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Is strain analysis the answer to improving the response to cardiac resynchronisation therapy? 08 May 2012BCS Editorial By: Pardeep Jhund Cardiac resynchronisation therapy (CRT), despite improving mortality in patients with heart failure (HF) [1,2], is hampered by a significant non-response rate . Up to one third of patients receiving CRT do not gain any improvement in functional status or quality of life scores [3]. A substantial body of work has been conducted to try and determine which individuals are likely to respond. It is thought that optimising the placement of the left ventricular (LV) lead may help lower non-response rates [4]. A new study tested this hypothesis, the Targeted Left Ventricular Lead Placement to guide Cardiac Resynchronization Therapy (TARGET) trial was presented and the American College of Cardiology Sessions and recently published in full [5]. The study used echocardiography and speckle strain analysis to determine the site of latest peak contraction to help guide the placement of the LV lead.
The authors randomised 247 patients with NYHA class III/IV HF, an ejection fraction of ≤35% and QRS duration of ≥120ms. Patients were randomised to strain guided LV lead placement or standard placement of the lead. In the intervention group patients underwent radial speckle tracking strain analysis to define the area of latest peak contraction (where the lead was to be placed) and any areas of myocardial scar (defined as deformation of <=10%), which were to be avoided. In the control group the lead was placed in the posterolateral or lateral vein. The outcomes assessed were a ≥15% reduction in LV end-systolic volume at 6 months with secondary endpoints of change in NYHA class (≥1 class improvement), all-cause mortality and the composite of all-cause mortality or HF hospitalisation.
The intervention group there were more responders (a ≥15% reduction in LV end-systolic volume) than in the usual care group (70% vs. 55%, p=0.031). The improvement in NYHA class was also greater in the intervention group (83% vs. 65%, p=0.003). There were also improvements in the 6 minute walk test performance, Minnesota Living with Heart Failure Questionnaire score and ejection fraction. A reduction in the composite of all-cause mortality or HF hospitalisation was also observed (log rank, p=0.03) mainly as a result of lower HF hospitalisations.
However, despite these encouraging results a number of interesting aspects of this trial merit further attention. The use of echocardiography to guide LV lead placement is not an infallible method. Not all patients have suitable echocardiographic windows, and even if they do the image quality may not be sufficient to permit speckle tracking analysis. In the study around 10% of eligible patients were excluded as they did not have sufficient images to allow the use of speckle tracking. This represents a substantial proportion of individuals and this proportion may be higher in the real world. The authors also only used radial strain analysis; they did not look at circumferential strain which may have improved the results or targeting of LV lead placement further.
Perhaps the most intriguing issue with the study is one that has been widely debated before, the use of surrogate endpoints [6,7]. The size of the sample of this study was relatively small. Therefore, the results of the analysis of the secondary mortality and hospitalisation endpoints should be viewed with a caution. To adequately power a study to look at these endpoints would require many thousands of patients. This is unlikely ever to happen and to all intents is impractical. The use of surrogates therefore is perhaps the most sensible approach. However, the surrogate must fulfil certain criteria, it must be biologically plausible, there should be consistency of the association and there should be a proportional change in the surrogate and the outcome that it is intended to replace [8]. Measures of LV dimensions and function meet these criteria. Ejection fraction is a powerful predictor of prognosis. Treatments that improve survival in HF are associated with favourable improvements in LV dimensions and function in the imaging sub-studies of the major trials of preventing and treating HF [9, 10,11]. There is also a proportional relationship between ejection fraction and outcome, with greater improvements ejection fraction leading to greater reductions in mortality [12]. Therefore, in the absence of a large scale outcome trials, which are unlikely to ever happen, studies such as this may be the best available evidence. Certainly the information gained from the study adds to our understanding of this difficult problem even if it does not solve it.
References
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