Risk Of QTc Interval Prolongation Research Articles

Concentration-QTc modeling of sitravatinib in patients with advanced solid malignancies.

Sitravatinib (MGCD516) is an orally available, small molecule, tyrosine kinase inhibitor that has been evaluated in patients with advanced solid tumors. Concentration-corrected QT interval (QTc; C-QTc) modeling was undertaken, using 767 matched concentration-ECG observations from 187 patients across two clinical studies in patients with advanced solid malignancies, across a dose range of 10-200 mg, via a linear mixed-effects (LME) model. The effect on heart rate (HR)-corrected QT interval via Fridericia's correction method (QTcF) at the steady-state maximum concentration (Cmax,ss) for the sitravatinib proposed therapeutic dosing regimen (100 mg malate once daily [q.d.]) without and with relevant intrinsic and extrinsic factors were predicted. No significant changes in HR from baseline were observed. Hysteresis between sitravatinib plasma concentration and change in QTcF from baseline (ΔQTcF) was not observed. There was no significant relationship between sitravatinib plasma concentration and ΔQTcF. The final C-QTc model predicted a mean (90% confidence interval [CI]) ΔQTcF of 3.92 (1.95-5.89) ms and 2.94 (0.23-6.10) ms at the proposed therapeutic dosing regimen in patients with normal organ function (best case scenario) and patients with hepatic impairment (worst-case scenario), respectively. The upper bounds of the 90% CIs were below the regulatory threshold of concern of 10 ms. The results of the described C-QTc analysis, along with corroborating results from nonclinical safety pharmacology studies, indicate that sitravatinib has a low risk of QTc interval prolongation at the proposed therapeutic dose of 100 mg malate q.d.

Improving Corrected QT Interval Monitoring in Critical Care Units: A Single Center Report.

Corrected QT (QTc) interval prolongation is a type of ventricular tachyarrhythmia. Recommendations for QTc interval monitoring for critical care nurses are limited and variable. The intensive care unit at the study institution had no policies for QTc interval monitoring. A quality improvement initiative for identifying and monitoring at-risk patients was begun. A QTc interval monitoring protocol was developed according to current recommendations for electrocardiogram monitoring and input from experts. Nursing staff received education on the QTc monitoring protocol. Numbers of patients with indications for monitoring were collected for 60 days before and 60 days after implementation. The rate of protocol adherence was collected for 60 days after implementation. Aknowledge assessment was administered to nurses at baseline, immediately after education, and 4 months after education. Before protocol implementation, 537 patients had indications for monitoring. No QTc intervals were documented by nurses. After protocol implementation, 544 patients had indications for monitoring. Protocol adherence was higher during day shifts than during night shifts (45.3% and 38.4%, respectively). Of 170 documented QTc prolongation events, 26 (15%) were reported to physicians. Nurses' knowledge significantly improved after education and was retained 4 months after education (correct responses to assessment questions: 59% at baseline, 96% immediately after education, and 86% at 4 months after education). This QTc interval monitoring protocol improved nurses' ability to identify and monitor patients with increased risk of QTc interval prolongation. Adherence was less than desired, suggesting that further protocol revisions are required.

QTc interval prolongation in the patients with primary biliary cholangitis.

BackgroundThe QT interval prolongation was associated with fatal arrhythmias and cardiac death. However, there were not adequate data to clarify the situation of QT interval prolongation in primary biliary cholangitis (PBC) patients. The aim of this study was to clarify the rate and the associated risk factors of corrected QT (QTc) interval prolongation in PBC patients.MethodsFrom January 2016 to December 2020, PBC patients were retrospectively enrolled. The rate of QTc interval prolongation was surveyed and the associated risk factors were clarified by univariate and multivariate analyses.ResultsAmong the 189 PBC patients, 24.3% (46/189) had the QTc interval prolongation. The univariate analysis showed that age, Child‐Pugh classification, creatinine, international normalized ratio (INR), and platelet (PLT) were associated with QTc interval prolongation in the PBC patients. The multivariate analysis further showed only age (p = .028) and Child‐Pugh classification (p = .035) were the associated risk factors. It had the highest risk of QTc interval prolongation (as high as 64.3%) in the patients who were more than 62.5 years old and with Child‐Pugh C.ConclusionThe QTc interval prolongation was frequent in PBC patients, especially in the patients with decompensated cirrhosis. The rate of QTc interval prolongation was as high as 64.3% in the PBC patients who were more than 62.5 years old and classified as Child‐Pugh C.

