Frequency Of QTc Prolongation Research Articles

Safety and Efficacy of Clofazimine as an Alternative for Rifampicin in Mycobacterium avium Complex Pulmonary Disease Treatment: Outcomes of a Randomized Trial

BackgroundRetrospective studies have suggested clofazimine as an alternative for rifampicin in MAC-PD treatment. Research questionIs a treatment regimen consisting of clofazimine-ethambutol-macrolide non inferior to the standard treatment regimen (rifampicin-ethambutol-macrolide) in the treatment of M.avium complex pulmonary disease? Study design and MethodsIn this single centre non-blinded clinical trial, we randomly assigned adult patients with MAC-PD in a 1:1 ratio to receive rifampicin or clofazimine as adjuncts to an ethambutol-macrolide backbone. The primary outcome was sputum culture conversion after six months of treatment. ResultsForty patients were assigned to receive either rifampicin (n=19) or clofazimine (n=21) ) next to ethambutol and a macrolide. After 6 months of treatment, both arms showed similar percentages of sputum culture conversion based on intention to treat analysis: 58% (11/19) for rifampicin; 62% (13/21) for clofazimine. Study discontinuation, mainly due to adverse events, was equal in both arms (26% vs 33%). Based on an on treatment analysis sputum culture conversion after 6 months of treatment was 79% in both groups.In the clofazimine arm, diarrhoea was more prevalent (76% vs 37%; p=0.012), while arthralgia was more frequent in the rifampicin arm (37% vs 5%; p=0.011). No difference in the frequency of QTc prolongation was seen between both groups. InterpretationA clofazimine-ethambutol-macrolide regimen showed similar results to the standard rifampicin-ethambutol-macrolide regimen and should be considered in the treatment of MAC-PD. The frequency of adverse events was similar in both arms, but their nature was different. Individual patients characteristics and possible drug-drug interactions should be taken into consideration when choosing an antibiotic regimen for MAC-PD.

Assessment of Corrected QT Interval Prolongation in Liver Cirrhosis

Objective: To find out the frequency of corrected QT interval (QTc) prolongation in patients with liver cirrhosis. Study Design: Cross-sectional study. Place and Duration: The department of medicine, “Aziz Bhatti Shaheed Teaching Hospital”, Gujrat from April 2021 to October 2021. Methodology: A total of 150 patients of both genders aged 18-65 years having liver cirrhosis were included. Proper medical history and clinical examination were performed while electrocardiogram (ECG) was obtained to find out QT interval in all the patients. The frequency of QTc prolongation was recorded. Results: In a total of 150 patients, 66 (44.0%) were males and 84 (56.0%) females. The mean age was 48.67±16.67 years while the mean duration of cirrhosis was 4.71±1.18 years. Frequency of QTc prolongation was noted in 44 (29.3%) patients. Among ninty patients of liver cirrhosis with age more than 40 years, 31 (70.5%) had corrected QT interval prolongation (p=0.040). Among 84 female patients, there were 25 (56.8%) cases of corrected QT interval prolongation (p=0.047). Practical Implications: Potential cases of liver transplantation may be prioritized as per their risk of prolongation of QTc but further research is required in this regard. Conclusion: The frequency of QTc prolongation was quite high among patients of liver cirrhosis. Keywords: Cardiovascular disease, Electrocardiogram, liver cirrhosis, mortality, QT prolongation.

The QT Interval in Patients With the Turner Syndrome

Patients with the Turner syndrome (TS) often have longer QT intervals compared with age-matched peers although the significance of this remains unknown. We sought to determine the degree, frequency and impact of QTc prolongation in patients with TS. A chart review of all patients with an electrocardiogram (ECG) and genetically proven TS was performed. Medications at the time of the ECG were reviewed and QTc calculated. Medications were classified according to QTc risk using www.crediblemeds.com. ECG parameters were compared with an age, gender, and cardiac lesion-matched control group. Over the 10-year period of review, 112 TS patients with a mean age of 34 ± 25 years underwent 226 ECGs. At least 1 QTc prolonging medication was prescribed in 81 (74%) patients. Longer QTc interval correlated with absence of y chromosomal material (p = 0.01), older age (p <0.0001), increased number of QTc prolonging and nonprolonging medications (p <0.0001 each). During the 7.0 ± 5.1 years of follow-up, no patient had ventricular arrhythmia or unexplained sudden death. QTc was significantly shorter in matched controls using either Bazett or Hodges formula (424 ± 16 ms vs 448 ± 28 ms, p <0.0001; and 414.8 ± 16 ms vs 424.2 ± 20 ms; p = 0.0002, respectively). However, there was no difference in the frequency of QTc prolongation >460 msec (2.8% vs 2.6%, p = 0.9). In conclusion, despite frequent use of QT-prolonging medications, ventricular arrhythmias are rare in TS.

