C.J. Plummer

Expert opinion on the use of anthracyclines in patients with advanced breast cancer at cardiac risk

Anthracyclines are considered to be among the most active agents for the treatment of breast cancer. However, their use is limited by cumulative, dose-related cardiotoxicity. Such cardiotoxicity results in a permanent loss of cardiac myocytes and a progressive reduction in cardiac function following each subsequent dose of anthracycline. Initially, damage to the heart is subclinical; however, increasingly impaired cardiac function can result in cardiovascular symptoms, with serious cardiac injury resulting in chronic heart failure. Since the early detection and treatment of cardiotoxicity can reduce its clinical effects, it is important that oncologists are aware of these adverse effects and manage them appropriately. This review examines the risk factors for anthracycline-associated cardiotoxicity and offers recommendations on strategies to reduce the cardiotoxicity of anthracyclines in the management of patients with advanced breast cancer.

Individual patient data network meta-analysis of mortality effects of implantable cardiac devices

Objective Implantable cardioverter defibrillators (ICD), cardiac resynchronisation therapy pacemakers (CRT-P) and the combination therapy (CRT-D) have been shown to reduce all-cause mortality compared with medical therapy alone in patients with heart failure and reduced EF. Our aim was to synthesise data from major randomised controlled trials to estimate the comparative mortality effects of these devices and how these vary according to patients’ characteristics. Methods Data from 13 randomised trials (12 638 patients) were provided by medical technology companies. Individual patient data were synthesised using network meta-analysis. Results Unadjusted analyses found CRT-D to be the most effective treatment (reduction in rate of death vs medical therapy: 42% (95% credible interval: 32–50%), followed by ICD (29% (20–37%)) and CRT-P (28% (15–40%)). CRT-D reduced mortality compared with CRT-P (19% (1–33%)) and ICD (18% (7–28%)). QRS duration, left bundle branch block (LBBB) morphology, age and gender were included as predictors of benefit in the final adjusted model. In this model, CRT-D reduced mortality in all subgroups (range: 53% (34–66%) to 28% (−1% to 49%)). Patients with QRS duration ≥150 ms, LBBB morphology and female gender benefited more from CRT-P and CRT-D. Men and those <60 years benefited more from ICD. Conclusions These data provide estimates for the mortality benefits of device therapy conditional upon multiple patient characteristics. They can be used to estimate an individual patients expected relative benefit and thus inform shared decision making. Clinical guidelines should discuss age and gender as predictors of device benefits.

Bevacizumab with peri-operative epirubicin, cisplatin and capecitabine (ECX) in localised gastro-oesophageal adenocarcinoma: a safety report

BACKGROUND Peri-operative chemotherapy and surgery is a standard treatment of localised oesophagogastric adenocarcinoma; however, the outcomes remain poor. PATIENTS AND METHODS ST03 is a multicentre, randomised, phase II/III study comparing peri-operative ECX with or without bevacizumab (ECX-B). The primary outcome measure of phase II (n = 200) was safety, specifically gastrointestinal (GI) perforation rates and cardiotoxicity. RESULTS Two hundred patients were randomised between October 2007 and April 2010. Ninety-one/101 (90%) ECX and 86/99 (87%) ECX-B patients completed pre-operative chemotherapy; 7 ECX and 9 ECX-B patients stopped due to toxicity. Gastrointestinal perforations (3 ECX, 1 ECX-B), cardiac events (1 ECX, 4 ECX-B) and venous thromboembolic events (VTEs, 8 ECX, 7 ECX-B) were uncommon. Arterial thromboembolic events (ATEs, myocardial infarction (MI) or cerebrovascular accident) were more frequent with ECX-B (5 versus 1 with ECX). Delayed wound healing, anastomotic leaks and GI bleeding rates were similar. More asymptomatic left ventricular ejection fraction (LVEF) falls (≥15% and/or to <50%) occurred with ECX-B (21.2% versus 11.1% with ECX). Clinically significant falls (≥10% to below lower limit of normal, LLN) occurred in (15.3%) and (8.9%) respectively, with no associated cardiac failure (median 22 months follow-up). CONCLUSIONS Addition of bevacizumab to peri-operative ECX chemotherapy is feasible with acceptable toxicity and no negative impact on surgical outcomes.