Relationship between Corrected QT Interval (QTc) Prolongation and Insulin Resistance in Obese Adult Male Subjects

QT Interval prolongation is common in insulin resistance state obesity. Insulin-induced hyperpolarization might be involved in ventricular repolarization leading to QTc lengthening. Therefore, this study is designated to investigate the relationship between corrected QT interval (QTc) prolongation and insulin resistance in obese adult male subjects. Apparently healthy adult male subjects (n=100) aged between 18-35 years residing in Magway Township were recruited by simple random sampling method. Then all the eligible subjects were categorized into 2 groups: non-obese [body mass index (BMI) 18.5 to 24.9 kg/m2, n= 40] and obese group [BMI ≥ 30.0 kg/m2, n=60] by their anthropometric parameters. Serum fasting glucose was measured by glucose oxidase method. Serum insulin level was determined by Enzyme-Linked Immunosorbent Assay (ELISA). Insulin sensitivity was calculated by Homeostatic Model Assessment (HOMA-IR). The QT interval was measured by routine 12-lead ECG and corrected QT interval (QTc) was calculated according to Bazett’s formula. In the present study, insulin sensitivity (HOMA-IR) was higher in obese subjects (4.64±2.3) than that of non-obese subjects (2.5±0.89) (p< 0.001). There was significant positive correlation between QTc and HOMA-IR (r = 0.41, p< 0.001, n = 100) in this study. HOMA-IR >3.8 was considered as insulin resistance (IR) and QTc > 440ms was regarded as QTc interval prolongation. Insulin resistance was significantly associated with prolonged QTc interval in the study population (X2=7.3, p< 0.05, n=100). Risk of QTc interval prolongation was 3.4 times higher in subjects with IR (Odd ratio = 3.4; 95% confidence interval = 1.37 to 8.45). It was concluded that prolonged QTc interval is associated with insulin resistance state.

Evaluation of QTc Interval Effects of Antipsychotic Medications for Intensive Care Unit Delirium in Pediatric Patients.

Intensive care unit delirium is an increasingly recognized problem in pediatric patients. Controversy exists regarding the safety and efficacy of antipsychotic medications for this indication. The objective of this study was to determine the incidence of and risk factors for QTc interval prolongation in pediatric patients treated with antipsychotics for ICU delirium. Retrospective chart review of pediatric patients admitted to the pediatric ICU or pediatric cardiac ICU and diagnosed with ICU delirium between October 1, 2014, and October 31, 2015. Patients were included if they received at least 1 dose of an antipsychotic for the treatment of delirium after a positive screen using the Cornell Assessment of Pediatric Delirium scoring tool. For the 26 patients included, the median change in QTc interval on treatment was -4 msecs. Two patients (8%) had QTc interval prolongation while on antipsychotic therapy. No risk factors were identified in these 2 patients that put them at increased risk for QTc interval prolongation. The incidence of QTc interval prolongation in pediatric patients who were treated with antipsychotics for ICU delirium was low. There is need for future research to determine which pediatric patients are at risk for QTc interval prolongation when antipsychotic medications are used for the treatment of ICU delirium.

Relationship between Plasma Adiponectin Level and Corrected QT Interval in Smoker and Non-smoker Adult Male Subjects.

