Merete Vaage-Nilsen

Cardiotoxicity in cancer patients treated with 5-fluorouracil or capecitabine: A systematic review of incidence, manifestations and predisposing factors

PURPOSE To systematically review the incidence, manifestations and predisposing factors for cardiovascular toxicity in cancer patients treated with systemic 5-fluorouracil or capecitabine. DESIGN We searched PubMed, EMBASE and Web of science for studies with ≥ 20 cancer patients evaluating cardiovascular toxicity of 5-fluorouracil and capecitabine. We hand searched the reference lists of all included studies. Study selection and assessment of risk of bias were performed by two authors independently. RESULTS We identified 30 eligible studies (1 meta-analyses of 4 RCTs, 18 prospective and 11 retrospective). Symptomatic cardiotoxicity occurred in 0-20% of the patients treated with 5-fluorouracil and in 3-35% with capecitabine. The most common symptom was chest pain (0-18.6%) followed by palpitations (0-23.1%), dyspnoea (0-7.6%) and hypotension (0-6%). Severe clinical events such as myocardial infarction, cardiogenic shock and cardiac arrest occurred in 0-2%. Mortality rates ranged from 0 to 8%. Asymptomatic cardiac influence was demonstrated on ECG, in NT-proBNP measurements and with ultrasonic cyclic variation of integrated backscatter. Predisposing factors were mostly tested in univariate analyses. Preexisting cardiac disease was a risk factor in some studies, but there were divergent results. There was some evidence for increased cardiotoxicity during continuous infusion schedules and with concomitant cisplatin treatment. The effects of previous or current chest-radiotherapy were ambiguous. CONCLUSION Larger studies suggest an incidence of symptomatic cardiotoxicity of 1.2-4.3% during fluorouracil treatment, however subclinical cardiac influence are common. Possible risk factors are cardiac co-morbidity, continuous infusion schedules and concomitant cisplatin treatment, but existing evidence are of insufficient quality.

A systematic review of the pathophysiology of 5-fluorouracil-induced cardiotoxicity.

BackgroundCardiotoxicity is a serious side effect to treatment with 5-fluorouracil (5-FU), but the underlying mechanisms are not fully understood. The objective of this systematic review was to evaluate the pathophysiology of 5-FU- induced cardiotoxicity.MethodsWe systematically searched PubMed for articles in English using the search terms: 5-FU OR 5-fluorouracil OR capecitabine AND cardiotoxicity. Papers evaluating the pathophysiology of this cardiotoxicity were included.ResultsWe identified 27 articles of 26 studies concerning the pathophysiology of 5-FU-induced cardiotoxicity. The studies demonstrated 5-FU-induced: hemorrhagic infarction, interstitial fibrosis and inflammatory reaction in the myocardium; damage of the arterial endothelium followed by platelet aggregation; increased myocardial energy metabolism and depletion of high energy phosphate compounds; increased superoxide anion levels and a reduced antioxidant capacity; vasoconstriction of arteries; changes in red blood cell (RBC) structure, function and metabolism; alterations in plasma levels of substances involved in coagulation and fibrinolysis and increased endothelin-1 levels and N-terminal-pro brain natriuretic peptide levels. Based on these findings the proposed mechanisms are: endothelial injury followed by thrombosis, increased metabolism leading to energy depletion and ischemia, oxidative stress causing cellular damage, coronary artery spasm leading to myocardial ischemia and diminished ability of RBCs to transfer oxygen resulting in myocardial ischemia.ConclusionsThere is no evidence for a single mechanism responsible for 5-FU-induced cardiotoxicity, and the underlying mechanisms might be multifactorial. Further research is needed to elucidate the pathogenesis of this side effect.

ST-segment deviation during 24-hour ambulatory electrocardiographic monitoring and exercise stress test in healthy male subjects 51 to 75 years of age: the Copenhagen City Heart Study.

