corrected QT of 500 milliseconds or longer or an increase in corrected QT of 60 milliseconds or greater from baseline level. Risk factors and medications administered were collected from patients' medical records. The syndrome occurred in 46 patients (52%); mean time of onset was 7.4 hours (SD, 9.4) from time of admission. Among the 88 patients, 52 (59%) received a known QTc-prolonging medication. Among the 46 with the syndrome, 23 (50%) received a known QT-prolonging medication. No other risk factor studied was significantly predictive of the syndrome. Acquired long QT syndrome occurs in patients not treated with a known QT-prolonging medication, indicating the importance of frequent QT monitoring of all intensive care patients.

Risperidone and Corrected QT-interval Prolongation in Surface Electrocardiogram

Risperidone is an antipsychotic medication suspected of causing QT prolongation and several cases are reported in this regard. However, available information with respect to its effect on QT interval is limited especially from different settings. The aim of this study was to assess the effect of risperidone in lengthening QT interval among psychotic patients referred to a psychiatric ward in North West of Iran. A controlled cohort study was conducted on psychotic patients referred to Razi Hospital from April 2010-2011. The treatment cohort groups were 120 patients receiving risperidone for the first time during their treatment. The comparison cohort included 60 control patients who were not receiving risperidone. An electrocardiogram was obtained from all the study participants at admission time, one week afterwards and at discharge. Corrected QT interval (QTc) was determined using Bazett's formula. QTc dispersion was calculated as Max(QTc)-Min(QTc). Data were analyzed using SPSS statistical software package. The mean change in QTc measures over time was not statistically significant in control group. However, QTc increment was statistically significant over time in V1 and V3 leads in risperidone group. Multivariate longitudinal data analysis, using between-effects model, to manage multiple measurements over time found the overall QTc trend to be different between the groups (p < 0.01). Risperidone may have significant effects on QT interval and QT dispersion. Physicians and psychiatrists should be aware that prolonged QTc interval is a potential indicator of cardiovascular risk and should be cautious in prescribing potentially QT-prolonging medications, at least to certain patients.

Key role of the molecular autopsy in sudden unexpected death

Sudden Cardiac Death (SCD) is a major and tragic complication of a number of cardiovascular diseases. While in the older populations, SCD is most frequently caused by underlying coronary artery disease and heart failure, in those aged under 40 years, the causes of SCD commonly include genetic disorders, such as inherited cardiomyopathies and primary arrhythmogenic diseases. As part of the evaluation of families in which SCD has occurred, the role of genetic testing has evolved as an important feature in both establishing an underlying diagnosis and in screening at-risk family relatives. Specifically, in cases where no definitive cause is identified at postmortem, i.e. Sudden Unexpected Death (SUD), the "molecular autopsy" has emerged as a key process in the investigation of the cause of death. The combination of clinical and genetic evaluation of families in which SUD has occurred provides a platform for early initiation of therapeutic and prevention strategies, with the ultimate goal to reduce sudden death among the young in our communities.