ObjectiveThis study determined the relationship between plasma adiponectin level and corrected QT interval (QTc) in smokers and non-smokers.MethodologyThis cross-sectional analytical study was undertaken in 30 smokers and 30 non-smokers. Plasma adiponectin level was determined by enzyme-linked immunosorbent assay (ELISA). The QT interval was measured by routine 12-lead ECG with Lead II rhythm and QTc was calculated.ResultsMean plasma adiponectin level was significantly lower in smokers (27.89±15 μg/ml) than that of non-smokers (52.13±21.57pg/ml) (p<0.001). Mean QTc interval was significantly longer in smokers than that of non-smokers (415.37±29.9 versus 395.63±26.13 ms, p<0.01). Higher risk of low adiponectin level (odds ratio [OR],8.1; 95% confidence interval [CI],1.61-40.77) and QTc interval prolongation (OR,6; 95%CI,1.17-30.73) were observed in smokers. There was weak significant negative correlation between plasma adiponectin level and QTc interval in the study population (n=60, r=-0.407, p=0.001). Moreover, low plasma adiponectin level was significantly associated with prolonged QTc interval in the study population (n=60, Fisher’s exact p value<0.05). Risk of QTc interval prolongation was 4.3 times higher in subjects with low plasma adiponectin level (OR,4.27; 95% CI,1.05-17.46).ConclusionSmokers have greater risk for low plasma adiponectin level and prolonged QTc interval. There is a relationship between plasma adiponectin level and QTc interval.

Predictive factors for cardiac conduction abnormalities with hydroxychloroquine-containing combinations for COVID-19

This longitudinal, prospective cohort study aimed to assess risk of QTc interval prolongation and its predicting factors in subjects treated with combinations containing hydroxychloroquine (HCQ) for COVID-19. Moderate-to-severe QTc prolongation during therapy was defined as a QTc interval >470 ms in men or >480 ms in women. Patients were treated under strict cardiac supervision. A total of 105 adults were included [56% male; median (IQR) age 69 (57-79) years]. All patients received therapy with HCQ in combination with azithromycin (AZM), and 95 (90%) also with lopinavir/ritonavir (LPV/r). Concomitant medications classified as having risk of developing torsades de pointes (TdP) were simultaneously used in 81 patients (77%). Moderate-to-severe QTc prolongation was observed in 14 patients (13%), mostly at Days 3-5 from baseline, with 6 (6%) developing severe prolongation (>500 ms). There was no evidence of TdP arrhythmia or TdP-associated death. Adding LPV/r to HCQ+AZM did not significantly prolong the QTc interval. Multivariable Cox regression revealed that comedications with known risk of TdP (HR=11.28, 95% CI 1.08-117.41), higher neutrophil-to-lymphocyte (NLR) ratio (HR=1.10, 95% CI 1.03-1.18 per unit increase) and higher serum hs-cardiac troponin I (HR=4.09, 95% CI 1.36-12.2 per unit increase) were major contributors to moderate-to-severe QTc prolongation. In this closely screened and monitored cohort, no complications derived from QTc prolongation were observed during pharmacological therapy containing HCQ for COVID-19. Evidence of myocardial injury with elevated troponin and strong inflammatory response, specifically higher NLR, are conditions requiring careful QTc interval monitoring.

The risk of QTc-interval prolongation in COVID-19 patients treated with chloroquine.

BackgroundChloroquine, a quinolone antimalarial drug, is known to potentially inhibit pH-dependent viral replication of the SARS-CoV‑2 infection. Therefore, chloroquine is considered as a treatment option for coronavirus disease 2019 (COVID-19). Chloroquine is known for prolonging the QT interval, but limited data are available on the extent of this QT-prolonging effect.ObjectiveTo assess the QTc-prolonging potential of chloroquine in COVID-19 patients and to evaluate whether this prolongation increases with the cumulative dose of chloroquine and is associated with the peak plasma concentration of chloroquine. Furthermore, the number of patients who prematurely discontinued treatment or had an adjustment in dose due to QTc-interval prolongation was established.MethodsA retrospective, observational study was performed in patients aged over 18 years, hospitalised for a suspected or proven infection with COVID-19, and therefore treated with chloroquine, with a baseline electrocardiogram (ECG) performed prior to the start of treatment and at least one ECG after starting the treatment.ResultsIn total, 397 patients were included. The mean increase in QTc interval throughout the treatment with chloroquine was 33 ms. Nineteen out of 344 patients unnecessarily had their treatment prematurely discontinued or adjusted due to a prolonged QTc interval based on the computerised interpretation of the ECG.ConclusionChloroquine treatment in COVID-19 patients gradually increased the QTc interval. Due to a significant number of overestimated QTc intervals by computer analysis, it is advisable to measure the QTc interval manually before adjusting the dose or withdrawing this potentially beneficial medication.

Predictive Validity of a QTc Interval Prolongation Risk Score in the Intensive Care Unit.

