Pre-existing Cardiac Disorders Research Articles

Medication-based Comorbidity Measures and Prostate Cancer Treatment Selection

IntroductionWe aimed to assess the association between comorbidities and prostate cancer management. Patients and methodsWe studied 12,603 South Australian men diagnosed with prostate cancer between 2003 and 2019. Comorbidity was measured one year prior to prostate cancer diagnosis using a medication-based comorbidity index (Rx-Risk). Binomial logistic regression analyses were used to assess the association between comorbidities and primary treatment selection (active surveillance, radical prostatectomy (RP), external beam radiotherapy (EBRT) with or without androgen deprivation therapy (ADT), brachytherapy, ADT alone, and watchful waiting (WW)). Certain common comorbidities within Rx-Risk (cardiac disorders, diabetes, chronic airway diseases, depression and anxiety, thrombosis, and chronic pain) were also assessed. All models were adjusted for sociodemographic and tumor characteristics. ResultsLikelihood of receiving RP was lower among men with Rx-Risk score ≥3 (odds ratio (OR) 0.62, 95%CI:0.56-0.69) and Rx-Risk 2 (OR 0.80, 95%CI:0.70-0.92) compared with no comorbidity (Rx-Risk ≤0). Men with high comorbidity (Rx-Risk ≥3) were more likely to have received ADT alone (OR 1.76, 95%CI:1.40-2.21), EBRT (OR 1.30, 95%CI:1.17-1.45) or WW (OR 1.49, 95%CI:1.19-1.88) compared with Rx-Risk ≤0. Pre-existing cardiac and respiratory disorders, thrombosis, diabetes, depression and anxiety, and chronic pain were associated with lower likelihood of selecting RP and higher likelihood of EBRT (except chronic airway disease) or WW (except diabetes and depression and anxiety). Cardiac disorders and thrombosis were associated with higher likelihood of selecting ADT alone. Furthermore, age had greater effect on treatment choice than the level of comorbidity. ConclusionHigh comorbidity burden was associated with primary treatment choice, with significantly less RP and more EBRT, WW and ADT alone among men with higher levels of comorbidity. Each of the individual comorbid conditions also influenced treatment selection.

Drug-induced atrial fibrillation. A narrative review of a forgotten adverse effect

Atrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with an increased morbidity and mortality. There is clinical evidence that an increasing number of cardiovascular and non-cardiovascular drugs, mainly anticancer drugs, can induce AF either in patients with or without pre-existing cardiac disorders, but drug-induced AF (DIAF) has not received the attention that it might deserve. In many cases DIAF is asymptomatic and paroxysmal and patients recover sinus rhythm spontaneously, but sometimes, DIAF persists, and it is necessary to perform a cardioversion. Furthermore, DIAF is not mentioned in clinical guidelines on the treatment of AF. The risk of DIAF increases in elderly and in patients treated with polypharmacy and with risk factors and comorbidities that commonly coexist with AF. This is the case of cancer patients. Under these circumstances ascribing causality of DIAF to a given drug often represents a clinical challenge. We review the incidence, the pathophysiological mechanisms, risk factors, clinical relevance, and treatment of DIAF. Because of the limited information presently available, further research is needed to obtain a deeper insight into DIAF. Meanwhile, it is important that clinicians are aware of the problem that DIAF represents, recognize which drugs may cause DIAF, and consider the possibility that a drug may be responsible for a new-onset AF episode.

Complete Heart Block Secondary to Section Concomitant Use of Metoprolol and Fluoxetine in a Case of Chronic Depression and Systemic Hypertension: A Case Report

Bradyarrhythmia can be brought on by intrinsic or extrinsic causes that disrupt the cardiac conduction system, with iatrogenic drug usage being the most common extrinsic cause. Atrioventricular (AV) block is frequently brought on by beta-blockers, calcium channel blockers, anti-arrhythmics, and digoxin. The first course of treatment for heart block involves stopping the problematic medications. Psychotropic medications have the potential to cause cardiotoxic adverse effects that affect the heart. In a patient with a pre-existing cardiac disorder, psychotropic drugs can manifest with dangerous arrhythmias. It is yet unknown what intricate processes cause these effects. A variety of arrhythmias may be brought on by or made worse by many commonly used drugs. Hereby, the authors present a case report of 56-year-old hypertensive male, a known case of chronic depression with chest heaviness. The Electrocardiogram (ECG) revealed Complete Heart Block (CHB) with Right Bundle Branch Block (RBBB). The patient was on fluoxetine and beta-blockers for his mental illness and hypertension. Three days after withholding the drugs, the CHB resolved, and his baseline ECG remained as RBBB. The present case highlights the interaction of drugs leading to CHB in present patient. Therefore, the importance of a detailed drug history in such cases becomes imperative.

