I – Role of CRT
a) Why pharmacological treatment is not enough
The concepts in the treatment of chronic heart failure have largely evolved since the 80’s. ACE inhibitors, beta blockers, aldosterone antagonists and angiotensin receptor blockers have been successively incorporated into the armamentarium of chronic heart failure therapy as effective agents to reduce mortality. However further attempts to manipulate pharmacological therapy are disappointing because they leave a considerable number of patients who are symptomatic.
Yet symptomatic heart failure carries a poor prognosis (1). Pump failure is the leading cause of death in NYHA class III-IV patients while arrhythmias are the leading cause of death in NYHA class II heart failure patients. Thus, non pharmacological therapies have emerged as novel modalities to improve survival by either reducing SCD, or preventing progression of pump failure.
b) The mechanical effects of CRT
- CRT, with biventricular pacing, is likely to provide additional benefits to the reverse remodeling achieved through renin-angiotensin-aldosterone blockade
Both ischemic and non ischemic heart failure are accompanied by electrical and mechanical abnormalities. Mechanical dyssynchrony, which isfrequently seen in patients with a prolonged QRS duration (>120ms) not only results in inefficient pumping but also accounts for abnormal wall stretching and remodeling of the left ventricle which further compromises systolic performance. (2) Cardiac resynchronisation therapy (CRT) using biventricular pacing is effective in heart failure through a variety of mechanisms.(3,4)
Conventional dual chamber pacemakers have only two leads; one placed in the right atrium, the other in the right ventricle. Biventricular pacemakers have a third lead which is placed through the coronary sinus into an epicardial vein running along the left ventricular free wall - the third lead allowing simultaneous pacing of both right and left ventricles. Biventricular pacing thus reduces QRS duration, (5) improves systolic performance by allowing a more coordinated contraction of the left and right ventricle as well as the septum and free wall of the left ventricle without increasing myocardial oxygen cost (6,7).
As a consequence, resynchronisation therapy results in restoration of inter and intraventricular synchrony which in turn increases the left ventricular ejection fraction, +dp/dt, reduces mitral regurgitation (MR), optimisation of the AV delay improves diastolic filling and again reduces the MR. (4,8,9)
Furthermore biventricular pacing may potentially facilitate the administration and up-titration of pharmacological therapy by preventing excessive bradycardia and hypotension in intolerant patients through improvement in hemodynamics (increased cardiac output, stroke work, decreased PCWP), and left ventricular contractility (+dp/dt).(10)
Other very important effects of biventricular pacemakers are the induction of reverse remodeling evidenced by reduction of left ventricular end systolic and end diastolic dimensions and favorable neurohumoral changes documented by BNP levels and cardiac iodine-123 metaiodobenzylguanidine (123I-MIBG) imaging. (3,11) All these favorable changes translate into improvements in symptoms, functional class, exercise capacity, quality of life, and reduction in hospitalisations for worsening heart failure.(12,13)
Therefore CRT is likely to provide additional benefits to the reverse remodeling achieved through renin-angiotensin-aldosterone blockade.
- Yet echocardiographic quantification of LV dyssynchrony is still of clinical importance
On the other hand, data suggest that echocardiographic quantification of LV dyssynchrony is of clinical importance both in predicting acute hemodynamic improvement and the overall benefit including improvement in ejection fraction, symptoms, quality of life and more importantly , long-term outcome. (14-16)
II - Trials
1) COMPANION studied the effect of CRT on mortality
Until the randomised controlled multicenter Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) trial, published in 2004, none of the studies addressed the effect of CRT on mortality.(17) COMPANION showed that CRT alone or in combination with an implantable defibrillator (CRT-D) reduced the primary composite end point defined as death from or hospitalisation for heart failure during a mean follow-up of 16 months by 34% and 40% respectively. The secondary endpoint of death from any cause decreased also significantly in the CRT-D group (36% risk reduction, p=0.003) but did not reach statistical significance in the CRT alone group (24% risk reduction, p=0.059).
Although the COMPANION trial was not designed to investigate the difference between CRT and CRT-D, it was speculated that much of the effect of the latter approach could be explained by the contribution of cardiac resynchronisation component.
2) Meta-analysis confirms results regarding mortality and studies effects on hospitalisations
A meta-analysis, conducted in 2003 including CONTAK CD, InSync ICD, Cardiac Resynchronisation in Chronic Heart Failure (MIRACLE) and Effect of Multisite Biventricular Pacing in Patients With Heart Failure and Intraventricular Conduction Delay (MUSTIC) trials, showed that CRT reduces death from progressive heart failure by 51%, and hospitalisations from heart failure by 29% and is associated with a trend towards reduced mortality at 3-6 months follow-up. (18)
Another meta-analysis one year later combining the results from 9 trials of CRT including the COMPANION Trial concluded that CRT reduces both all cause mortality and heart failure hospitalisations by approximately one third. (19) According to this meta-analysis CRT confers a 20% relative reduction in all-cause mortality (largely driven by a 40% reduction in deaths from progressive heart failure) and a 35% reduction in heart failure hospitalisations in patients with NYHA class III-IV symptoms despite medical management. These benefits are similar to those reported for ACE inhibitors, beta blockers, and aldosterone antagonists.(20-22)
Although one should be cautious regarding these results as the metaanalysis included the ICD arm of the COMPANION trial which could have inappropriately enhanced the benefits related truly to CRT, the authors pointed out that the survival benefit with CRT seemed to be largely driven by reduction in progressive heart failure deaths and became apparent by 3 months after implantation suggesting that benefits were mediated through cardiac remodeling rather than acute changes in the neurohumoral system.