Torsade de pointes is a form of polymorphic ventricular tachycardia associated with heart rate-corrected QT (QTc ) interval prolongation. With approximately 24-61% of critically ill patients experiencing QTc interval prolongation, a predictive tool to identify high-risk patients could assist in themonitoring and management in the intensive care unit (ICU). The Tisdale et al. Risk Score (TRS) is a predictive tool that was developed and validated in a cardiac critical care unit. The objective of this study was to evaluate the predictive validity (sensitivity and specificity) and likelihood ratios of the TRS in a medical ICU. This was a longitudinal, retrospective, cohort study of consecutive patients who met the inclusion criteria from October 2017 to June 2018 with a sample size of 264 patients. The sample size was derived based on the number of TRS covariates and an exploratory variable. Baseline characteristics and risk factors were documented from electronic health records. The first occurrence of QTc interval prolongation, defined as a QTc interval >500ms or an increase ≥60ms above baseline, was the primary endpoint. The sensitivity and specificity of the TRS for low-risk patients against the moderate-risk and high-risk patients were 97% (95% CI 91-99%) and 16% (95% CI 11-23%), respectively. These results corresponded to a positive likelihood ratio of 1.15 (95% CI 1.07-1.24) and a negative likelihood ratio of 0.20 (95% CI 0.06-0.65). In conclusion, the TRS showed a high sensitivity, making it useful in identifying patients at risk of developing QTc interval prolongation. Furthermore, patients categorized as low risk by the tool can be considered as having minimal risk of developing QTc interval prolongation. Given the tool's low specificity, it does not reliably identify all patients at low risk of QTc interval prolongation.

The Risk of QTc-Interval Prolongation in Breast Cancer Patients Treated with Tamoxifen in Combination with Serotonin Reuptake Inhibitors

PurposeAntidepressants like the serotonin reuptake inhibitors (SRIs) are often used concomitantly with tamoxifen (e.g. for treatment of depression). This may lead to an additional prolongation of the QTc-interval, with an increased risk of cardiac side effects. Therefore we investigated whether there is a drug-drug interaction between tamoxifen and SRIs resulting in a prolonged QTc-interval.MethodsElectrocardiograms (ECGs) of 100 patients were collected at steady state tamoxifen treatment, with or without concomitant SRI co-medication. QTc-interval was manually measured and calculated using the Fridericia formula. Primary outcome was difference in QTc-interval between tamoxifen monotherapy and tamoxifen concomitantly with an SRI.ResultsThe mean QTc-interval was 12.4 ms longer when tamoxifen was given concomitantly with an SRI (95% CI:1.8–23.1 ms; P = 0.023). Prolongation of the QTc-interval was particularly pronounced for paroxetine (17.2 ms; 95%CI:1.4–33.0 ms; P = 0.04), escitalopram (12.5 ms; 95%CI:4.4–20.6 ms; P < 0.01) and citalopram (20.7 ms; 95%CI:0.7–40.7 ms; P = 0.047), where other agents like venlafaxine did not seem to prolong the QTc-interval. None of the patients had a QTc-interval of >500 ms.ConclusionsConcomitant use of tamoxifen and SRIs resulted in a significantly higher mean QTc-interval, which was especially the case for paroxetine, escitalopram and citalopram. When concomitant administration with an SRI is warranted venlafaxine is preferred.

Treatment of Helicobacter pylori in Special Patient Populations.

Helicobacter pylori infection can lead to gastritis, gastric and duodenal ulcers, and gastric cancer. Consequently, complete eradication is the goal of therapy. First-line therapy for H.pylori infection includes clarithromycin triple therapy (clarithromycin, proton pump inhibitor [PPI], and amoxicillin or metronidazole), bismuth quadruple therapy (bismuth salt, PPI, tetracycline, and metronidazole or amoxicillin), or concomitant therapy (clarithromycin, PPI, amoxicillin, and metronidazole). However, many patients have relative contraindications to the antibiotics included in these regimens, making therapy selection difficult. Furthermore, failure of initial therapy makes selection of second-line therapy challenging due to concerns for potential resistance to agents included in the initial regimen. This review discusses H.pylori microbiology, including antibiotic resistance, and summarizes the existing evidence for first- and second-line treatment regimens that may be considered for special populations such as patients with penicillin allergies, patients with or at risk for QTc-interval prolongation, and patients who are pregnant, breastfeeding, or elderly.