Time for paying attention to fluoropyrimidine-associated cardiotoxicity: A pooled data analysis for epidemiology based on 60537 cases.

12071 Background: With the rise of cardio-oncology discipline, treatment-related cardiotoxicity has become a growing concern. However, fluoropyrimidine induced cardiotoxicity has been underestimated for a long time. The aim of this study was to comprehensively investigate the incidence and profiles of the cardiotoxicity associated with fluoropyrimidine using a pooled data meta-analysis. Methods: A systematic literature review was performed using PubMed, Embase, Medline, Web of Science, Cochrane library databases and clinical trials on studies published between the establishment of each database and March 31, 2021, investigating fluoropyrimidine associated cardiotoxicity (FAC). The main outcome was pooled incidence of FAC, and the secondary outcome were specific treatment-related cardiac AEs. Random-effects or fixed-effects modeling was used for analyses according to the heterogeneity assessed by Cochran’s Q test. Subgroup analysis and meta-regression were conducted to explore the source of heterogeneity, and the incidence of FAC was compared among different clinical characteristics. The protocol was registered in PROSPERO (No. CRD42021282155). Results: Two hundred and six studies involving 60537 patients were included in this meta-analysis, covering 31 countries or regions in the world. The pooled incidence of FAC was 5.18% (95% CI 4.32%-6.10%) for all grade and 1.5% (95% CI 1.09%-1.96%) for grade 3 or higher. A total of 0.29% of patients died from severe cardiotoxicity. Cardiac ischemia and arrhythmia were the two most common cardiac AEs, occurring in 2.31% (95% CI 1.70%-3.00%) and 1.69% (95% CI 1.08%-2.42%) of patients, respectively. ECG alterations occurred in 5.85% (95% CI 3.4%-8.9%) of patients, indicating asymptomatic ECG alterations in a subset of the population. The incidence of cardiotoxicity varied among different regions, gender, cancer types and treatment regimens. Studies conducted in Asia outlined a significant higher pooled incidence of FAC than in Europe (χ2 = 4.47, p = 0.03) and America (χ2 = 4.49, p = 0.03). Female population had a lower pooled incidence than general population (χ2 = 9.90, p= 0.01). The highest pooled incidence was observed in esophagus cancer (10.53%, 95% CI 5.8%-16.35%), and the lowest occurred in breast cancer (3.66%, 95% CI 2.4%-5.12%). In addition, combination therapy, high cumulative dose, anthracycline addition, and pre-existing cardiac disorder significantly increased the risk of FAC ( p< 0.05). No obvious publication bias was detected by funnel plots and Egger’s test (p < 0.05), and the stability of our results was confirmed by the sensitivity analysis. Conclusions: FAC is not a rare condition during treatment containing fluoropyrimidines. Our results provide comprehensive global data on epidemiology of FAC, potentially representing an important reference on cancer management in clinical practice.

P038 Ozanimod First-Dose Cardiac Effects in Patients with Moderately to Severely Active Ulcerative Colitis and Relapsing Multiple Sclerosis.