BACKGROUND Although ST-segment deviation has been evaluated and used during many years both on continuous electrocardiographic Holter monitoring and during exercise stress testing, considerable controversy still remains concerning the prevalence and diagnostic significance of fortuitously discovered ST-segment deviation in asymptomatic healthy persons. METHODS AND RESULTS The occurrence of ST-segment deviation was studied in a population of 63 clinically healthy male subjects 51 to 75 years of age, with the use of 24-hour Holter monitoring and exercise stress testing. The subjects were recruited from the Copenhagen City Heart Study and were without cardiovascular risk factors, chronic diseases, or medication and without cardiovascular events during 5 to 12 years before and 3 to 5 years after admission. The specificity, that is, the probability of displaying a negative test result in healthy subjects without disease, was 1.0 when using as criterion for significant ST-segment deviation a horizontal or descending ST-segment depression of >0.20 mV or ST-segment elevation >/=0.15 mV during Holter monitoring, and acceptable, for example, 0.95, when using as criterion a horizontal or descending ST-segment depression of >/=0.15 mV during Holter monitoring or at the exercise test, respectively. Furthermore, the specificity was 0.95 when a horizontal or downsloping ST-segment depression of 0.1 mV was displayed in both the Holter and exercise electrocardiographic recording system. CONCLUSIONS Thus in asymptomatic persons, the usual criterion for significant ST-segment depression of 0.1 mV can be applied when occurring in both electrocardiographic recording systems. However, if one test alone is used, the criterion of significant ST-segment depression should be 0.15 mV. Absence of ST-segment deviation during Holter monitoring and exercise stress testing, indicated with a specificity of 1.0 or 0.95 according to choice of criterion, implies that the person is in a healthy state.

Incidence and risk factors for capecitabine-induced symptomatic cardiotoxicity: a retrospective study of 452 consecutive patients with metastatic breast cancer

Objectives Case reports of capecitabine cardiotoxicity resemble those seen with intravenous 5-fluorouracil (5-FU) with chest pain as the predominant manifestation, but few studies of capecitabine cardiotoxicity are available. We aimed to determine the incidence of symptomatic cardiotoxicity from capecitabine in patients with breast cancer and to identify risk factors. Methods We reviewed medical records of consecutive women with breast cancer treated with capecitabine (1000 mg/m2 two times per day) from 2002 to 2012 at one institution. Results 22 of 452 patients (4.9%) (95% CI 2.9% to 6.9%) had symptoms of cardiotoxicity (chest pain: n=13, dyspnoea: n=9, palpitations: n=2). 11 patients had changes on ECG (atrial fibrillation: n=5, ST deviations: n=3, T-wave abnormalities: n=2 and QTc prolongation: n=1). 2 patients (0.4%) sustained acute myocardial infarction. 1 patient (0.2%) developed cardiac arrest with lethal outcome. 4 of 6 patients (66%) retreated with capecitabine had recurrent symptoms at retreatment. Cardiac comorbidity (p=0.001), hypercholesterolaemia (p=0.005) and current smoking (p=0.023) were risk factors for cardiotoxicity in univariate analyses and remained significant when adjusted for age. Patients with cardiac comorbidity were 5.5 times (95% CI 2.0 to 14.8) more likely to develop cardiotoxicity. In the subgroup of patients with apparently no cardiac comorbidity, the incidence of cardiotoxicity was lower (3.7%) and hypercholesterolaemia (p=0.035) and current smoking (p=0.020) were risk factors of cardiotoxicity. Conclusions The incidence of cardiotoxicity from capecitabine resembles that of intravenous 5-FU (≈5%). Cardiac comorbidity, hypercholesterolaemia and current smoking were associated with development of cardiotoxicity.