Inequity of access to implantable cardioverter defibrillator therapy in England: possible causes of geographical variation in implantation rates

AIMS There is marked geographical variation in implantable cardioverter defibrillator (ICD) implantation rates in England. This study examined factors which might explain this variation. METHODS AND RESULTS Detailed data relating to 1510 patients who received an implanted defibrillator and who were reported to a national pacemaker and implantable defibrillator registry in 2002 were examined and correlated with factors which have been suggested as affecting ICD implantation. None of the factors examined, which included factors related both to the need for ICD implantation and service provision, in addition to socio-economic deprivation, was found to correlate with regional ICD implantation rates. CONCLUSION There appears to have been no systematic planning of ICD services. Whether this has led to the marked regional variation and in inequity of service provision is not clear.

Comparison of Sprint Fidelis and Riata defibrillator lead failure rates

BACKGROUND/OBJECTIVES Sprint Fidelis and Riata defibrillator leads are prone to early failure. Few data exist on the comparative failure rates and mortality related to lead failure. The aims of this study were to determine the failure rate of Sprint Fidelis and Riata leads, and to compare failure rates and mortality rates in both groups. METHODS Patients implanted with Sprint Fidelis leads and Riata leads at a single centre were identified and in July 2012, records were reviewed to ascertain lead failures, deaths, and relationship to device/lead problems. RESULTS 113 patients had Sprint Fidelis leads implanted between June 2005 and September 2007; Riata leads were implanted in 106 patients between January 2003 and February 2008. During 53.0 ± 22.3 months of follow-up there were 13 Sprint Fidelis lead failures (11.5%, 2.60% per year) and 25 deaths. Mean time to failure was 45.1 ± 15.5 months. In the Riata lead cohort there were 32 deaths, and 13 lead failures (11.3%, 2.71% per year) over 54.8 ± 26.3 months follow-up with a mean time to failure of 53.5 ± 24.5 months. There were no significant differences in the lead failure-free Kaplan-Meier survival curve (p=0.77), deaths overall (p=0.17), or deaths categorised as sudden/cause unknown (p=0.54). CONCLUSIONS Sprint Fidelis and Riata leads have a significant but comparable failure rate at 2.60% per year and 2.71% per year of follow-up respectively. The number of deaths in both groups is similar and no deaths have been identified as being related to lead failure in either cohort.

Safe use of MRI in people with cardiac implantable electronic devices

MR scanning in patients with cardiac implantable electronic devices (CIEDs) was formerly felt to be contraindicated, but an increasing number of patients have an implanted MR conditional device, allowing them to safely undergo MR scanning, provided the manufacturers guidance is adhered to. In addition, some patients with non-MR conditional devices may undergo MR scanning if no other imaging modality is deemed suitable and there is a clear clinical indication for scanning which outweighs the potential risk. The following guidance has been formulated by the British Heart Rhythm Society and endorsed by the British Cardiovascular Society and others. It describes protocols that should be followed for patients with CIEDs undergoing MR scanning. The recommendations, principles and conclusions are supported by the Royal College of Radiologists.

CRT Survey II: a European Society of Cardiology survey of cardiac resynchronisation therapy in 11 088 patients-who is doing what to whom and how?

Cardiac resynchronisation therapy (CRT) reduces morbidity and mortality in appropriately selected patients with heart failure and is strongly recommended for such patients by guidelines. A European Society of Cardiology (ESC) CRT survey conducted in 2008–2009 showed considerable variation in guideline adherence and large individual, national and regional differences in patient selection, implantation practice and follow‐up. Accordingly, two ESC associations, the European Heart Rhythm Association and the Heart Failure Association, designed a second prospective survey to describe contemporary clinical practice regarding CRT.