Ozanimod, an oral sphingosine 1-phosphate (S1P) receptor modulator that selectively targets S1P1 and S1P5, is approved in the US for treating moderately to severely active ulcerative colitis (UC) and in multiple countries for treating relapsing forms of multiple sclerosis (MS). In a Phase 1 study of ozanimod in healthy participants, first-dose cardiac effects were mitigated with gradual dose escalation. Based on these results, an initial 7-day ozanimod dose escalation regimen was implemented in all Phase 2 and 3 UC and MS trials. The objective of this analysis was to evaluate the number of patients who were excluded from ozanimod treatment due to contraindications of pre-existing cardiac disorders and to evaluate the incidence of cardiac-related treatment-emergent adverse events (TEAEs) following first-dose ozanimod administration in all patients and patients with a history of non-exclusionary cardiac disorders in the UC and MS clinical trials. For UC, the analysis included pooled data from the Phase 2 Touchstone (NCT01647516) and Phase 3 True North (NCT02435992) trials. For MS, the analysis included pooled data from the Phase 3 Radiance (NCT02047734) and Sunbeam (NCT02294058) trials. Patients with clinically relevant cardiac conditions or clinically significant electrocardiogram (ECG) disorders were excluded from the trials. On Day 1, all patients received ozanimod 0.23 mg (equivalent to ozanimod HCl 0.25 mg). Day 1 cardiac monitoring included collection of vital signs (including heart rate) prior to dosing and hourly for at least 6 hours after dosing, and ECG prior to dosing and at Hour 6 after dosing. Among patients screened, 26/2178 (1.2%) in the UC studies and 47/3351 (1.4%) in the MS studies were excluded due to protocol-defined pre-existing cardiac disorders. Of 496 patients who received ozanimod in the UC studies, 1 (0.2%) experienced a cardiac-related TEAE on Day 1 (asymptomatic bradycardia). Of 1774 patients who received ozanimod in the MS studies, 11 (0.6%) experienced a cardiac-related TEAE on Day 1. In both the UC and MS studies, no cases of second- or third-degree AV block were observed. A decrease in mean heart rate from baseline (UC, 0.7 bpm; MS, 1.2 bpm) was observed at first-dose that reached a nadir at Hour 5 and returned to baseline by Hour 6. Among 496 patients with UC who received ozanimod, 34 (6.9%) had a known history of cardiac disorders, of whom 1 experienced a cardiac-related TEAE on Day 1 (asymptomatic bradycardia). Among the 1774 patients with MS who received ozanimod, 96 (5.4%) had a known history of cardiac disorders, of whom 2 experienced symptomatic bradycardia on Day 1. In clinical trials of ozanimod, the number of patients with UC or MS who failed screening because of exclusionary cardiac disorders was low. Most patients with a history of cardiac disorders who were enrolled in ozanimod clinical trials did not have Day 1 cardiac events, and the events that occurred were manageable.

Echocardiographic findings in children with obstructive sleep apnea: A systematic review

ObjectiveTo systematically review the incidence of cardiac abnormalities in pediatric patients with obstructive sleep apnea (OSA) in order to assess the utility of preoperative echocardiographic evaluation for patients undergoing surgery. Study designA systematic literature review was performed following the Preferred Reporting Items for Systematic Reviews (PRISMA) guidelines. Data sources were searched from January 1, 1980 to March 25, 2020. Studies that examined echocardiographic findings and polysomnographic data for patients between birth and 18 years of age with polysomnogram-confirmed OSA were included. Studies that included patients with preexisting cardiac, metabolic, or hematologic disorders that could affect hemodynamic parameters were excluded. Included studies were assessed for quality and risk of bias using the U.S. National Institute of Health's Quality Assessment Tools. ResultsThirteen studies met inclusion criteria. Five studies were categorized as high risk of bias, three were categorized as medium risk, and five were categorized as low risk. Study design varied considerably between studies, including heterogeneous classifications of OSA severity, discrepant reporting of echocardiographic parameters, and differing estimations of pulmonary hemodynamics. Significant disagreement regarding the effect of OSA on cardiac function was found between all included studies. ConclusionData demonstrating significant associations between OSA and cardiac abnormalities in children is inconsistent. Echocardiographic abnormalities are inconsistently found and, when present, their clinical significance remains poorly understood. Assessing the utility of preoperative echocardiography in children with OSA requires further investigation with prospective studies utilizing standardized classifications of OSA severity, reporting of echocardiographic parameters, and estimations of pulmonary hemodynamics.

Long-term safety of tiotropium/olodaterol in older patients with moderate-to-very-severe COPD in the TONADO\xae studies

Older patients with chronic obstructive pulmonary disease (COPD) may be at increased risk of adverse events (AEs) due to decreased protective organ function and increased comorbidities. TONADO® 1 + 2 were replicate, randomized, double-blind, parallel-group, 52-week, Phase III trials comparing the efficacy and safety of tiotropium/olodaterol (5/5 µg) versus the monocomponents via the Respimat® inhaler in patients with moderate-to-very-severe COPD. In this prespecified safety analysis, patients were grouped by age. Of 3100 patients, 1585 (51.1%) were aged <65 years, 1198 (38.7%) 65–<75 years, 309 (10.0%) 75–<85 years, and eight (0.3%) ≥85 years. At baseline, 23.4% had a pre-existing cardiac disorder, 45.6% had hypertension, and 13.3% had glucose metabolism disorders, including diagnosed diabetes. Overall, there was no increase in major adverse cardiac events, other AEs, or serious AEs with tiotropium/olodaterol versus the monocomponents in any age group, supporting the safety of tiotropium/olodaterol in older patients with COPD.

