Multi-chamber pacing: a perfect solution for cardiac mechanical dyssynchrony?

John G.F. Clelanda,*, Justin Ghosha, Nasrin K. Khana, Stefano Ghiob, Luigi Tavazzib and Gerry Kayea

a Department of Cardiology, University of Hull, Castle Hill Hospital, Castle Road, Kingston upon Hull HU16 5JQ, UK
b Department of Cardiology, Policlinico S. Matteo, Institute of Care and Research, Pavia, Italy

* Corresponding author. Tel.: +44-1482-624084; fax: +44-1482-624085
E-mail address: j.g.cleland{at}hull.ac.uk

See doi:10.1016/S1095-668X(02)00475-Xfor the article to which this editorial refers.

When the heart fails, it becomes less efficient, as myocardial energy consumption rises without a corresponding increase in cardiac output. There are many possible reasons for this decline in cardiac efficiency (Fig. 1). Recently, because of the potential value of multi-site pacing, interest has focused on mechanical dyssynchrony, which encompasses a complex array of problems that often coexist in varying degrees along with ‘functional’ mitral regurgitation.1–3



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Fig. 1 Some mechanisms of heart failure causation and progression (usually multiple mechanisms operating simultaneously conspire to cause progression of heart failure).

 
It is likely that mechanical dyssynchrony is common, although precisely how common is unclear, and will depend on the definition and the tools used to measure it. The presence and severity of cardiac dyssynchrony can be assessed directly using imaging techniques or indirectly by measuring time-intervals from a standard 12-lead echocardiography (ECG). ECG is the current method of choice owing to its wide availability, high temporal resolution and its ability to assess flow across the valves, although diagnostic criteria for cardiac dyssynchrony are still being refined.4 In the meantime, studies on relatively small numbers of patients have suggested that patients who have a QRS width ≥150ms very often have evidence of major inter- and intra-ventricular dyssynchrony on imaging.5 A high, but as yet uncertain, proportion of patients with QRS 120–150ms will also fulfil current echocardiographic criteria for ventricular dyssynchrony.6,7 Approximately, one in every four patients with heart failure secondary to left ventricular systolic dysfunction (LVSD) will have a QRS width >120ms on their surface ECG.8 The PR interval may be a useful marker for atrio-ventricular dyssynchrony,1 but <5% of patients with heart failure and LVSD will have a PR interval ≥220ms.8–11

Mechanical dyssynchrony and the possibility of modifying it with treatment are not new concepts.12–16 The first attempts to use pacing to resynchronise the heart focussed on atrio-ventricular dyssynchrony.11,17 The studies reported were relatively small and the results equivocal, possibly because any benefit from improved atrio-ventricular synchrony was offset by impairment of ventricular synchrony due to right ventricular pacing.18 Subsequently, further developments in technology allowed atrio-biventricular pacing19–21 ushering in the modern era of cardiac resynchronisation.

Six substantial randomised, multi-centre trials of atrio-biventricular pacing have been reported so far (Table 1).22–28 All the studies were conducted to the rigorous standards that would be expected in a trial of a pharmacological agent for heart failure, and three studies were conducted in a double-blind fashion.22,25,27 The principal analysis was, by intention, to treat, but randomisation took place after device implantation, and a substantial number of patients did not complete follow-up assessments and, therefore, could not be included in the analysis of the primary outcome, which were generally a measure of exercise capacity or symptoms, in most of the studies. The studies generally focussed on patients with LVSD and more severe symptoms and used QRS width rather than echocardiographic criteria as a marker of cardiac dyssynchrony (see Table 1). Overall, these studies showed a highly consistent and apparently substantial improvement in symptoms, a less consistent effect on hospitalisation and no convincing evidence for a reduction in mortality. Improvements in quality of life, cardiac function29 and exercise capacity were small, but generally statistically significant.22,24–27 The single study of patients with atrial fibrillation reported so far26 is consistent with the findings of the other trials, although it hints that there might be less benefit in this population. This may only reflect inadequate study size, but loss of the benefits of atrio-ventricular resynchronisation and/or the need to maintain a high pacing rate to maintain ventricular capture may result in less benefit from cardiac resynchronisation in this patient population.30,31