Thorough QTc Evaluation and the Safety of Supratherapeutic Doses of Odanacatib in Healthy Subjects.

Assessing risk for QTc interval prolongation in a thorough QTc study is a standard recommendation when evaluating new chemical entities. As part of the clinical development program for odanacatib, an oral selective inhibitor of cathepsinK previously in development for the treatment of osteoporosis, 2 clinical studies in healthy subjects assessed pharmacokinetics and overall safety (including potential for delayed ventricular repolarization) of a supratherapeutic dose. In study 1, subjects received a supratherapeutic dose regimen of odanacatib (300mg on day 1, then daily multiple doses of 25mg to day 21) or placebo. In study 2 (days 1-4), subjects received the odanacatib supratherapeutic dose regimen or moxifloxacin (positive control, single 400-mg dose on day 4; matching placebo for odanacatib/moxifloxacin) or placebo. All doses were administered with a high-fat meal. In study 1 (N = 12), the supratherapeutic dosing regimen achieved exposure ∼3.5-fold of the proposed therapeutic dose (50mg once weekly) and was sufficiently well tolerated to permit assessment in the thorough QTc study (study 2). In study 2 (N = 116), the primary objective was placebo-corrected change from baseline in QTcF interval (Fridericia's correction), assessed by replicate electrocardiograms (12-lead Holter recordings; days -1 through 7). Supratherapeutic odanacatib dosing was not associated with increased risk of prolonged QT interval, unlike moxifloxacin (confirming assay sensitivity). Pooled safety data across both studies suggested that the safety profile of odanacatib at high exposures was similar to placebo, with a small clustering of oral cavity adverse events. Odanacatib was not associated with increased risk of prolonged QT interval.

Risk of QTc interval prolongation among cancer patients treated with tyrosine kinase inhibitors.

3033 Background: QTc interval prolongation can lead to life-threatening complications such as torsade de pointes (TdP), ventricular tachycardia (VT), and sudden cardiac death (SCD). It can occur with various tyrosine kinase inhibitors (TKIs) but comparative analyses on the incidence and complication rates are scarce. We thus conducted a comprehensive analysis of TKI use and QTc prolongation in clinical practice. Methods: We retrospectively reviewed the electronic medical records of all cancer patients who were treated with TKI between 01/2005 and 12/2018 at our institution. QTc prolongation was defined as a QTc ≥ 450 ms or 460 ms among male or female patients, respectively. For each type of TKIs, we determined the administration rate and incidence of QTc interval prolongation. We also studied the frequency of QTc prolongation ≥ 500 ms, rate of increase of the QTc interval by ≥ 60 ms, and the development of complications (VT, TdP and SCD). Results: In the present study, we analyzed the data of 685 cancer patients (431 male and 254 female), including 299 patients with RCC, 188 with chronic leukemia, 55 with acute leukemia, 65 with thyroid cancer, 48 with lung cancer and 39 with GIST. These patients received 902 TKI administrations and QTc prolongation was reported in 1/3 of these (289 administrations). The highest frequency was seen with imatinib, nilotinib and dasatinib (30, 40 and 50%). Among cases of QTc prolongation, a QTc interval ≥ 500 ms was documented in 53 (18.3%) and QTc progression ≥ 60 ms in 72 (25%). Complications were found in 14 cases (5%) including VT in 9, TdP in 2 and SCD in 3 administrations. Conclusions: The current findings suggest that TKI therapy leads to QTc prolongation in 1/3 of patients on average and most commonly with the Bcr-Abl TKIs, imatinib, nilotinib and dasatinib. While SCD is rare (1%) it can still evolve and in 5% of all QTc prolongations with TKIs are potentially life-threatening. These data support recommendations for serial ECGs in cancer patients undergoing TKI therapy. [Table: see text]

Evaluation of Medication-Related QTc Prolongation Risks in Patients Receiving Hospice Care (QI727)