Implications of National Guidance for Implantable Cardioverter Defibrillation Implantation in the United Kingdom

PLUMMER, C.J., et al.: Implications of National Guidance for Implantable Cardioverter Defibrillation Implantation in the United Kingdom. To determine the number of patients fulfilling recently issued national guidelines on the use of ICDs in patients with arrhythmias, the authors undertook two observational audits of clinical records. The first audit included patients investigated and treated at a tertiary referral cardiothoracic center during a 1‐month period, and the second included patients admitted to the three coronary care units serving a circumscribed district population during a second month. Patient records were audited against the recommendations for ICD implantation made by the National Institute for Clinical Excellence to determine if the patient fulfilled the criteria for ICD implantation. The audit was repeated with the same patient records against the MADIT 2 selection criteria. The audit identified underprovision of ICD therapy in the United Kingdom for a variety of reasons. It also demonstrated that the number of patients fulfilling selection criteria defined by the national guidelines for ICD implantation is far in excess of the numbers predicted. The annual incidence of patients fulfilling national criteria is about 150/million, with an additional “prevalence” of at least 41/million. Applying the less restrictive MADIT II criteria to select patients for ICDs as a primary prevention increased the numbers to 504/million (“new incidence”) and 311/million (“prevalence”) per year, in excess of the predictions by a factor of between 10 and 25. (PACE 2003; 26[Pt. II]:479–482)

Cost-effectiveness of implantable cardiac devices in patients with systolic heart failure

Objective To evaluate the cost-effectiveness of implantable cardioverter defibrillators (ICDs), cardiac resynchronisation therapy pacemakers (CRT-Ps) and combination therapy (CRT-D) in patients with heart failure with reduced ejection fraction based on a range of clinical characteristics. Methods Individual patient data from 13 randomised trials were used to inform a decision analytical model. A series of regression equations were used to predict baseline all-cause mortality, hospitalisation rates and health-related quality of life and device-related treatment effects. Clinical variables used in these equations were age, QRS duration, New York Heart Association (NYHA) class, ischaemic aetiology and left bundle branch block (LBBB). A UK National Health Service perspective and a lifetime time horizon were used. Benefits were expressed as quality-adjusted life-years (QALYs). Results were reported for 24 subgroups based on LBBB status, QRS duration and NYHA class. Results At a threshold of £30 000 per QALY gained, CRT-D was cost-effective in 10 of the 24 subgroups including all LBBB morphology patients with NYHA I/II/III. ICD is cost-effective for all non-NYHA IV patients with QRS duration <120 ms and for NYHA I/II non-LBBB morphology patients with QRS duration between 120 ms and 149 ms. CRT-P was also cost-effective in all NYHA III/IV patients with QRS duration >120 ms. Device therapy is cost-effective in most patient groups with LBBB at a threshold of £20 000 per QALY gained. Results were robust to altering key model parameters. Conclusions At a threshold of £30 000 per QALY gained, CRT-D is cost-effective in a far wider group than previously recommended in the UK. In some subgroups ICD and CRT-P remain the cost-effective choice.

Time to manual activation of implantable loop recorders—implications for programming recording period: a 10-year single-centre experience

AIM A new generation of commercially available implantable loop recorders (ILRs) has improved arrhythmia detection algorithms but reduced manually activated ECG storage duration. We investigated the effect that this would have had on symptom-arrhythmia correlation in a retrospective patient cohort. METHOD AND RESULTS Retrospective review of all patients receiving a Medtronic Reveal 9525/9526 for the investigation of unexplained syncope or pre-syncope in our centre between 1998 and 2008. All ILRs were programmed for a single manual activation with 40 min retrospective ECG recording. We identified all patients who subsequently underwent permanent pacemaker implantation and analysed the time delay between bradycardia onset and manual ILR activation. Five hundred and sixty-four patients underwent implantation of an ILR during the study period. Of these, 57 (10%) subsequently underwent the implantation of a pacemaker (31 male, median age 66 years, range 9-86 years). In this group, 35 of 57 (61%) bradycardia diagnoses were made in patients (18 male, median age 65 years, range 9-86 years) after manual activation of the ILR. The median time from bradycardia onset to ILR activation was 136 s (0-488 s). Nineteen recordings showed high-grade atrio-ventricular block and 16 sinus node disease. CONCLUSION Ten-year experience with the ILR confirms its utility in establishing a pacemaker indication as the cause for syncope or pre-syncope in 6% (34 of 564) of recipients following manual activation. This requires a recording loop of sufficient duration to reliably include both symptoms and activation.