Evaluating the risk of hyperkalaemia and acute kidney injury with cotrimoxazole: a retrospective observational study

ObjectivesIncreasing antimicrobial resistance has renewed interest in older, less used antimicrobials. Cotrimoxazole shows promise; however, hyperkalaemia and acute kidney injury (AKI) are potential complications. Identifying risk factors for and quantification of these events is required for safe use. This study aimed to evaluate predictors of cotrimoxazole-associated AKI and hyperkalaemia in a clinical setting. MethodsPatients prescribed cotrimoxazole were identified using electronic healthcare records over 3 years (1 April 2016 to 31 March 2019). Individual risk factors were recognized. Serum creatinine and potassium trends were analysed over the subsequent 21 days. AKI and patients with hyperkalaemia were classified using Kidney Disease Improving Global Outcomes (KDIGO) and laboratory criteria. Univariate and multiple logistic regression analyses were performed. ResultsAmong 214 patients prescribed cotrimoxazole, 42 (19.6%, 95% confidence interval (CI) 14.6–25.7) met AKI criteria and 33 (15.4%, 95% CI 11.0–21.1) developed hyperkalaemia. Low baseline estimated glomerular filtration rate (<60 mL/min/1.73 m2, odds ratio (OR) 7.78, 95% CI 3.57–16.13, p < 0.0001) and cardiac disorders (OR 2.40, 95% CI 1.17–4.82, p 0.011) predicted AKI, while low baseline estimated glomerular filtration rate (<60 mL/min/1.73 m2, OR 6.80, 95% CI 3.09–15.06, p < 0.0001) and higher baseline serum potassium (p 0.001) predicted hyperkalaemia. Low-dose cotrimoxazole (<1920 mg/d) was associated with lower AKI and hyperkalaemia risk (p 0.007 and 0.019 respectively). Early (within the first 2–4 days of therapy) serum creatinine changes predicted AKI (OR 3.65, 95% CI 1.73–7.41, p 0.001), and early serum potassium changes predicted hyperkalaemia (>0.6 mmol/L, OR 2.47, 95% CI 1.14–5.27, p 0.0236). ConclusionsCotrimoxazole-associated AKI and hyperkalaemia is frequent and dose dependent. Renal function, serum potassium and preexisting cardiac disorders should be evaluated before prescribing cotrimoxazole. Serum creatinine and potassium monitoring within first 2 to 4 days of treatment to identify susceptible patients is recommended, and the lowest effective dose ought to be prescribed.

Predicting Cotrimoxazole-Associated Acute Kidney Injury and Hyperkalaemia

Background: Increasing antimicrobial resistance has renewed interest in older, infrequently used antimicrobials. Cotrimoxazole shows future promise; however, acute kidney injury (AKI) and hyperkalaemia are potential complications. Recognising risk factors for cotrimoxazole-associated AKI and hyperkalaemia, and quantifying the impact, are required for safe use against future antimicrobial resistance. Method: A single-centre retrospective observational study using electronic-healthcare records of patients prescribed cotrimoxazole was conducted. Patient risk factors were identified, and serum creatinine and potassium levels were analysed over the subsequent 21-days from prescription. Univariate and multiple logistic regression analyses were performed. The project was registered locally with the clinical governance team as service evaluation [Ref: CSS033]. Results: Of 214 patients, 42 (20%) developed AKI and 33 (15.4%) developed hyperkalaemia. Low baseline eGFR (&lt;60mls/min/1,73m2, OR = 7.78, 95%CI 3.57-16.13, p&lt;0.0001) and pre-existing cardiac disorders (OR = 2.40, 95%CI 1.17-4.82, p=0.011) significantly predicted AKI. Early serum creatinine increases within 2-4 days of therapy predicted future AKI (OR = 3.65, 95%CI 1.73-7.41, p = 0.001). A low baseline eGFR also significantly predicted future hyperkalaemia (&lt;60mls/min/1.73m2, OR = 6.80, 95%CI 3.09-15.06, p&lt;0.0001). Low-dose cotrimoxazole (&lt;1920mg/day) was associated with lower AKI and hyperkalaemia risk (p = 0.007 and 0.019, respectively). Conclusions: Cotrimoxazole-associated AKI and hyperkalaemia is frequent and dose-dependant. Renal function and pre-existing cardiac disorders should be carefully evaluated before prescribing cotrimoxazole. Serum creatinine should be monitored in the first 2-4 days of treatment to identify susceptible patients, and low-doses considered if AKI or hyperkalaemia is suspected.