3) CARE HF
More recently, the Effect of Cardiac Resynchronisation on Morbidity and Mortality in Heart Failure (CARE HF) trial filled the gap in terms of mortality benefit provided by CRT. (23) In this trial the primary end point was the time to first event for the composite outcome of all cause mortality or hospitalisation for a major cardiovascular event which was reduced by 37% (p<0.001). In this trial the secondary end point of all cause mortality significantly reduced by 36% (p<0.002) and heart failure hospitalisations by 52% (p<0.001) with CRT at a mean follow-up of 29.4 months.
Results suggested that, for every 9 devices implanted 1 death and 3 hospitalisations for major cardiovascular events are prevented. Even more impressive results were driven from a 7 months of extension period in terms of all cause mortality (HR 0.60 (95% CI 0.47-0.77; p <0.0001), the risk of death due to heart failure (HR 0.55 (95% CI 0.37-0.82; p =0 .003) and sudden death (HR 0.54 (95% CI 0.35-0.84; p = 0.006). (24) This effect came on top of the benefits of optimal pharmacological therapy and were even more intense than in any previous CRT trial. Benefits were similar in patients with ischemic heart disease and non-ischemic heart disease.
In the CARE HF trial CRT conferred a hasard ratio of 0.64 that is similar to that among patients who received both a resynchronisation device and a defibrillator, as compared to optimal medical treatment alone in the COMPANION trial. This suggests that CRT induced reverse remodeling may potentially prevent malignant arrhythmias. The authors also pointed out that a defibrillator may further reduce the risk of sudden death as 7% of patients in the CRT group died suddenly in CARE HF trial.(23)
III – Questions that still need to be addressed
1) What is a reliable indicator for intra-and interventricular dyssynchrony?
Although prolonged QRS duration causes intra- and interventricular dyssynchrony and contributes to the progression of heart failure, it is now well recognised that QRS duration previously proposed as a reflection of cardiac dyssynchrony, is not a reliable indicator because as many as 30% of patients do not improve or they may even worsen with CRT implantation based on prolonged QRS duration as a means of cardiac dyssynchrony.(6,13,25)
Unfortunately there is no consensus on the definition regarding thecriteria to predict responders. New echocardiographic tools including tissue Doppler imaging seem to be promising in refining patient selection and predicting responders.
It is also true that mechanical dysynchrony may be present in 27-36% of patients with congestive heart failure, low ejection fraction but normal QRS duration. (26,27) Efficacy of CRT in patients with narrow QRS but with an echocardiographically demonstrated mechanical dyssynchrony remains also to be investigated in large randomised controlled trials. Prediction of responders irrespective of the QRS duration is crucial for a cost effective approach.
2) CRT in patients requiring bradycardia support or with permanent fibrillation require further study
Trials excluded patients requiring bradycardia support pacing as well as patients with permanent atrial fibrillation (except the MUSTIC trial).(28) Yet almost one third of patients with chronic heart failure have atrial fibrillation or indications for conventional pacemakers. (29)
Therefore CRT in these patients remains uncertain and requires further study. Patients who require bradyarrhythmia support pacing will eventually develop dyssynchrony and possibly heart failure. Upgrading standard pacing to CRT has revealed some benefit in terms of symptoms and cardiac function as shown in non-randomised trials.(30) As a consequence, prophylactic CRT may be useful in patients requiring pacemaker and being at risk for developing heart failure.
3) Criteria for choosing between CRT only versus CRT-D are to be addressed in further large scale studies
Results from COMPANION trial suggest that CRT-D may be more effective than CRT alone in reducing mortality. (17) It is still not clear whether all patients meeting the criteria for CRT should also receive an ICD or only those having the MADIT II profile (previous MI with an EF=30%). Criteria for choosing between CRT only versus CRT-D are to be addressed in further large scale studies. Also potential antiarrhythmic effect of CRT through inducing reverse remodeling needs further investigation.(31)
4) Effectiveness of CRT for patients in NYHA class II is now under evaluation.
Patients in NYHA class III - IV constituted the main population of the studies so far. Effectiveness of CRT for patients in NYHA class II is now under evaluation.
5) Current Perspective
Finally, according to the current ESC guidelines on heart failure, resynchronization therapy using biventricular pacing can be considered in patients with reduced ejection fraction (=35%), increased left ventricular end diastolic dimension (=55mm), and ventricular dyssynchrony (QRS= 120 ms) and who remain symptomatic (NYHA III - IV) despite optimal medical therapy to improve symptoms ( Class I recommendation, level of evidence A), hospitalizations (Class 1 recommendation, level of evidence A) and mortality (class 1 recommendation, level of evidence B).(32)
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.
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