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 patient's expected relative benefit and thus inform shared decision making. Clinical guidelines should discuss age and gender as predictors of device benefits.

Delays and adverse clinical outcomes associated with unrecognized pacing indications.

BACKGROUND: A recent UK audit showed that a significant proportion of patients who received pacemakers had pacing indications previously overlooked, leading to significant delays to pacemaker implantation. AIM: To investigate the reasons for, and morbidity associated with, overlooked pacing indications. DESIGN: Prospective observational study in a UK regional pacing centre and its referring district hospitals. METHODS: Hospital records from referring and implanting centres were reviewed for 95 consecutive patients undergoing first pacemaker implant to determine symptoms, investigations and hospitalisations occurring after documentation of a pacing indication. RESULTS: Thirty-three of ninety-five patients (35%) had a pacing indication overlooked, which was Class I in 14 patients and Class IIa in 19. Reasons for not making a pacing referral in these patients included: failure to recognize the indication in 14, making adjustments to potentially culprit medication in 15 and requesting additional 'confirmatory' tests in 4. Twenty-six patients (79%) with missed indications experienced adverse events after documentation of an indication, and before receiving a pacemaker: 23 had ongoing symptoms (including one cardiac arrest), three received temporary pacing wires and 18 were hospitalized with symptoms related to cardiac rhythm. Twenty-seven patients (82%) had a total of 38 additional specialist investigations after documentation of a pacing indication. CONCLUSION: Documentation of an indication for pacing failed to trigger referral for permanent pacing in 35% of patients. This failure led to significant delays, morbidity and use of health service resource, which may have been avoided if timely recognition of the pacing indication had prompted referral. Failure to recognize pacing indications and reassessing symptoms and repeating investigation after changes to medication, often required for the management of associated tachyarrhythmias or other medical conditions, contribute to these delays, perhaps unnecessarily.

Management of cardiac health in trastuzumab-treated patients with breast cancer: updated United Kingdom National Cancer Research Institute recommendations for monitoring.

More women are living with and surviving breast cancer, because of improvements in breast cancer care. Trastuzumab (Herceptin) has significantly improved outcomes for women with HER2-positive tumours. Concerns about the cardiac effects of trastuzumab (which fundamentally differ from the permanent myocyte loss associated with anthracyclines) led to the development of cardiac guidelines for adjuvant trials, which are used to monitor patient safety in clinical practice. Clinical experience has shown that the trial protocols are not truly applicable to the breast cancer population as a whole, and exclude some women from receiving trastuzumab, even though they might benefit from treatment without long-term adverse cardiac sequelae. Consequently, five oncologists who recruited patients to trastuzumab trials, some cardiologists with whom they work, and a cardiovascular lead general practitioner reviewed the current cardiac guidelines in the light of recent safety data and their experience with adjuvant trastuzumab. The group devised recommendations that promote proactive pharmacological management of cardiac function in trastuzumab-treated patients, and that apply to all patients who are likely to receive standard cytotoxic chemotherapy. Key recommendations include: a monitoring schedule that assesses baseline and on-treatment cardiac function and potentially reduces the overall number of assessments required; intervention strategies with cardiovascular medication to improve cardiac status before, during, and after treatment; simplified rules for starting, interrupting and discontinuing trastuzumab; and a multidisciplinary approach to breast cancer care.

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.

The patient journey from symptom onset to pacemaker implantation.

BACKGROUND: Regional variation in permanent pacemaker (PPM) implantation rates is well described, the reasons for which are unclear. Significant delays to PPM implantation in UK practice were described 20 years ago, but contemporary data are lacking. AIM: To investigate delays to PPM implantation and their causes. DESIGN: Prospective observational study in a UK regional pacing centre and its referring district hospitals. METHODS: A total of 95 consecutive patients receiving first PPM implant for bradycardia indications from 1 June 2006 to 31 August 2006 were included. Hospital records from the referring and implanting centres were reviewed to determine the timings of: symptom onset; first hospital contact; documented pacing indication (defined by 2002 ACC/AHA/NASPE guidelines); referral to implanter; and PPM implantation. RESULTS: Forty-eight patients (51%) were referred for pacing urgently; median delay from symptoms to PPM 15 days (range 0-7332 days). Forty-seven patients (49%) were referred electively; median delay from symptoms to PPM 380 days (range 33-7505 days), P < 0.0001. Twenty-three of the 47 elective patients (49%) had previous hospitalization with symptoms suggestive of bradycardia. Thirty-three of the 95 patients (35%) had a Class I or IIa pacing indication which did not trigger a pacing referral. CONCLUSION: There are significant delays to PPM implantation in the United Kingdom, longer in those treated electively than those managed as emergencies. Some delays are due to 'process' problems including waiting lists, but a substantial proportion of patients had delays due to failure to refer for pacing once a pacing indication was documented.

The implantable cardioverter-defibrillator: postcode prescribing in the UK 1998-2002.

OBJECTIVE: To determine the rate of implantable cardioverter-defibrillator (ICD) implantation across the UK during the period 1998 to 2002. DESIGN: Observational self reporting with cross checking. SETTING: All ICD implanting centres coordinated by the National Pacemaker and ICD Database. PATIENTS: Every patient receiving an ICD in the UK from 1998 to 2002. MAIN OUTCOME MEASURES: Date of implantation and postcode of each ICD recipient during the study period. RESULTS: ICD implantation increased in the UK in the five year period studied but fell far short of the European average and national targets. Implantation rates varied greatly by region. CONCLUSIONS: The low rate of ICD implantation in the UK and the disparity between regions require further study to determine the barriers to this evidence based treatment.

Detection of atrial fibrillation by permanent pacemakers: observations from the STOP AF trial.