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Table 1 Completed, randomised controlled trials comparing atrio-biventricular resynchronisation with control in patients with heart failure

 
The consistency of the symptomatic benefits of resynchronisation in the previously mentioned trials has led some enthusiasts to use these devices in their own clinical practice, and to advocate widespread use to others. However, while the trials scientifically show that resynchronisation leads to a short-term improvement in symptoms, they were not designed to show that this was the best clinical strategy nor were they designed to demonstrate whether the benefit persisted for more than a few months. It is possible that further manipulation of diuretic or other therapy for the relief of symptoms would have achieved equally good results. If symptoms do improve substantially with resynchronisation, it is reasonable to expect that this would lead to a reduction in hospitalisations, a benefit that could also offset the cost of devices. The trial results on this outcome remain inconclusive so far.27 A substantial improvement in cardiac efficiency might also be expected to lead to a reduction in mortality. The trials reported so far, whilst showing a trend to fewer deaths with resynchronisation, have not been large enough or long enough to address this question.22 Although the trials do not raise serious concerns about the theoretical risks of resynchronisation by pacing, they are relatively small and do not entirely dispel fears about safety. The design of these trials required both active and control groups to receive a device and, therefore, they cannot assess the risks of device implantation. Device implantation failed in about 10% of patients, another 5–10% of patients developed device complications, some were excluded for other reasons and a few of them died between implantation and randomisation. Cardiologists should await the outcome of two large, long-term trials of resynchronisation therapy that will soon complete recruitment before deciding whether implanting such a device is of real benefit to a patient.

The CArdiac REsynchronisation in Heart Failure (CARE-HF) study6 tests the hypothesis that in addition to optimal medical therapy, implantation of a resynchronisation device will reduce the composite endpoint of death or unplanned hospitalisation for major cardiovascular morbidity in patients with moderate to severe heart failure due to LVSD and ventricular dyssynchrony (Table 2). QRS width >150ms is accepted as evidence of ventricular dyssynchrony, but echocardiographic criteria are required in patients with QRS width of 120–150ms. A large amount of baseline clinical, pacing, echocardiographic and neuro-endocrine data are being collected that may assist in defining precisely which patients have the greatest benefit to risk ratio from such devices.


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Table 2 Characteristics of on-going morbidity/mortality trials of atrio-biventricular resynchronisation versus control in patients with heart failure

 
The COmparison of Medical therapy, Pacing ANd defibrillatION in chronic heart failure (COMPANION) trial32 is best designed to assess whether adding a defibrillator function to a resynchronisation device is of benefit compared to a resynchronisation device alone although this is not part of the prespecified primary outcome. Any difference observed could reflect the effects of the defibrillator alone, additive benefits from combined therapy or reversal of resynchronisation induced arrhythmias, should the theoretical risk of such events prove real. Patients in a smaller third arm of the study do not receive any devices, allowing some assessment of the effects of resynchronisation alone compared to control. There are no echocardiographic entry criteria for dyssynchrony, but the patients require both a QRS >120ms and PR interval >150ms, markers of ventricular and atrio-ventricular dyssynchrony, respectively. The primary outcome measure is the composite of all-cause mortality and all-cause hospitalisation, a less focussed end-point than in CARE-HF.

Two trials of cardiac resynchronisation have been conducted solely in patients undergoing implantation of an implantable cardiac defibrillator (ICD).22,27 The benefits of cardiac resynchronisation have been less conclusive in these trials, possibly pointing to a reduction in benefit with combined CRT/ICD devices. The Multi-centre automatic defibrillator implantation trial-II study33 suggests that implantation of an ICD leads to a modest reduction in mortality (only six lives saved for every 100 patients implanted) and, from a subgroup analysis, that the benefit may be greater in patients with QRS >150ms (with about 33 out of every 100 patients being benefited). It is unclear whether the modest increase in hospitalisation in the ICD group in this study merely reflected an increase in longevity and, therefore, a greater duration of risk for hospitalisation, or whether ICD implantation with conventional right ventricular back-up pacing has an adverse effect either by increasing tricuspid regurgitation or causing ventricular desynchronisation.34 The COMPANION trial and data from a further trial, sudden cardiac death in heart failure (SCD-HeFT), in which patients with heart failure and LVSD of either ischaemic or non-ischaemic origin are randomised to placebo, amiodarone or ICD, should provide conclusive evidence of the presence and the size of the benefit of ICD's in patients with heart failure, who have been selected by the severity of their cardiac dysfunction rather than by an electrophysiological marker.34 Further trials that target patients who may benefit more precisely will undoubtedly follow.34