The effects and reliability of the hydroxychloroquine-azithromycin combination on the cardiac conduction system in patients with coronavirus disease 2019

Aim: The COVID-19 virus influenced the world since late 2019 and affected millions of people. Although there is no unambiguous evidence in the treatment of COVID-19, the combination of hydroxychloroquine and azithromycin entered the protocols globally to reduce virus replication and take advantage of its immunomodulatory effects. It has been stated that both drugs extend QTc. However, the frequency of QTc prolongation in combinational drug use, and its effect on the primary endpoint, as well as the predictive values of QTc prolongation are not clear. Methods: A total of 135 patients who received hydroxychloroquine, azithromycin, and oseltamivir for suspected / definitive COVID-19 with viral pneumonia were examined in this single-center, retrospective study, Results: The mean age was 55.6 (19.1) years, and 61 (45%) patients were female. According to the initial ECG values, the QTc1 value was 422.44 (35.72) ms, while the QTc2 value was 446.91 (36.71) ms (P500 ms was 6 (4.4%). The number of patients with prolongation in QTc values >60 ms was 7 (5.1%). The frequency of prolongation in QTc was 26% in intensive care unit patients, and 2% in low-risk patients in the inpatient unit. An elevation in troponin values >14 ng/L and a low GFR are predictors for QTc prolongation. None of these patients developed malignant arrhythmia or sudden cardiac death. Conclusion: Hydroxychloroquine and azithromycin combinations used in COVID-19 patients cause a prolongation in the QTc. The incidence of prolongation in QTc varies according to the comorbid characteristics and clinical status of the patients. Before starting hydroxychloroquine and azithromycin, the risk factors and clinical status of the patients should be well evaluated.

Efficacy and Safety of Hydroxychloroquine vs Placebo for Pre-exposure SARS-CoV-2 Prophylaxis Among Health Care Workers

Health care workers (HCWs) caring for patients with coronavirus disease 2019 (COVID-19) are at risk of exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Currently, to our knowledge, there is no effective pharmacologic prophylaxis for individuals at risk. To evaluate the efficacy of hydroxychloroquine to prevent transmission of SARS-CoV-2 in hospital-based HCWs with exposure to patients with COVID-19 using a pre-exposure prophylaxis strategy. This randomized, double-blind, placebo-controlled clinical trial (the Prevention and Treatment of COVID-19 With Hydroxychloroquine Study) was conducted at 2 tertiary urban hospitals, with enrollment from April 9, 2020, to July 14, 2020; follow-up ended August 4, 2020. The trial randomized 132 full-time, hospital-based HCWs (physicians, nurses, certified nursing assistants, emergency technicians, and respiratory therapists), of whom 125 were initially asymptomatic and had negative results for SARS-CoV-2 by nasopharyngeal swab. The trial was terminated early for futility before reaching a planned enrollment of 200 participants. Hydroxychloroquine, 600 mg, daily, or size-matched placebo taken orally for 8 weeks. The primary outcome was the incidence of SARS-CoV-2 infection as determined by a nasopharyngeal swab during the 8 weeks of treatment. Secondary outcomes included adverse effects, treatment discontinuation, presence of SARS-CoV-2 antibodies, frequency of QTc prolongation, and clinical outcomes for SARS-CoV-2-positive participants. Of the 132 randomized participants (median age, 33 years [range, 20-66 years]; 91 women [69%]), 125 (94.7%) were evaluable for the primary outcome. There was no significant difference in infection rates in participants randomized to receive hydroxychloroquine compared with placebo (4 of 64 [6.3%] vs 4 of 61 [6.6%]; P > .99). Mild adverse events were more common in participants taking hydroxychloroquine compared with placebo (45% vs 26%; P = .04); rates of treatment discontinuation were similar in both arms (19% vs 16%; P = .81). The median change in QTc (baseline to 4-week evaluation) did not differ between arms (hydroxychloroquine: 4 milliseconds; 95% CI, -9 to 17; vs placebo: 3 milliseconds; 95% CI, -5 to 11; P = .98). Of the 8 participants with positive results for SARS-CoV-2 (6.4%), 6 developed viral symptoms; none required hospitalization, and all clinically recovered. In this randomized clinical trial, although limited by early termination, there was no clinical benefit of hydroxychloroquine administered daily for 8 weeks as pre-exposure prophylaxis in hospital-based HCWs exposed to patients with COVID-19. ClinicalTrials.gov Identifier: NCT04329923.