Peritonitis Due to Rothia dentocariosa in Iran: A Case Report

Rothia dentocariosa (R. dentocariosa) is a gram-positive bacterium, which is a microorganism that normally resides in the mouth and respiratory tract. R. dentocariosa is known to involve in dental plaques and periodontal diseases. However, it is considered an organism with low pathogenicity and is associated with opportunistic infections. Originally thought not to be pathogenic in humans, R. dentocariosa was first described to cause infections in a 19-year-old female with periappendiceal abscess in 1975. The most prevalent human infections caused by R. dentocariosa include infective endocarditis, bacteremia, endophthalmitis, corneal ulcer, septic arthritis, pneumonia, and peritonitis associated with continuous ambulatory peritoneal dialysis. Three main factors have been reported to increase the risk of the cardiac and extra-cardiac infections caused by R. dentocariosa, including immunocompromised conditions, pre-existing cardiac disorders, and poor oral hygiene. Peritoneal dialysis (PD) may induce peritonitis presumably due to hematogenous spread from gingival or periodontal sources. This case study aimed to describe a former PD patient presenting with peritonitis. Oral hygiene is a basic principle in PD patients for the prevention of peritonitis. It is speculated that our patient might have had an occult oral source of R. dentocariosa.

T57. EFFECTS OF 0.5MS AND 1.5MS PULSE-WIDTHS ON CARDIOVASCULAR FUNCTION IN SCHIZOPHRENIA PATIENTS RECEIVING ELECTROCONVULSIVE THERAPY

BackgroundElectroconvulsive therapy (ECT) has been shown to have a profound effect on cardiovascular functions. The initial parasympathetic response, followed by the sympathetic surge and the second parasympathetic peak characterize a typical ECT session and in patients with pre-existing cardiac disorders, this ‘roller-coaster ride’ of autonomic discharges can drastically increase morbidity and mortality; albeit such incidences are rare nowadays with the advances in medical technology. While laterality and stimulus dose (in terms of millicoulombs, mC) are known to affect cardiovascular response, the effect of pulse-width (PW) on the latter has not been explored. Compared to 1.5-milisecond (ms) stimulus pulse trains, trains with 0.5ms PW last 3 times longer for equivalent stimulus charges, other parameters remaining constant. This would translate to greater initial parasympathetic response duration, and the implications of such occurrences for cardiovascular well-being are largely unknown.MethodsSeventy-one consenting adult (M=33, F=38; mean age 30.87 ± 9.59 years, mean duration of illness 89.68 ± 77.98 months) patients, with a diagnosis of Schizophrenia, were randomly assigned to receive bilateral ECT with either 0.5ms (n=35) or 1.5ms (n=36) PW stimulus; after obtaining institutional ethical-committee’s approval. Seizure threshold was determined during the first session. Rate-Pressure product (RPP; pulse*systolic blood-pressure) was calculated during the second ECT session, in which stimulus was administered at 1.5–2 times the threshold for the two groups, at 5 time points (RPP1-5, viz. pre-anaesthesia, during anaesthesia, during convulsive motor seizure, 1 and 2 minutes post seizure, respectively). They were compared between the groups using independent-sample t-test. At baseline, the patients were assessed on PANSS for psychopathology.ResultsTwo groups did not differ on socio-demographic and clinical characteristics at baseline. Mean administered dose of anaesthetic agent and muscle relaxant were comparable. While the mean seizure threshold and mean charge administered at 2nd ECT were significantly lower in the 0.5 ms group, they were otherwise comparable on mean duration of seizure (motor and EEG), and the RPPs at all 5 time-points. Both Max.RPP (18102.84 ± 4477.4 mmHg/min in 0.5ms, 17935.33 ± 3598.5 mmHg/min, p=0.864) and Max.RPP-RPP2 (5010.58 ± 2893.3 mmHg/min in 0.5ms, 5811.12 ± 4270.9 mmHg/min in 1.5ms, p=0.389) were comparable between the two groups.DiscussionThe characteristic sequence of cardiac events unfolding in an ECT session comprises of a temporary asystole during the administration of the stimulus, followed by an increase in blood pressure and pulse rate during clonic phase, and another slowing of heart rate at the end of motor seizure. The stimulus train duration in 0.5ms group lasts 3 times longer than in 1.5ms group for an equivalent amount of charge, thus increasing the asystole duration and theoretically altering subsequent autonomic responses. However, the groups failed to demonstrate any significant effects of these alterations in terms of altered cardiac activity implying that such alterations might not be clinically relevant. It is well known that briefer PWs cause lesser cognitive side-effects, are more efficient in eliciting seizures. present analysis shows that the two PWs of 0.5ms and 1.5ms might have similar effects on cardiovascular function, at least in otherwise-healthy adult schizophrenia patients, for similar anaesthetic agents, even if the train with 0.5ms PW lasts for double the time as with 1.5ms PW.