Recovery of autonomic nervous activity after myocardial infarction demonstrated by short-term measurements of SDNN

Objective - Heart rate variability (HRV) has been demonstrated to be a risk factor after acute myocardial infarction (AMI). In the present study serial measurement of SDNN (standard deviation of the mean of qualified NN-interval) in short intervals was used to assess HRV changes after AMI, and determine the role of these as independent risk factors compared to clinical, arrhythmic, ischemic and anamnestic variables. Measurements from a normal healthy middle-aged male population were used as reference (n = 63). Methods - SDNN from a five-minute period during day and night-time, respectively, was examined in 103 patients 1 week (n = 54), 1 month (n = 72) and 12-16 months (n = 54) after infarction. Results - Day SDNN did not change during one-and-a-half years after AMI, and was significantly reduced compared with healthy males. Night SDNN, low after 1 week, with recovery 1 month after AMI, was significantly reduced compared with healthy males early, but not late after AMI. Thus, the study indicated during day-time a continuous abnormal sympathetic preponderance in the course of 16 months after AMI, and during night-time a gradual recovery of parasympathetic preponderance beginning early after AMI. Conclusion

Effect of verapamil on arrhythmias and heart rate during 16 months following an acute myocardial infarction

SummaryThe present study was a prospectively planned subset of the postinfarction, double blind, randomized, multicenter, placebo controlled trial of verapamil, DAVIT II. Patients had 24 hours of Holter monitoring before randomization, i.e., second week after infarction (placebo, n=122; verapamil, n=128), after 1 month (placebo, n=108; verapamil, n=94) and after 16 months (placebo, n=75; verapamil, n = 63) of treatment. The purpose was to evaluate the effect of verapamil on the prevalence and changes over time of arrhythmias and heart rate. In patients monitored twice, a significant increase of average ventricular premature complexes (VPC) per hour from before to 1 month (p=0.0007) and 16 months (p=0.02) after was demonstrated in the placebo group, and from before to 1 months (p=0.01) after in the verapamil group. Average VPC/hr did not change from 1 to 16 months of treatment. A significant increment of >10 VPC/hr was found after 1 (p=0.03) and 16 months (p=0.05) compared to prerandomization in the placebo, but not in the verapamil group. A significant increase of supraventricular arrhythmias after 1 month compared with prerandomization was found in the placebo group (p=0.003) but not in the verapamil group. The prevalence of VPC and supraventricular tachycardia was significantly lower in the verapamil compared with the placebo group after 1 month of treatment. At 16 months no significant difference was found between the two groups. The 24 hour mean heart rate was significantly lower, 3 beats/min, in the verapamil compared with placebo after 1 and 16 months of treatment. Thus a significant increase of ventricular and supraventricular arrhythmias during the first postinfarction month, without change the following year, was seen in the placebo group. Verapamil significantly lowered heart rate, prevented supraventricular tachycardia, and reduced VPC early after an AMI. This rather limited effect of verapamil on postinfarction arrhythmias cannot explain the beneficial effect of verapamil on mortality and major events in patients without heart failure.

Short- and Long-Term Prognostic Implications of In-Hospital Postinfarction Arrhythmias

The purpose of the present study was to evaluate, in patients surviving the first postinfarction week, the short- and long-term prognostic implications of arrhythmias, and their relation to easily obt

Effect of verapamil on the prognosis of patients with early postinfarction electrical or mechanical complications

The Danish Verapamil Infarction Trial II (DAVIT II) demonstrated from the second postinfarction week, that long term treatment with verapamil significantly improved reinfarction free survival after an acute myocardial infarction (AMI). The present post hoc analysis of DAVIT II was undertaken with the purpose of evaluating the effect of treatment with verapamil in patients with early electrical complications, i.e. ventricular or atrial fibrillation, ventricular tachycardia, or second or third degree atrioventricular block, with or without mechanical complication, i.e. heart failure, during the first post-AMI week. In the placebo group, the 18-month mortality rate was lowest (9.5%) in patients without electrical or mechanical complications, highest (24.6%) in patients with electrical events only, and in-between (17.5%) in patients with mechanical problems regardless of presence of electrical complications. Verapamil significantly reduced the 18-month mortality rate in patients with early electrical without mechanical complications (60% reduction, P = 0.02), and in patients without mechanical complications (35% reduction, P = 0.02). Verapamil did not change the mortality rate in patients with mechanical complications.