Cardiac Arrest Risk During Acute Infections: Systemic Inflammation Directly Prolongs QTc Interval via Cytokine-Mediated Effects on Potassium Channel Expression.

During acute infections, the risk of malignant ventricular arrhythmias is increased, partly because of a higher propensity to develop QTc prolongation. Although it is generally believed that QTc changes almost exclusively result from concomitant treatment with QT-prolonging antimicrobials, direct effects of inflammatory cytokines on ventricular repolarization are increasingly recognized. We hypothesized that systemic inflammation per se can significantly prolong QTc during acute infections, via cytokine-mediated changes in K+ channel expression. We evaluated (1) the frequency of QTc prolongation and its association with inflammatory markers, in patients with different types of acute infections, during active disease and remission; (2) the prevalence of acute infections in a cohort of consecutive patients with Torsades de Pointes; (3) the relationship between K+ channel mRNA levels in ventricles and peripheral blood mononuclear cells and their changes in patients with acute infection over time. In patients with acute infections, regardless of concomitant QT-prolonging antimicrobial treatments, QTc was significantly prolonged but rapidly normalized in parallel to CRP (C-reactive protein) and cytokine level reduction. Consistently in the Torsades de Pointes cohort, concomitant acute infections were highly prevalent (30%), despite only a minority (25%) of these cases were treated with QT-prolonging antimicrobials. KCNJ2 K+ channel expression in peripheral blood mononuclear cell, which strongly correlated to that in ventricles, inversely associated to CRP and IL (interleukin)-1 changes in acute infection patients. During acute infections, systemic inflammation rapidly induces cytokine-mediated ventricular electrical remodeling and significant QTc prolongation, regardless concomitant antimicrobial therapy. Although transient, these changes may significantly increase the risk of life-threatening ventricular arrhythmia in these patients. It is timely and warranted to transpose these findings to the current coronavirus disease 2019 (COVID-19) pandemic, in which both increased amounts of circulating cytokines and cardiac arrhythmias are demonstrated along with a frequent concomitant treatment with several QT-prolonging drugs. Graphic Abstract: A graphic abstract is available for this article.

P5717Risk of QTC interval prolongation among cancer patients treated with tyrosine kinase inhibitors

Abstract Objective 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, the 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. Table 1 demonstrates the findings for each TKI. Findings for TKIs in all patients Total Prolonged QTc QTc ≥500 QTc progression ≥60 VT SCD TdP Imatinib 165 54 13 10 2 Nilotinib 75 33 8 19 Dasatinib 115 58 10 16 2 1 Sunitinib 134 31 1 2 1 1 Pazopanib 165 36 5 6 2 1 Others 248 77 16 18 2 1 1 Conclusion 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. Acknowledgement/Funding None

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]

The Frequency of Qtc Prolongation Among Pediatric Patients Receiving Methadone for Cancer Pain

The Frequency of Qtc Prolongation Among Pediatric Patients Receiving Methadone for Cancer Pain

The Use of First Line Highly Active Anti-Retroviral Therapy (HAART) is Not Associated with Qtc Prolongation in HIV Patients.