Inhibition of inwardly rectifying Kir2.x channels by the novel anti-cancer agent gambogic acid depends on both pore block and PIP2 interference.

The caged xanthone gambogic acid (GA) is a novel anti-cancer agent which exhibits anti-proliferative, anti-inflammatory and cytotoxic effects in many types of cancer tissues. In a recent phase IIa study, GA exhibits a favourable safety profile. However, limited data are available concerning its interaction with cardiac ion channels. Heteromeric assembly of Kir2.x channels underlies the cardiac inwardly rectifying IK1 current which is responsible for the stabilization of the diastolic resting membrane potential. Inhibition of the cardiac IK1 current may lead to ventricular arrhythmia due to delayed afterdepolarizations. Compared to Kv2.1, hERG and Kir1.1, a slow, delayed inhibition of Kir2.1 channels by GA in a mammalian cell line was reported before but no data exist in literature concerning action of GA on homomeric Kir2.2 and Kir2.3 and heteromeric Kir2.x channels. Therefore, the aim of this study was to provide comparative data on the effect of GA on homomeric and heteromeric Kir2.x channels. Homomeric and heteromeric Kir2.x channels were heterologously expressed in Xenopus oocytes, and the two-microelectrode voltage-clamp technique was used to record Kir2.x currents. To investigate the mechanism of the channel inhibition by GA, alanine-mutated Kir2.x channels with modifications in the channels pore region or at phosphatidylinositol 4,5-bisphosphate (PIP2)-binding sites were employed. GA caused a slow inhibition of homomeric and heteromeric Kir2.x channels at low micromolar concentrations (with IC50 Kir2.1/2.2<Kir2.2<Kir2.2/2.3<Kir2.3<Kir2.1<Kir2.1/2.3). The effect did not reach saturation within 60min and was not reversible upon washout for 30min. The inhibition showed no strong voltage dependence. We provide evidence for a combination of direct channel pore blockade and a PIP2-dependent mechanism as a molecular basis for the observed effect. We conclude that Kir2.x channel inhibition by GA may be relevant in patients with pre-existing cardiac disorders such as chronic heart failure or certain rhythm disorders and recommend a close cardiac monitoring for those patients when treated with GA.

Cardiovascular Safety of Droxidopa in Patients With Symptomatic Neurogenic Orthostatic Hypotension

The norepinephrine prodrug droxidopa improves symptoms of neurogenic orthostatic hypotension, a condition that is associated with diseases of neurogenic autonomic failure (e.g., Parkinson disease, multiple system atrophy, pure autonomic failure). These conditions are more prevalent in older patients who also have cardiovascular co-morbidities. Hence, we evaluated the cardiovascular safety of droxidopa in patients with symptomatic neurogenic orthostatic hypotension who participated in randomized controlled studies (short-term studies of 1 to 2weeks and an intermediate 8- to 10-week study) and long-term open-label studies. Rates of cardiovascular adverse events (AEs) for patients treated with droxidopa were 4.4% in the intermediate study and 10.8% in the long-term open-label studies. Adjusting for exposure time, cardiovascular AE rates were 0.30 events/patient-year in the short-term and intermediate studies and 0.15 events/patient-year in the long-term open-label studies. The incidence of treatment discontinuation due to blood pressure-related events was approximately 2.5%. Among patients with a history of cardiac disorders at baseline, the rates of cardiovascular-related and blood pressure-related AEs were nominally higher with droxidopa compared to placebo. Most of these events were minor atrial arrhythmias; none were major adverse cardiovascular events or deaths. In conclusion, small increases in cardiovascular AEs were observed with droxidopa compared to placebo; this was most evident in patients with preexisting cardiac disorders.

Cardiotoxicity associated with CTLA4 and PD1 blocking immunotherapy

Immune-checkpoint blocking antibodies have demonstrated objective antitumor responses in multiple tumor types including melanoma, non-small cell lung cancer (NSCLC), and renal cell cancer (RCC). In melanoma, an increase in overall...

