Chronic heart failure (HF) is a common, malignant disease and is a major economic burden for healthcare systems in developed nations. It affects 5% to 10% of all people. In Germany, approximately 150,000 people are newly diagnosed with HF per year. Fifteen per cent of approximately 1.6 million HF patients in Germany are in advanced HF status, being classified as stage III-IV according to the HF criteria of the New York Heart Association (NYHA). The prognosis of these patients is poor, despite major advances in HF therapy during the last 20 years. The one-year mortality is 10% in patients with HF class II-III, 20% to 40% in patients with HF class III-IV and up to 50% in patients with HF class IV. Since HF incidence increases with age, and because of the increasing number of elderly in modern industrialised societies, HF is regarded as one of the major epidemics of the 21st century.
The aetiology of HF is diverse. It can develop as a consequence of long-standing arterial hypertension and can be a consequence of coronary artery disease (CAD). Besides these two major aetiological factors, there are other reasons leading to HF such as primary cardiomyopathies, anaemia, hyper- and hypothyroidism, diabetes mellitus, valve defects, cardiac arrythmias, such as atrial fibrillation, and drug or alcohol intoxication.
Pharmacological Therapy of Chronic HF
In some cases, specific therapy of the underlying disease leads to an improvement of HF status or a complete cure. Examples are hyperthyroidism, atrial fibrillation or coronary artery occlusion; however, most patients with systolic and diastolic HF are treated with a similar combination of pharmacological substances independent of the primary cause of HF. In this respect, ACE-inhibitors, beta-blockers, aldosterone antagonists and AT1-receptor antagonists have been demonstrated to be highly potent substances decreasing the morbidity, and especially the mortality, of HF patients. The convincing results of large clinical trials on the effects of these neurohormonal antagonists in HF patients have underlined the pathophysiological concept that chronic activation of the reninangiotensin system and the sympathetic nervous system are major reasons for the progression of HF.
Despite optimal standard therapy, progression of HF therapy cannot be antagonised completely and HF mortality remains high. Unfortunately, new pharmacological approaches in the therapy of HF, such as the introduction of endothelin antagonists or the treatment with tumour necrosis factor (TNF) inhibitors, have not been successful.1,2 Only one AT1-receptor antagonist, candesartan, has so far been demonstrated to decrease the combined incidence of HF deterioration and death when given in combination with ACE-inhibitors and beta-blockers.3 Others might even have adverse effects when added to these drugs.4 These experiences suggest that a further extension of neurohormonal blockade might not be very efficient at improving morbidity and mortality in HF patients and other therapeutical approaches might be necessary.
Ventricular Conduction Abnormalities in Chronic HF
Many patients with advanced HF (30% to 50%) present with electrical conduction abnormalities including left bundle branch block, right bundle branch block or non-specific inter- and intraventricular conduction delay.5 This conduction delay has been demonstrated to lead to a disturbed synchrony of the septal to posterior left ventricular (LV) wall and in consequence to an impaired LV diastolic function, mitral regurgitation, a reduction in stroke volume and a decrease in LV pressure rise.6,7 As a consequence of the poor co-ordination of ventricular contraction and relaxation, cardiac output decreases and HF worsens. Occurrence of prolonged QRS duration (more than 120ms) correlates with the severity of HF and is associated with increased mortality.8,9 These clinical and pathophysiological findings suggest that an electrophysiological therapy might be helpful to improve the outcome in HF patients. One approach in this respect is the correction of ventricular asynchrony by biventricular pacing to overcome the inter- or intraventricular conduction delay.
Biventricular Pacemaker Therapy
For cardiac resynchronisation therapy (CRT), a sensing electrode is placed in the right atrium and pacing electrodes are placed in the right ventricle (RV) near the apical interventricular septum. The LV electrode is placed in the posterolateral coronary venous branches. Maximal improvement of LV function is obtained when both electrodes are placed at anatomically remote positions. In most hospitals, correct positioning of the LV electrode has been achieved in more than 90% of cases.10-12 The ideal patient for CRT is an NYHA class III-IV HF patient with a QRS duration of more than 120ms and an LV ejection fraction of less than 35%.