HAART has improved survival of HIV patients. Its contribution to the development of new cardiovascular abnormalities has generated much interest. This study aimed at determining the prevalence of QTc prolongation among HIV patients and determining the influence if any of the use of HAART on the QTc and on the risk of having QTc prolongation. One hundred and fifty HIV positive subjects comprising 76 HIV positive subjects on HAART (Group A), 74 who were HAART- naïve (Group B), and 150 age and sex-matched healthy controls (Group C) were studied. All subjects had electrocardiography, and QTc duration was calculated. Mean QTc was significantly different among the three groups (P <0.001), highest in Group B > Group A > Group C. Frequency of QTc prolongation was highest in Group B (32%)>, Group A (17.3%)> Group C (4.7%) (P<0.001). Mean QTc was significantly longer among patients with CD4 count <200 cells/mm3 than among those with >200 cells/mm3 0.445 ± 0.03secs vs 0.421 ± 0.03secs (P<0.001). QTc prolongation was commoner among individuals with CD4 count <200 cells/mm3 50% vs 20.5% (P<0.001). On binary logistic regression, none of the HAART medications used by our patients was predictive of the occurrence of QTc prolongation. The QTc is longer, and QTc prolongation occurs more frequently in HAART-naïve HIV patients than patients on HAART and healthy controls. None of the HAART medications used by our patients was predictive of the development of QTc prolongation.

An analysis of QTc prolongation with atypical antipsychotic medications and selective serotonin reuptake inhibitors using a large ECG record database

ABSTRACTBackground: This study evaluated the effects of atypical antipsychotic drugs and selective serotonin reuptake inhibitors (SSRIs) on the corrected QT (QTc) interval using a large database obtained from clinical settings. Additionally, the effects of factors including age on QTc intervals were estimated.Methods: Using an open-access QT database (ECG-ViEW), QTc-lengthening effects of 14 selected atypical antipsychotics and SSRIs were compared to those of a positive control drug, cilostazol, and a negative control drug, diazepam. We also evaluated effects of age, sexgender, and select electrolyte levels on observed QTc intervals.Results: The frequency of QTc prolongation with the pooled data of the 14 study drugs was lower than that with cilostazol (age-adjusted odds ratio (OR) = 0.43, 95% confidence interval (CI) = 0.27-0.69), but no significant difference was found relative to when compared with that with diazepam (age-adjusted OR = 0.89, 95% CI = 0.55-1.47). Furthermore, administration of the 14 study drugs significantly increased the QTc interval by 2.89 ms after each 10-year age increment (p-value < 0.0001).Conclusions: This study suggests that atypical antipsychotic drugs and SSRIs are less likely to be associated with QTc prolongation in clinical settings. In addition, age showed a significant association with the QTc interval. Further studies with well-characterized cohorts are warranted.

QTc prolongation in schizophrenia patients in Asia: clinical correlates and trends between 2004 and 2008/2009.

Little is known about the pattern of QT interval (QTc) prolongation in Asian patients with schizophrenia. This study examined trends of QTc prolongation in schizophrenia inpatients in six Asian countries and territories between 2004 and 2008/2009 and its independent demographic and clinical correlates. Data on 3482 hospitalized schizophrenia patients (2004 = 1826 and 2008/2009 = 1656) in six Asian countries and territories were collected by either chart review or interviews during a 1-month period. Patients' sociodemographic and clinical characteristics, prescriptions of psychotropic drugs, and QTc interval were recorded using a standardized protocol and data collection procedure. The frequency of QTc prolongation (>456 ms) was 2.4% in the whole sample, decreasing from 3.1% in 2004 to 1.6% in 2008/2009 (p = 0.004) with wide intercountry variations. However, this decreased trend was driven by decreased QTc prolongation detected in China and Hong Kong (both p-values < 0.05). Multiple logistic regression analysis of the whole sample revealed that patients having more likely to have an illness lasting longer than 5 years and received antipsychotics classified as list-1 drugs according to the Arizona Centre for Education and Research on Therapeutics. Compared with 2004, patients in 2008/2009 were less likely to have QTc prolongation. Thioridazine caused QTc prolongation most frequently (odds ratio (OR) 4.4; 95% confidence interval (CI) 1.2-15.2), followed by sulpiride (OR 2.4; 95% CI 1.3-4.5), clozapine (OR 2.4; 95% CI 1.4-4.2), and chlorpromazine (OR 1.9; 95% CI 1.07-3.5). Frequency of QTc prolongation was low in Asian patients with schizophrenia. QTc prolongation in schizophrenia decreased in China and Hong Kong between 2004 and 2008/2009 but increased in Taiwan over the same period, remaining low in the other countries.