Prevalence, characteristics and outcome of non-cardiac chest pain and elevated copeptin levels

ObjectiveCopeptin, a quantitative marker of endogenous stress, seems to provide incremental value in addition to cardiac troponin in the early rule-out of acute myocardial infarction (AMI). Prevalence, characteristics and outcome...

Republished: Pro-arrhythmic and pro-ischaemic effects of inhaled anticholinergic medications

The majority of deaths in COPD are from cardiovascular causes. Several large randomized controlled trials demonstrate that inhaled anticholinergic agents ipratropium and tiotropium increase the risk of serious cardiovascular events,...

926P - Safety of Abiraterone Acetate (AA) in Patients with Castration Resistant Prostate Cancer (CRPC) and Concomitant Cardiac Risk

ABSTRACT Introduction Abiraterone acetate (AA) is an inhibitor of extragonadal androgen biosynthesis that prolongs overall survival in CRPC patients who have received a chemotherapy including docetaxel. The most common adverse events related to AA therapy were fluid retention, hypertension, hypokaliemia and cardiac disorders. No safety data are available in patients with concomitant cardiac disease. Methods Metastatic CRPC patients were enrolled in this prospective study if they were also suffering from a concomitant controlled cardiovascular disease. AA 1000 mg per day and prednisone 5 mg bid were administered orally until grade 3-4 adverse events (AE) or disease progression. The primary endpoint was the safety profile while the secondary endpoints were progression-free survival and PSA response. Results From April to September 2011, 46 CRPC patients with concomitant cardiovascular disorders have been treated with AA. Main patients characteristics were: median age 71 years (range 57-81); baseline mean PSA value 40 ng/ml (6.32-995); the most common sites of disease were bone (33 pts, 81 %), lung (13 pts, 33%) and liver (6 pts, 15 %). All patients were previously challenged with at least 2 lines of hormone therapy and 1 chemotherapy regimen including docetaxel. The most common pre-existing cardiac disorders were hypertension 24 (66%), arrhythmias 4 (12 %), cardiac ischemia 4 (9 %) and conduction irregularity 2 (4 %). Additionally 10 patients (27 %) had metabolic disorders including dyslipidemia and hyperglycemia. AA was feasible without inducing grade 3-4 AE nor treatment modification. The most common grade 1-2 AE were asthenia (27%), hypertension (18%) and fluid retention (28%). After a median time of treatment of 10 months (range 4-12 months) no dose modifications due to toxicity were required. No efficacy data are still available. Conclusions Treatment with AA was feasible and well tolerated also in patients suffering from cardiac comorbidities and risk factors for cardiovascular disease. Disclosure All authors have declared no conflicts of interest.

Pro-arrhythmic and pro-ischaemic effects of inhaled anticholinergic medications

The majority of deaths in COPD are from cardiovascular causes. Several large randomized controlled trials demonstrate that inhaled anticholinergic agents ipratropium and tiotropium increase the risk of serious cardiovascular events,...