Effect of CRT on LV Function
One major aim of HF therapy is an improvement in cardiac function and haemodynamics, which is accompanied by an increase in exercise tolerability and improvement of the wellbeing of the patient. In the beginning, small non-controlled trials demonstrated that chronic biventricular pacing leads to an improvement in terms of symptoms, exercise tolerance and the HF status of the patients.13,14 One early randomised study demonstrating a beneficial effect of CRT was the Pacing Therapy for Congestive Heart Failure (Path-CHF) Trial.15 Thirty-six patients were randomised to receive either univentricular or biventricular pacing for four weeks, followed by a four-week interval with medical treatment only and finally a cross-over treatment, again with univentricular or biventricular pacing for four weeks. Pacing led to an improvement of the six-minute walk test and in oxygen uptake during bicycle exercise. During the short observation period, no difference between univentricular and biventricular pacing was observed. This was in contrast to earlier studies providing for a special effect of biventricular pacing. These studies showed that biventricular, but not right sided pacing alone, led to an improvement in symptoms and cardiac function in HF patients with sinus rhythm.16-18
The initial studies were followed by a randomised cross-over study in 48 patients with severe HF (NYHA class III) and a QRS duration of more than 150ms.10 These patients obtained transvenous atriobiventricular pacemakers and were treated for three initial months with the pacemaker inactivated and for another three months with the pacemaker activated. Initial implants were successful in 92% of the patients. The result of the trial was in favour of biventricular pacing. Resynchronisation therapy led to an increase in the six-minute walk distance by 23%, an improvement of the quality of life score by 32%, an increase in peak oxygen uptake of 8% and a decrease in hospitalisations of 66%. Active pacing was preferred by 85% of the patients.
These findings were confirmed by the Multicenter InSyn Randomized Clinical Evaluation (MIRACLE) trial.11 This randomised controlled trial performed in 453 patients with severe HF (NYHA III-IV), reduced LV ejection fraction (less than 35%), LV dilatation (more than 55mm), and a QRS complex prolongation of more than 130ms showed a significant improvement in the six-minute walk test, functional class, time on treadmill during exercise duration and quality of life.
In addition, fewer patients assigned to cardiac resynchronisation than control patients required hospitalisation or intravenous medications for the treatment of HF. These favourable alterations were accompanied by a reduction in LV mass, a decrease in LV end-diastolic diameter, an improvement of LV ejection fraction, a reduction in mitral regurgitation and an improved myocardial performance index, which were interpreted as indicators for inverse cardiac remodelling due to biventricular pacing.19
In the MIRACLE-implanted cardioverter defibrillator (ICD) trial, 369 patients similar to those in the MIRACLE trial received devices with combined CRT and implantable defibrillator device capacities.12 In the verum group the CRT device was activated, whereas in the control group the CRT device was turned off. Again, six months of treatment with the CRT device in action led to an improvement in quality of life and NYHA score compared with controls, but did not lead to a difference in the six minutes walking distance. Peak oxygen consumption increased by 1.1ml/kg x min in the CRT group and by 0.1ml/kg x min in the control group, and treadmill exercise duration increased by 56 seconds in the CRT group and decreased by 11 seconds in controls. There was no change in LV size or function, overall HF status, survival and rates of hospitalisation. The important finding in this study testing the efficacy of resynchronisation therapy in the presence of an ICD was that no pro-arrhythmia was observed as a consequence of biventricular pacing and that cardiac resynchronisation did not impair defibrillator function.
Effect of CRT on Morbidity and Mortality
The second major aim of HF therapy is a reduction in mortality. The first large trial assessing the effect of CRT on hospitalisation and death was the Comparison of Medical Therapy, Pacing and Defibrillation in Heart Failure (COMPANION) trial.20 A total of 1,520 patients with advanced HF (NYHA class III-IV) due to ischaemic or non-ischaemic cardiomyopathies and a QRS interval ÔëÑ120ms received either optimal medical treatment alone or in combination with CRT with either a biventricular pacemaker or a pacemaker with defibrillator. The rationale behind this study was that defibrillator therapy had been demonstrated to reduce mortality but not morbidity in patients with ischaemic cardiomyopathy,21 whereas, so far, resynchronisation therapy had been demonstrated to only be beneficial concerning morbidity. The study was concluded early, two years after the start of enrolment. Compared with pharmacological treatment alone, CRT, as well as pacing plus defibrillator, marginally but significantly (p<0.014) decreased the risk of hospitalisation and death by any cause.
