Future Research

Cardiac Resynchronisation Therapy (CRT) has become an established therapy for heart failure over the last twenty years. Its transition from theory and initial pilot studies to large scale randomised controlled trials has been relatively rapid. It should be remembered as the CRT literature has expanded, medical therapy for heart failure has also improved with several large randomised trials reporting recently.

The evidence base has grown and there is clear evidence from various trials that CRT is effective at improving morbidity and mortality within selected populations of LVSD.

However like any other technology, what is unknown is the ability of CRT to be beneficial in patients outside of the current evidence base. The current recommendations for a patient to be considered for a CRT device are broadly similar in terms of European and American

guidelines (British guidelines are currently being revised).(22, 98) Currently this is a left ventricular ejection fraction (LVEF) of <35 percent, a surface QRS duration of >120 milliseconds on the electrocardiogram (ECG), optimal tolerated medical therapy and New York Heart Association (NYHA) class II to IV. However despite the number of trials and several thousand participants, it still unknown as to why a third of patients do not derive the clinical benefit anticipated prior to the procedure of CRT implantation. The reasons behind this are likely to be multifactorial. Each step of the process looking after a potential patient who is a CRT candidate is crucial and may have variation which ultimately impacts on the clinical experience and outcome for that individual.

Prior to CRT implantation, the patient should be assessed by a heart failure pacing specialist and suitability deemed by the guidelines and also clinical status. The decision to proceed to CRT implantation should be performed only once pharmacotherapy has been reviewed and co-morbidities addressed. The implantation stage of the procedure has become standardised with simplified transvenous techniques. However the left ventricular (LV) lead position and maybe the right ventricular lead (RV) is critical. Current fluoroscopic techniques preclude the on table demonstration of myocardial scar, but it is imperative that the LV lead avoids such regions and is placed where possible in a lateral or infero-lateral position.

Following successful implantation of CRT, the patient needs to have pacing checks, detailed imaging and frequent careful clinical supervision. The period of six months following CRT

implantation is an opportunity to review and uptitrate prognostic medication. They should also undergo optimisation of the AV and VV intervals.

Each of these steps has been evaluated in small single centre or limited multi centre studies. However none of these steps or processes has yet formed the basis for a larger randomised controlled trial. The other noteworthy development in the field is the ongoing technological development. Manufacturers of CRT are continuously refining generators and lead to improve performance. One such example is the development of a quadripolar left ventricular lead which is able to perform multi-site pacing via reconfiguration of pacing vectors.(263) Alternatively more sophisticated algorithms are becoming embedded into the device to monitor intra-thoracic impedance, pulmonary capillary wedge pressure. These tools when monitored, may allow the healthcare team looking after the patient to act and predict imminent decompensation.

The clinical trials have recruited and published with speed, several having been published over the last ten years. However though the clinical effectiveness of CRT is unquestionable, there are notable areas with a paucity of data including females, more elderly patients,

patients with atrial fibrillation, patients with significant levels of co-morbidities, patients with heart failure from the ethnic minorities and patients undergoing ‘upgrade’ procedures from conventional dual chamber pacing and ICD systems. The rapid speed whereby CRT has become an established therapy for selected patients with heart failure means that to deny a patient the benefit of CRT is unethical. Therefore either data needs to be collected and

published from observational studies or prespecified sub group analyses from the prospective randomised controlled trials. Both do exist but often give different results, which leads to debate in the sub area. Another alternative is to perform studies in geographical areas of the world with less exposure to CRT and thus compare the true effect of CRT versus modern heart failure therapy.

The boundaries described by the current recommendations are defined as a QRS

duration>120 milliseconds and a LVEF <35 percent. Apart from the issues described above the other question facing the field is whether CRT would be effective in those patients which currently fall outside of the cut points. Some data exists from sub studies from large trial data that this may be the case but further larger randomised trials are underway in the area. The

the guidelines.(190) Thus the areas I have described above need further clarification, thought and data to support such clinical extension of the technology. This is especially relevant in modern healthcare infrastructure, where the focus has shifted onto evidence based application of technology in association with the collection of clinical outcomes.

The ideas for future research on the basis of the studies presented within this thesis are:

A direct comparison of conventional ad hoc care of the patient with a CRT implant versus the structure approach described within chapter V. The primary endpoint would be the dose of evidence based pharmacotherapy.

The longer term follow up of patients described in hypothesis 1. Does this affect clinical outcome in terms of HF hospitalisation and mortality?

Optimisation using impedance cardiography versus echocardiographic guided optimisation in a prospective randomised study with symptomatic and clinical endpoints.

Optimisation of impedance cardiography should be performed at rest or on exercise- pilot study using a symptomatic endpoint

A long term multi centre prospective study observing all patients following CRT

implantation and optimisation with endpoints being clinical outcomes. Patients would be randomised to different optimisation techniques

A prospective large cohort of patients randomised to CRT or medical therapy implantation on the basis of right ventricular dysfunction and current selection criteria and clinical endpoints

The reproducibility and repeatability of RV assessment using cardiac magnetic resonance imaging in patients with CRT implants – a validation study

A comparative study of CMR versus echocardiographic measures of RV function in a cohort of patients with CRT on a prespecified endpoint

A validation study of impedance cardiography versus echocardiographic monitoring of cardiac output in a cardiac intensive care setting

A validation study of impedance cardiography versus echocardiographic monitoring of cardiac output in a intensive care setting

Optimisation of AV intervals in patients in a cardiac intensive care setting improves clinical outcome