Next Generation Therapy in Chronic Myeloid Leukemia

TKIs Imatinib is an established first-line therapy CP of CML. Before Imatinib therapy, IFN-alpha was a treatment option for CML because it induced durable remissions in a subset of CP patients. However, because of IFN toxicity, and its limited and unpredictable efficacy, IFN-alpha was displaced by Imatinib, with its limited toxicity and marked efficacy in the treatment of most CML patients. Imatinib has limitations, but the 5-year survival rate with Imatinib is approx. 89% compared with Interferon and Cytarabin (70%). About 15–20% CML become resistant to Imatinib, and the resistance is found in association with a BCR/ABL mutation T315I or with G250E mutations. Treatment of Imatinib-resistance CML is thus a challenge in clinical hematology. In addition, clinical evaluation of Imatinib has shown adverse effects, such as fatigue, severe nausea, vomiting, oedema, fluid retention, muscle cramps, muscular skeletal pain, and cutaneous disorders. With the prolonged survival time in CML, which with Imatinib is a median 40 months, BCC, SCC, melanoma (30% cases), breast cancer (the authors have found 1 case), prostate cancer (1 case), GI cancer, GU bladder cancer including RCC, a few pancreatic and cholangiocarcinomas, and metastatic carcinoma of unknown origin have also been reported in various literature [1]. These investigators concluded that increased rates of cancers were found at a large range of sites and there was immune deficiency, regardless of the mechanism of deficiency. There have also been scattered reports of co-existence of CML with other lymphoid malignancies such as CLL and multiple myeloma [1, 2]. It has also been shown that heart failure occurs in 1 in 1,000 patients receiving Imatinib, and that it also alters bone metabolism. Imatinib costs more than the Interferon + Cytarabin combination. The effects of Imatinib (as well as other kinase inhibitors) on leukemic stem or initiating cells are limited, and so it has been advisable to take a low dose of Imatinib over a long period. Now, the second generation TKIs, such as Dasatinib and Nilotinib, have appeared. A unique spectrum of adverse events has occurred and been reported for both these TKIs [3, 4]. For Dasatinib-treated patients, the occurrence of pleural effusion has been a clinical challenge, especially when pleural effusion becomes recurrent or is accompanied by pericardial effusion, pulmonary hypertension, or an infection. Also, potential risk factors such as a pre-existing cardiac disease, arterial hypertension, or auto-immune disorders have been described for these TKIs. Several non-hematologic adverse events have been described for Dasatinib, including diarrhea, skin rash, bleeding, viral re-activation, and sometimes also many opportunistic infections, which have been reported in patients receiving Dasatinib at a dose of 270 mg daily. Nilotinib-treated patients have developed increases in pancreatic enzymes, bilirubin, and fasting glucose levels. Other non-hematologic adverse events of Nilotinib include diarrhea, folliculitis-like skin rash, and bleeding. There are a few reports of severe peripheral arterial occlusive disease (PAOD) and other vascular occlusive events (infarction) in patients receiving Nilotinib [3, 4]. Several of these patients developed a rapidly progressive and highly resistant form of PAOD after switching from Imatinib to Nilotinib [3, 4]. The question is whether patients, who had a complete molecular response (CMR or MCyR) to Imatinib or Imatinib in combination with Interferon, could safely stop drug treatment? What should be done with relapses? Do TKIs act then? SCT is still the treatment for CML that is considered to be curative in patients with AP or blast-crisis CML. Other choices which are still in clinical trial include a vaccine called CMLVAX100 which is given along with Imatinib to see if there is an increase in its effectiveness. Research into this and other cancer vaccines is continuing. The oral agent AP24534 also appears to have some activity independent of Bcr-Abl mutation. Cortes and colleagues [5] conducted a trial of AP24534 in patients with refractory CML and other hematologic malignancies. This agent inhibits survival of cell lines expressing Bcr-Abl variants at an inhibitory concentration of less than 40 nM. It also inhibits Flt-3 and c-Src. And this agent has the advantage of being orally administered.

Safety of abiraterone acetate (AA) in castration-resistant prostate cancer (CRPC) patients with concomitant cardiovascular disease.

168 Background: Abiraterone acetate (AA) is an inhibitor of extragonadal androgen biosynthesis that prolongs overall survival in CRPC patients who have received a chemotherapy including docetaxel. The most common adverse events related to AA therapy were fluid retention, hypertension, hypokaliemia and cardiac disorders. No safety data are available in patients with concomitant cardiac disease. Methods: Metastatic CRPC patients were enrolled in this prospective study if they were also suffering from a concomitant controlled cardiovascular disease. AA 1000 mg per day and prednisone 5 mg bid were administered orally until grade 3-4 adverse events (AE) or disease progression. The primary endpoint was the safety profile while the secondary endpoints were progression-free survival and PSA response. Results: From April to September 2011, 33 CRPC patients with concomitant cardiovascular disorders have been treated with AA. Main patients characteristics were: median age 71 years (range 57–81); baseline mean PSA value 40 ng/ml (6.32-995); the most common sites of disease were bone (27 pts, 81%), lung (11 pts, 33%) and liver (5 pts, 15%). All patients were previously challenged with at least 2 lines of hormone therapy and 1 chemotherapy regimen including docetaxel. The most common pre-existing cardiac disorders were hypertension 22 (66%), arrhythmias 4 (12%), cardiac ischemia 3 (9%) and conduction irregularity 2 (4%). Additionally 9 patients (27%) had metabolic disorders including dislipidemy and hyperglicemia. AA was feasible without inducing grade 3-4 AE nor treatment modification. The most common grade 1-2 AE were asthenia (27%), hypertension (18%) and fluid retention (28%). After a median time of treatment of 4 months (range 2–7 months) no dose modifications due to toxicity were required. No efficacy data are still available. Conclusions: Treatment with AA was feasible and well tolerated also in patients suffering from cardiac comorbidities and risk factors for cardiovascular disease.