Clinical evidence of the trial ICD treatment.
Key points by Cecilia Linde MD.
Current evidence of benefits
The effect of cardiac resynchronization therapy has only been firmly established in heart failure patients in NYHA III-IV with and without an indication for an ICD, on optimal medical treatment and with left ventricular dysfunction as indicated by left ventricular ejection fraction below 35% and a QRS >120 ms, in sinus rhythm and with no conventional indication for cardiac pacing and no previous pacemaker.
Symptom relief
The effects of CRT on symptomatic improvement from the early studies that compared CRT to control treatment in 3 month crossover or 6 month parallel comparison has been firmly established. CRT improves the 6 minute walk distance by 13-20%, quality of life by 30% and improves NYHA class by a mean of 0.5-0.8 in all these studies.
Improvements in Morbidity and Mortallity
The COMPANION was an open all US study encompassing 1520 patients. They were included provided to have function class III-IV heart failure ES <35%, LVEDD >60 mm and as a sign of ventricular dyssynchrony QRS width had to be >120 ms. Patients were randomised into optimal medical treatment alone or optimal treatment + CRT and the 3rd arm was optimal medical treatment and CRT + ICD. Importantly, the study was designed to compare the two those device arms with the optimal medical treatment arm, but not to measure the difference between the two device arms. The primary end point was a combined one of total mortality or hospitalisation and the a secondary end point was either total mortality, morbidity etc. The mean follow up time in this trial was 15 months. The primary end was significantly reduced in both device arms by 18 or 20%, respectively compared to the optimal medical treatment arm. For the secondary end point at one year the 12 month event rate was reduced by relatively change of 23.9% by CRT and of 43.4% in the CRT ICD arm. Only the CRT ICD significantly reduced total mortality compared to optimal medical treatment.
In the European CARE-HF patients were included if they had NYHA III-IV with a chronic heart failure lasting at least 6 weeks and requiring diuretics orally. Patients had to be on optimal pharmacological therapy and as a sign of left ventricular dysfunction. QRS had to be > 120 ms and if it was in between 120-149 ms two out of three criteria of mechanical dyssynchrony also had to be confirmed.
800 European patients were randomised to optimal medical therapy or optimal medical therapy and cardiac resynchronization therapy. The follow up time had to be at least one and a half year. The primary end point was total mortality or unplanned cardiac vascular hospitalisation with total mortality at the principle secondary end point. The primary end point in the CARE-HF was reduced by 35% or 16 % in an absolute value. Importantly, all cause mortality was significantly reduced by in absolute terms 10% in CRT compared to medical therapy. In summary, total mortality and hospitalisation are indeed reduced by CRT.
Reverser remodeling
There is consistent evidence that CRT reverses left ventricular (LV) remodelling. It reduces LV endsystolic dimensions by 8-15% and increases LV ejection fraction by 4-7 %.
CRT in NYHA II
In the MIRACLE ICD II trial including only 180 NYHA II patients the primary end point CRT did not significantly change peak VO2, 6 minute walk distance or quality of life. But it did significantly improve the clinical composite end point in that: significantly more patients (58%) were improved by CRT compared to 36 in the control arm and significantly more patients were worse in the control (31%) compared to the CRT arm (20%). Moreover, there was also significant left ventricular reverse modelling by CRT. Therefore, it is important to further study to potentials of CRT to delay or reverse the disease process in mild heart failure. This is the topic of two ongoing trials.
Ongoing randomised studies on CRT in NYHA I-II patients. REVERSE MADIT-CRT
The study purpose of the REVERSE is to study if CRT on top of optimal medical treatment can prevent or reverse disease progression in patients with prior (NYHA I with ACC/AHA stage C) or mild heart failure symptom- NYHA II. It is a double-blind 12 months parallel comparison of optimal medical treatment and CRT to optimal medical treatment alone. The primary end point is the clinical composite end point and the secondary end point is reverse LV remodelling In this study 600 patients will be enrolled to a randomised 483.
The purpose of MADIT- CRT study is to determinate if prophylactic CRT in asymptomatic high risk patients ( NYHA I-II) reduces the risk of mortality and heart failure with LV reverse remodelling as the secondary end point. Patients are randomised to receive either CRT-ICD or ICD alone.1820 subjects will be randomised and the follow up time is estimated to be 2 years.
Conclusions
CRT in NYHA III-IV improves symptoms and reduces morbidity and total mortality. Therefore, CRT should be considered as part of routine therapy for patients with functional class III-IV heart failure due to left ventricular systolic dysfunction with evidence of cardiac dyssynchrony.
It is fair to point out the clinical response to CRT is at 60-70%. This will be expected to increase by the use of mechanical dyssychrony criteria currently evaluated in the PROSPECT trial and by optimisation of left ventricular lead position.
The clinical benefit of CRT in mild heart failure remains to be established in ongoing trials.