Prolonged QTc Interval Is an Electrophysiological Hallmark of Cirrhotic Cardiomyopathy

BACKGROUND: Cirrhotic Cardiomyopathy is a relatively ill-characterized condition, which is often under-diagnosed due to absence of defined diagnostic criteria. ECG showing corrected QT Interval prolongation is the most suitable available option for diagnosis of this condition. OBJECTIVE: To determine the frequency of corrected QT interval prolongation in patients with liver cirrhosis. METHODOLOGY: Patients (n = 166) with confirmed cirrhosis, 30 years or older, presented in the outpatient and emergency department of medicine at Capital Hospital Islamabad between 1 October 2011 and 30 September 2012, were enrolled in this cross-sectional study after taking consent. ECG was done using calibrated ECG machine, and the QT Interval was measured. Corrected QT was calculated using Bazett’s formula and a QTc of more than 0.44 seconds was considered as being prolonged. RESULTS: The mean age of the patients was 57.05 ± 12.03 years. The corrected QT Interval varied from 337 ms to 560 ms. The mean QTc Interval was 429.92 ms ± 45.11. QTc was prolonged in 41 out of 166 patients (24.7%). Frequency of QTc prolongation was 4.5% in Child Pugh Grade A, 23.2% in Child Pugh Grade B, and 32.0% in Child Pugh Grade C. Association of Child Pugh Scoring with QTc prolongation was determined and found to be statistically significant (P

P03-63 - QT prolongation: Which psychotropics?

Prolongation of the ventricular repolarisation manifests itself as a prolongation of the QT intervall on the surface ECG and represents a major risk for a special form of ventricular tachycardia called “torsades de pointes”, that are often self limited and are associated with palpitations, dizziness or syncope, but degeneration into ventricular fibrillation and sudden cardiac death can occur. Psychotropics are among the most common causes of drug induced acquired long QT syndrome. Blockage of Human ether-a-go-go-related gene (HERG) potassium channel by psychoactive drugs appears to be related to this adverse effect. Antipsychotics such as haloperidol, thioridazine, sertindole, pimozide, risperidone, ziprasidone, quetiapine, olanzapine and antidepressants such as amitriptyline, imipramine, doxepin, trazadone, fluoxetine depress the delayed rectifier potassium current (IKr) in a dose dependent manner in experimental models. The frequency of QTc prolongation (more than 456ms) in psychiatric patients is estimated to be 8%. In large epidemiological controlled studies a dose dependent increased risk of sudden death has been identified in current users of antipsychotics (conventional and atypical) and of TCA. The authors propose to further explore this theme, in a review of existing literature.

QT Alterations in Psychopharmacology: Proven Candidates and Suspects

Psychotropics are among the most common causes of drug induced acquired long QT syndrome. Blockage of Human ether-a-go-go-related gene (HERG) potassium channel by psychoactive drugs appears to be related to this adverse effect. Antipsychotics such as haloperidol, thioridazine, sertindole, pimozide, risperidone, ziprasidone, quetiapine, olanzapine and antidepressants such as amitriptyline, imipramine, doxepin, trazadone, fluoxetine depress the delayed rectifier potassium current (IKr) in a dose dependent manner in experimental models. The frequency of QTc prolongation (more than 456 ms) in psychiatric patients is estimated to be 8%. Age over 65 years, tricyclic antidepressants (TCA), thioridazine, droperidol, olanzapine, and higher antipsychotic doses were predictors of significant QTc prolongation. In large epidemiological controlled studies a dose dependent increased risk of sudden death has been identified in current users of antipsychotics (conventional and atypical) and of TCA. Thioridazine and haloperidol shared a similar relative risk of SCD. Lower doses of risperidone had a higher relative risk than haloperidol for cardiac arrest and ventricular arrhythmia. No increased risk was identified in current users of selective serotonin reuptake inhibitors (SSRI). Cases of TdP have been reported with thioridazine, haloperidol, ziprazidone, olanzapine and TCA. Evidence of QTc prolongation with sertindole is significant and this drug has not been approved by the Food and Drugs Administration (FDA). A large trial is ongoing to evaluate the cardiac risk profile of ziprazidone and olanzapine. Selective serotonin reuptake inhibitors have been associated with QTc prolongation but no cases of TdP have been reported with the use of these agents. There are no reported cases of lithium induced TdP. Risk factors for drug induced LQT syndrome and TdP include: female gender, concomitant cardiovascular disease, substance abuse, drug interactions, bradychardia, electrolyte disorders, anorexia nervosa, and congenital Long QT syndrome. Careful selection of the psychotropic and identification of patient's risk factors for QTc prolongation is applicable in current clinical practice.