Even after the results of all the previously discussed trials are known, there will still be important gaps in our knowledge. More information on the accuracy of QRS width as a marker of dyssynchrony is required. We need a more precise understanding as to which patients benefit.35 It is assumed that cardiac dyssynchrony is the target of this therapy, but this may be a false assumption. It is possible that the mechanism of benefit is other than what we assume, and that a far broader range of patients may benefit. We do not know whether patients with diastolic heart failure might also benefit, although broad QRS appears less common in this setting.8 Technology is evolving rapidly. Newer leads and devices may make implantation easier, optimise lead positioning, permit pacing from more than three sites and allow the relative timing of right and left ventricular stimulation to be fine-tuned.

One large population that has been excluded from study so far comprises patients who have a conventional indication for right ventricular pacing. Previous observational studies suggest that pacing the right ventricle of patients with heart failure or major ventricular dysfunction may be associated with a high incidence of worsening heart failure, which may reflect iatrogenic cardiac dyssynchronisation.18 A substantial European trial programme is being planned to address this issue (Pacing efficiently by resynchronisation for efficacy in CHF therapy, PERFECT).34

In summary, there is growing evidence that cardiac resynchronisation might be an effective treatment for many patients with heart failure. Which patients should be treated, and the nature and magnitude of the benefit have not yet been adequately determined. Two large trials are currently being conducted that should provide many answers to these questions. However, if premature assumptions about the benefits of resynchronisation lead to a high rate of device implantation (‘cross-overs’) in the control groups of these studies, it is unlikely that they will be able to show benefit. The clinical community should not jump to conclusions that it may later find very difficult to explain to colleagues, to those who decide how health services money should be spent and, ultimately, to patients.

Subsequent to this article being written and accepted for publication, the COMPANION study was stopped by its data and safety monitoring committee because of benefit. The study showed a significant reduction in the time to first event for the composite outcome, predominantly all-cause hospitalisation events, with either intervention compared to control. A statistically non-significant, relative reduction of 20% in mortality with resynchronisation alone compared to the control group was reported, amounting perhaps to 5 lives saved for every 100 devices implanted during the course of the study. A substantial and statistically significant relative reduction in mortality of 40% was also reported with the combined implantable defibrillator/cardiac resynchronisation device compared to control, amounting perhaps to about 10 lives saved for every 100 devices implanted compared to control during the course of the study. This supports the subgroup analysis of MADIT-II in patients with QRS>150msec.

These partially reported data are exciting but can only be properly interpreted in the light of the full results. It is important that potentially over-optimistic speculation is not applied in clinical practice in the meantime as this could undermine a number of ongoing trials. The above results do not yet provide strong evidence that cardiac resynchronisation has a role for the management of heart failure. The data revealed so far do not preclude an early hazard from device implantation. The COMPANION study was conducted unblinded and therefore all-cause hospitalisation, the major component of the primary outcome, is not a very robust measure of effect. For these reasons, further data are required before accepting that cardiac resynchronisation is truly beneficial. The CARE-HF study which has a larger control group, longer follow-up and ‘harder’ primary end-point for an open-label study than in the COMPANION study is well positioned to do this. On the other hand, resynchronisation alone was not inferior to combined device therapy for the primary outcome or all-cause mortality. It is important that more data are collected so that the respective roles of cardiac resynchronisation devices, implantable defibrillators and their combination can be clarified for the management of heart failure.

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Left ventricular remodelling and haemodynamic effects of multisite biventricular pacing in patients with left ventricular systolic dysfunction and activation disturbances in sinus rhythm: sub-study of the MUSTIC (Multisite Stimulationin Cardiomyopathies) trial
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