Pacemaker telemetry is increasingly being used to infer the presence or absence of arrhythmias in clinical practice. To evaluate the reliability of these data in patients with sick-sinus syndrome, a sub-study of eighteen consecutive patients in the Systematic Trial of Pacing to prevent Atrial Fibrillation (STOP AF) implanted with dual-chamber pacemakers had simultaneous 24-hour Holter recordings and pacemaker telemetry down-loaded. Whilst heart rate data were very similar, telemetry data achieved only 57% sensitivity with 64% specificity for the presence of atrial fibrillation on Holter recording over 24 hours. False-positive results were due to far-field sensing while false-negatives were seen with very short episodes of atrial fibrillation. The pacemaker's anti-tachycardia responses were not specific for the detection of atrial fibrillation. There are very few published reports correlating pacemaker diagnostic data and stored electrograms with external Holter monitoring. We believe that more validation studies of are needed before pacemaker diagnostic data can be used with confidence in clinical practice. It is unlikely that current devices with sophisticated detection algorithms will fail to detect prolonged episodes of arrhythmia and their capacity to confirm events with stored electrograms, intervals and markers reduces the possibility of false-positives, but care must be taken in the interpretation of stored data from devices without these capabilities. Equally, it cannot be assumed that if intracardiac electrograms from one episode confirm the presence of an arrhythmia, that all recorded events have been similarly correctly interpreted. We have shown in a sub-study of STOP-AF that simple mathematical models using heart rate bin analysis are not reliable for detection of arrhythmias with short durations. Despite these limitations, the potential of implanted pacemakers to record cardiac rhythm and trends, such as heart-rate variability, over time remains an exciting prospect, particularly in guiding individual patient therapy.

The use of permanent pacemakers in the detection of cardiac arrhythmias.

AIMS: To compare pacemaker telemetry with simultaneous Holter recordings in the diagnosis of atrial fibrillation and to evaluate the STOP-AF study telemetry criteria for the presence of atrial fibrillation. METHODS AND RESULTS: 18 consecutive patients enrolled in the STOP-AF study had simultaneous 24 h Holter recordings and down-loaded pacemaker telemetry. There was good agreement on heart rate, but the STOP-AF pacemaker criteria achieved only 57% sensitivity with 64% specificity for the presence of atrial fibrillation on Holter recording over 24 h. False-positives appeared to result from far-field sensing while false-negatives occurred with very short episodes of atrial fibrillation. The pacemaker's antitachycardia responses were not specific for the presence of atrial fibrillation. CONCLUSION: Pacemaker telemetry is a potentially important source of data on cardiac arrhythmias. Further studies are required to define the limitations of these data in specific devices before they can be interpreted with confidence.

A continuous patient activity monitor: validation and relation to disability.

The measurement of patient activity over prolonged periods has been attempted with accelerometer-based devices, but these summate total acceleration and deceleration over time periods, are difficult to relate to recognizable activities and are influenced by passive movement. We describe the development of a portable monitor of ambulation. This logs posture (sitting, standing and lying) and number and vigour of steps in real time over prolonged periods, usually 24 h. This is based on a system of position sensors and an accelerometer which is sampled when the subject is standing. Data are processed through an interface and stored on a Psion Series 3 'palm top' computer. The system has been validated against observation, and the relationship of activity to disability in rheumatoid arthritis explored.

Effects of processing conditions and in vitro ageing on the physical properties of Biomer.

Biomer is generally processed by repeated deposition of layers by solution casting onto a preshaped former. The precise nature of this processing route may influence the mechanical response and surface properties of the finished article and, as a result, its subsequent in vivo behaviour. Here we have studied the influence of a range of processing parameter: the type of former, the initial concentration of the solution from which the layers are cast and the time interval between casting of successive layers. The subsequent variation of physico-chemical properties on vitro ageing in isotonic saline solution has also been considered and, in particular, the possibility of cross-linking during long-term exposure.

Changing the light intensity of the visual environment results in large differences in numbers of synapses and in photoreceptor size in the retina of the young adult rat.

A quantitative light- and electron-microscopic study has been made of the retinae of rats which were exposed to different lighting conditions for between one and 15 weeks in young adulthood, having been reared in identical conditions during development. The width of the inner and outer segments of the photoreceptors and the width of the outer plexiform layer varied inversely with the light intensity under diurnal lighting conditions of 10 h light/14 h dark. Linear regression analysis showed that the widths were inversely related to the fourth root of the light intensity as measured in lux. Both central and peripheral areas of retina showed a similar change. No change was seen in the widths of the inner plexiform layer, or of the inner and outer nuclear cell layers. Nor was there a difference in the packing density or size of the nuclei in the nuclear cell layers. The number of ribbon synapses in the outer plexiform layer also varied inversely with the intensity of diurnal light. Linear regression analysis showed that the number of synapses was inversely correlated with the fourth root of the light intensity and was positively correlated with the width of the outer plexiform layer. The number of ribbon synapses was increased by up to two and a half times in constant darkness compared to diurnal light of 35 lux. The increase was present but not maximal after one week of exposure. The length of synaptic ribbons was unchanged. The nerve terminals forming such synapses were increased in size but not in number. After one week, there was little or no additional change in the retinal widths and number of synaptic ribbons with time. However, there was a progressive increase with time in nerve terminal size (two-fold in area) in constant darkness. There was some evidence of a slight decrease in nerve terminal number and increase in size of retinal nuclei with age. It is concluded that the adult retina responds to a different lighting environment by a relatively rapid change in the size of photoreceptor segments, by a progressive and large change in number of ribbon synapses and by a slower progressive and large change in the size of photoreceptor nerve terminals. The response is quantitatively determined by the strength of the stimulus but not in a linear fashion. These results are compared with the effects of environmental stimulation of other areas of the nervous system.