1.Characterize the use of QTc prolonging medications in hospice patients.2.Recall the average QTc prolonging medication burden is hospice patients. Medications commonly used for symptom management in the hospice population are linked with QTc interval prolongation, which may lead to torsades de pointes. Safety risk of QTc-prolonging medications in this population may be underestimated. To develop a risk assessment scoring tool for QTc prolongation in hospice patients. A retrospective chart review of a national hospice pharmacy provider was completed. Decedents with a cardiac-related primary hospice diagnosis and medication claims profiled during between January 1, 2018 and March 31, 2018 were included. Age, sex, and medications profiled were also collected. Charts of decedent’s age ≥ 65 years were reviewed for medications with a known or possible risk of QTc interval prolongation. Independent patient risk factors and profiled medications, based on CredibleMeds.org categories of QTc interval prolongation risk, were scored using a modified RISQ-PATH tool. Independent patient risk factors were also scored. A total of 16,501 decedents were reviewed with an average age of 87 years. The population is 56.6% (n=9,343) female. This subset of patients scored 9 on RISQ-PATH based on independent risk facts alone. Percentage of patients with QTc-prolonging drugs was 28.8% with 10.3% of the population on a drug that CredibleMeds.org ranks as known risk of torsades. Additionally, 6.9% of patients were prescribed diuretics. After the initial review of population data, additional statistical analysis is in progress for final risk assessment tool development. Results of this analysis will be incorporated in final presentation. Our population review illustrates utilization of medications with QTc prolongation risk in a patients with several independent risk factors already present. Evaluating patient risk for QTc interval prolongation will help prioritize significance of drug-drug interactions and inform our discussions with interdisciplinary teams about the risk vs benefits of these medications for symptom management.

Predictive Analytics for Identification of Patients at Risk for QT Interval Prolongation: A Systematic Review

Prolongation of the heart rate-corrected QT (QTc) interval increases the risk for torsade de pointes (TdP), a potentially fatal arrhythmia. The likelihood of TdP is higher in patients with risk factors that include female sex, older age, heart failure with reduced ejection fraction, hypokalemia, hypomagnesemia, concomitant administration of two or more QTc interval-prolonging medications, among others. Assessment and quantification of risk factors may facilitate prediction of patients at highest risk for developing QTc interval prolongation and TdP. Investigators have utilized the field of predictive analytics, which generates predictions using techniques including data mining, modeling, machine learning, and others, to develop methods of risk quantification and prediction of QTc interval prolongation. Predictive analytics have also been incorporated into clinical decision support (CDS) tools to alert clinicians regarding patients at increased risk of developing QTc interval prolongation. The objectives of this article are to assess the effectiveness of predictive analytics for identification of patients at risk of drug-induced QTc interval prolongation and to discuss the efficacy of incorporation of predictive analytics into CDS tools in clinical practice. A systematic review of English-language articles (human subjects only) was performed, yielding 57 articles, with an additional 4 articles identified from other sources; a total of 10 articles were included in this review. Risk scores for QTc interval prolongation have been developed in various patient populations including those in cardiac intensive care units (ICUs) and in broader populations of hospitalized or health system patients. One group developed a risk score that includes information regarding genetic polymorphisms; this score significantly predicted TdP. Development of QTc interval prolongation risk prediction models and incorporation of these models into CDS tools reduce the risk of QTc interval prolongation in cardiac ICUs and identify health system patients at increased risk for mortality. The impact of these QTc interval prolongation predictive analytics on overall patient safety outcomes, such as TdP and sudden cardiac death relative to the cost of development and implementation, requires further study.

Ciprofloxacin does not Prolong the QTc Interval: A Clinical Study in ICU Patients and Review of the Literature.