The most prominent effect was observed concerning the combined end-point death for any cause or hospitalisation for HF. Compared with pharmacological treatment alone, CRT decreased the risk of hospitalisation and death by 34% (p<0.002). Biventricular pacing plus defibrillator decreased the risk of hospitalisation and death by 40% (p<0.001). When the secondary end-point - risk of death from all causes - was analysed, the effect of biventricular pacing was not significant compared with medical therapy (-24%, p=0.059). Only when a defibrillator was added was the reduction in all-cause mortality significant (−36%, p=0.003). According to the COMPANION trial, it therefore appeared that resynchronisation therapy alone reduces morbidity, but shows only a trend to reduce mortality in HF patients.
This view has now been challenged by the most recent clinical trial, the Cardiac Resynchronization - Heart Failure (CARE-HF) study.22 In this trial, a total of 813 patients were enrolled with advanced HF (NYHA III-IV), an ejection fraction of less than 35%, an LV end diastolic diameter ≥30mm and a QRS interval of ≥120ms. The patients were randomly assigned to receive either medical treatment alone or medical treatment plus CRT. Mean observation time was 29.4 months. The primary end-point (death from any cause or an unplanned hospitalisation for a major cardiovascular (CV) event) and the secondary end-point (death from any cause) in the European study were very similar as in the US-driven COMPANION trial. In contrast to this earlier trial, the CARE-HF study showed a highly significant reduction in the incidence of the primary end-point death for any cause or hospitalisation for a major CV event, from 55% to 39% (p<0.001) in response to additional cardiac resynchronisation. It also demonstrated a highly significant (p<0.002) reduction in the number of deaths from 120 in the control group to 82 in the pacing group. Again, beneficial effects of CRT were accompanied by a highly significant increase in LV ejection fraction, a decrease in mitral regurgitation and a decrease in N-terminal pro-brain natriuretic peptide. It is this latter finding that suggests that, most likely via a reduction of mechanical load on the myocardium, CRT also decreases neurohormonal activation. Based on hazard ratios, the investigators calculated that, for every nine devices implanted, one death and three hospitalisations for major CV events are prevented. The effect of CRT is therefore similar to the beneficial effect of beta-blocker treatment in very similar patients.
The different outcomes of the COMPANION and the CARE-HF trial may set the stage for a long discussion about the effects of CRT on mortality. These differences cannot be explained by a difference between pharmacological therapies, because the prescription frequency of beta-blockers, ACE-inhibitors, AT1-receptor antagonists and spironolactone was similar in both studies and in the individual study arms. It is also unlikely that a difference between biventricular pacemakers from different manufacturers explains the different outcomes. One major difference is the statistical power of both studies. In CARE-HF the size of the group receiving medical therapy and the group receiving medical therapy plus cardiac resynchronisation was identical (404 compared with 409). In contrast, in the COMPANION trial, 1,520 patients were assigned in a 1:2:2 ratio to medical therapy, medical therapy plus resynchronisation and medical therapy plus resynchronisation and defibrillator. This distribution of study participants reduced the number of patients in the first group to 308. As a matter of fact, towards the study end the curves for the incidence of death from any cause did not differ between the groups treated with a pacemaker and the group treated with pacemaker and defibrillator. The COMPANION trial was not designed to show a difference between pacemaker therapy and pacemaker plus defibrillator therapy. The COMPANION trial does therefore not provide any evidence for a significant effect of an addition of a defibrillator to a biventricular pacemaker; however, the CARE-HF trial provides evidence that cardiac resynchronisation prolongs life in HF patients.
Over the last 20 years, HF therapy has been improved dramatically by the introduction of ACE-inhibitors, beta-blockers, spironolactone and also potentially by AT1- antagonists. The therapeutic spectrum has now been increased by the introduction of biventricular pacemakers. Biventricular pacemakers allow cardiac resynchronisation in HF patients often presenting with ventricular conduction deficits. This new electrophysiological approach has highly significant effects on hospitalisation rate and, according to the very recent data of the CARE-HF study, also on the mortality of HF patients. Cardiac resynchronisation therefore provides an effective therapy for patients with advanced HF, marked LV systolic dysfunction and a ventricular conduction delay as indicated by a QRS complex more than 120ms. Whether CRT is as effective as a defibrillator, or whether resynchronisation therapy can be further improved by addition of a defibrillator, is so far unknown.