Prolonged QTc in Sickle Cell Disease: A Potential Risk Factor for Early Death?

Background: Sudden unexplained death is one of the leading causes of mortality in sickle cell disease (SCD). Prolonged QTc has been associated with sudden death in older patients and in those with cardiac disease. Sudden death due to cardiac arrhythmias occurs in thalassemia (Thal) patients from cardiac iron toxicity, and recently, QTc prolongation has also been identified in this transfusion-dependent population. Chronic transfusion and iron overload have become more frequent in patients with SCD due to treatment regimens aimed at stroke prevention and treatment of stroke, pulmonary hypertension (PH) and recurrent vaso-occlusive crisis. Cardiac iron toxicity is thought to be rare in SCD but other factors such as anemia, PH, and hemolysis-associated nitric oxide dysregulation may predispose SCD to prolongation of the QTc interval. The purpose of this study was to examine the prevalence of QTc prolongation in chronically transfused and iron-overloaded SCD (txSCD) patients compared to a control group of non-transfused SCD patients.Methods: In this study, electrocardiograms (EKGs) were reviewed from SCD patients participating in the MCSIO, a five-year prospective study of the complications of iron toxicity in SCD and Thal. Using Bazett's formula, a subset of 96 EKGs were analyzed for QTc prolongation, defined as ≥ 0.45 seconds and borderline as 0.44 to 0.449 seconds. Echocardiograms (ECHOs) obtained within an average of seven months were analyzed for left ventricular dysfunction (LVD) –which was defined as an ejection fraction < 55% or shortening fraction < 28% –and the presence of PH, defined as a tricuspid regurgitant jet velocity (TRJV) of ≥ 2.5 m/second.Results: There was no difference in mean age (25.3 ± 13.6) or gender (64% female) between the 65 txSCD and 31 control SCD patients. The txSCD group had been transfused 10 ± 6.2 years and their baseline ferritin was 3107 compared to 116 in the controls. QTc prolongation was present in 32% of the txSCD and 29% of the control group (n.s.); borderline prolongation was seen in an additional 17% and 13%, respectively. Mean QTc in txSCD was also not significantly different from the SCD controls: 0.45±.04 vs. 43±.03 (n.s.). None of the 68 patients with ECHOs had LVD. 36 patients had TRJV measured during the study: 50% of the txSCD had PH compared to 30% of non-transfused SCD (n.s.). The average QTc in PH patients was 0.45 ± .04 compared to 0.43 ± .04 in those without PH (p=.09). However, the frequency of either prolonged or borderline QTc was significantly higher in patients with PH (72% vs. 22%, p= .007). No correlations between QTc and age, gender, or baseline laboratory values (hemoglobin, white blood count, or platelets) were found. In the txSCD, QTc was not correlated to ferritin or years of transfusion.Conclusions: Overall, QTc prolongation was found in 31 % of SCD patients and borderline prolongation in an additional 16%. QTc intervals ≥ 0.44 were more common in patients with PH. Transfusion exposure and iron overload were not associated with QTc prolongation in this group of txSCD patients. The frequency of QTc prolongation is concerning in SCD patients, who often have pulmonary hypertension and are treated with medications known to contribute to QTc prolongation. Routine screening for QTc prolongation appears warranted with treatment of high-risk SCD patients.