Ciprofloxacin may prolong the QT interval and increase the risk of Torsade de Pointes (TdP). Intravenous administration of ciprofloxacin in patients with additional risks may elevate the risk of QTc interval prolongation. We prospectively assessed whether intravenous ciprofloxacin prolongs the QT interval in patients with additional co-morbidities and risk factors. We also reviewed the literature on the QT prolonging effect or TdP inducing effect of ciprofloxacin. ICU Patients who were treated with intravenous ciprofloxacin as part of their therapy were recruited. ECG was recorded within 60 min before start and in the last 30 min of 1 h infusion, or within 30 min after the end of ciprofloxacin infusion. QT interval was corrected for the heart rate using both Bazett's and Fridericia's formula. The changes were analyzed using the paired Student's t-test. Ten patients were included in the study (average age 74-y, 6 males). The average baseline QTc interval corrected with Bazett's formula was 448 ms that was shortened during or after ciprofloxacin infusion by 3 ms and 2 ms based on Bazett's (p=0.67) and Fridericia's (p=0.68) formula, respectively. No observational study or cohort study thus far has shown that ciprofloxacin has a QT prolonging effect or increases the risk of TdP or (cardiovascular) mortality. Conclusion. Based on our results and the results of previous studies, it is unlikely that ciprofloxacin has a clinically relevant QT prolonging effect or an increased risk of TdP.This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

ASSESSMENT OF SAFETY PARAMETERS FOLLOWING REPEATED ARTEMISIN-BASED TREATMENTS OF MALARIA-INFECTED PATIENT LIVING IN ENDEMIC AREA OF BURKINA FASO

BackgroundArtemisinin-based combination therapies (ACTs) constitute the worldwide recommended antimalarial drug as first-line treatment of uncomplicated malaria. However, the safety of repeated administration of a given ACT is poorly documented. The...

Hyperbaric oxygen therapy reduces the risk of QTc interval prolongation in patients with diabetes and hard-to-heal foot ulcers

AimsHeart rate corrected QT (QTc) interval prolongation is a risk factor associated with increased mortality. Hyperbaric oxygen therapy (HBO) has previously been shown to have acute beneficial effects on QTc dispersion. The aim of this study was to evaluate long-term effects of HBO on QTc time in diabetic patients with hard-to-heal foot ulcers. MethodsIn a prospective, double-blinded placebo-controlled study, patients were randomized to 40 treatment sessions with either HBO or air (placebo), at 2.5 ATA. Patients fulfilling >35 completed treatment sessions were included in the evaluation. ResultsOf the initial 75 patients (38 HBO/37 placebo), two were excluded due to pacemaker use. Baseline characteristics were similar between groups. At the 2-year follow-up, QTc time was significantly shorter in the HBO compared to the placebo group (438 vs. 453ms, p<0.05). Further, fewer HBO treated patients had a QTc time >450ms (22 vs. 53 %, p<0.02). This difference seemed to be caused by a significant prolongation of the QTc interval in the placebo group (427 (419–459) at baseline vs. 456ms (424–469) after 2years), whereas no significant change was seen in HBO treated patients. ConclusionsHBO treatment might protect against QTc prolongation in this high-risk diabetic population.

Use of the Low-Dose Buprenorphine Patch: A Response

Dear Editor: As the NDA holder and distributor of Butrans® (buprenorphine) Transdermal System, Purdue Pharma L.P. works to ensure the dissemination of accurate and complete information regarding our products. Purdue commends the Journal of Palliative Medicine on its commitment to end-of-life care and patients with intractable pain; however, we are writing to notify you of misinformation published in Fast Fact #268, “Low-Dose Buprenorphine Patch for Pain.” While the review was well written and informative, there are several statements about Butrans (i.e., low-dose buprenorphine patch) that warrant correction or clarification. Listed below by section of the article and article statement in quotes is a summary of significant misinformation that can lead to safety concerns and/or the improper use of Butrans. • Background: ∘ In addition to being approved for use in treatment of opioid addiction, buprenorphine is approved, as an injectable, for relief of moderate to severe pain, as referenced in the Equianalgesic Ratios section. The U.S. approval for this pain indication predates approval for use in addiction treatment by over 20 years (12/29/1981).1 • Pharmacology: ∘ Buprenorphine is described as providing “analgesia with decreased incidence of sedation, euphoria, and respiratory depression compared to other opioids.” There are no head-to-head studies evaluating these outcomes with Butrans in comparison to other opioids. Although buprenorphine is considered a partial agonist at mu opioid receptors, it can be expected to produce pharmacological effects similar to those of full mu-agonists, especially at the buprenorphine doses delivered by Butrans.2 Therefore, sedation, euphoria, and respiratory depression can occur. In fact, respiratory depression is the primary risk of Butrans.3 • Using the low-dose buprenorphine patch: ∘ This section states, “The U.S. formulation of the buprenorphine transdermal system is recommended for opioid tolerant patients requiring up to 80 mg/day of oral morphine equivalents.” The use of Butrans is not limited to opioid-tolerant patients. Butrans has been studied and is approved for use in opioid-naive patients or in opioid-experienced patients requiring up to 80 mg/day of oral morphine equivalents.3–5 ∘ Butrans is described as being “available in strengths of 5, 10, and 20 mcg/hour.” Butrans 15 mcg/hour was approved in July 2013 and Butrans is now available in four dosage strengths.3 We understand that the reason for this omission is because the new strength became available after the writing of this article. ∘ Withdrawal symptoms are described as “symptoms tend to be milder than with other long-acting opioids.” Although this has been demonstrated with other buprenorphine formulations, clinical studies comparing withdrawal symptoms with Butrans to other long-acting opioids have not been conducted. When a patient no longer requires therapy with Butrans, a gradual downward titration of the dose every seven days to prevent signs and symptoms of withdrawal in the physically dependent patient is recommended. Butrans should not be abruptly discontinued.3 ∘ The article states, “Use of more than one patch at a time is not recommended due to risk of QT prolongation.” Although applying more than one patch at a time is not recommended, it is important to clarify that QTc interval prolongation is not dependent on the number of patches worn, but rather on the buprenorphine dose delivered. The maximum dose of Butrans is 20 mcg/hour due to the risk of QTc interval prolongation (which was detected at a dose of 40 mcg/hour).3 • Clinical applications: ∘ This section states, “Other advantages of buprenorphine include a decreased risk of respiratory depression.” While this effect may have been demonstrated with other buprenorphine products, it has not been demonstrated with Butrans. Respiratory depression is the primary risk of Butrans.3 • Summary: ∘ The article concludes by stating, “The low-dose transdermal buprenorphine patch is effective for mild to moderate chronic pain, both malignant and nonmalignant.” Butrans is not recommended for use in treating mild chronic pain. Butrans is indicated for the management of moderate to severe chronic pain when a continuous, around-the-clock opioid analgesic is needed for an extended period of time.3 ∘ The low-dose buprenorphine patch is described as being “a reasonable second- or third-line option in patients with low opioid requirements who experience intolerable side effects with other opioids.” Categorizing Butrans as an option for patients only with low opioid requirements misrepresents the patient population for which Butrans is approved. Butrans is approved for use in opioid-naive patients as the first opioid analgesic, as well as in opioid-experienced patients requiring up to 80 mg/day of oral morphine equivalents.3–5 This article provides clinicians with a concise overview of the low-dose buprenorphine patch. We would appreciate a correction that accurately presents the product information in order for clinicians to have the necessary information to use Butrans safely and effectively.

QT Interval Prolongation in Users of Selective Serotonin Reuptake Inhibitors in an Elderly Surgical Population

To investigate the association between the use of a selective serotonin reuptake inhibitor (SSRI) and the occurrence of QT interval prolongation in an elderly surgical population. A cross-sectional study was conducted among patients (> 60 years) scheduled for outpatient preanesthesia evaluation in the period 2007 until 2012. The index group included elderly users of an SSRI. The reference group of nonusers of antidepressants was matched to the index group on sex and year of scheduled surgery (ratio, 1:1). The primary outcome was the occurrence of QT interval prolongation shown on electrocardiogram. The QT interval was corrected for heart rate (QTc interval). The secondary outcome was the duration of the QTc interval. The outcomes were adjusted for confounding by using regression techniques. The index and reference groups included 397 users of an SSRI and 397 nonusers, respectively. QTc interval prolongation occurred in 25 (6%) and 19 (5%) index and reference patients, respectively. After adjustment for confounding, users of an SSRI did not have a higher risk for QTc interval prolongation compared to nonusers: OR = 1.1 (95% CI, 0.5 to 2.0). The adjusted mean QTc interval length in users of an SSRI and nonusers was comparable (difference of 1.5 milliseconds [95% CI, -1.8 to 4.8]). Use of the most frequently used SSRIs citalopram and paroxetine was not associated with a higher risk of QTc interval prolongation nor with lengthening of the QTc interval duration. The use of an SSRI by elderly surgical patients was not associated with the occurrence of QT interval prolongation.