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the reverse trial was a prospective , randomized , double blind , parallel - controlled multinational study designed to determine whether crt limited the progression of hf compared with optimal medical therapy alone .
the study included 610 patients with acc / aha stage c , nyha class i or ii hf patients with qrs more than 120 msec , and lvef less than 40% on optimal medical therapy .
patients were implanted with a crt - device with ( crt - d ) or without ( crt - p ) defibrillator and randomized 2:1 to crt on ( n  =  419 ) or crt off ( n  =  191 ) .
patients were then programmed as randomized through 12 months in north america and through 24 months in europe . by the study design , all patients were programmed to crt on after the randomization period and followed for 5 years from implantation .
first enrollment occurred in september 2004 , and enrollment was completed in september 2006.the final 5-year follow - up was in november 2011.the primary end point was hf clinical composite response , which scores patients as improved , unchanged , or worsened .
the initial results were published in 2009 in the journal of american college of cardiology .
they showed the hf clinical composite response end point , which compared only the percent worsened , indicated 16% worsened in crt - on compared with 21% in crt - off ( p 0.10 ) .
patients assigned to crt - on experienced a greater improvement in lv end - systolic volume index ( 18.4 29.5 ml / m 2 vs. 1.3 23.4 ml / m 2 , p 0.0001 ) and other measures of lv remodeling .
time - to - first hf hospitalization was significantly delayed in crt - on ( hazard ratio : 0.47 , p 0.03 ) .
the five - year follow up analysis was confined to 419 subjects randomized to crt on , who received up to 5 years of crt therapy .
the 6-min hall walk increased by 18.8    102.3 minutes and the minnesota and kansas city scores improved by 8.2    17.8 and 8.2    17.2 unites , respectively .
the mean decrease in left ventricular end - systolic volume index and left ventricular end - diastolic volume index was 23.5    34.1  ml / m and 25.4     37.0  ml / m and the mean increase in lvef 6.0    10.8% with sustained improvement thereafter ( figure 1 ) .
the annualized and 5-year mortality was 2.9 and 13.5% and the annualized and 5-year rate of death or first hf hospitalization 6.4 , and 28.1% .
the 5-year results of reverse confirmed that crt in mildly symptomatic hf and wide qrs reverses remodeling and is associated with low rates of hf hospitalization and all - cause mortality over the entire follow - up .
crt effect in mildly symptomatic hf patients was first tested on 186 patients ( 101 control and 85 crt ) in the miracle icd ii trial , which was published in 2004 .
the results from the study demonstrated that crt significantly improved the cardiac structure and function over a 6-month period of follow up in optimally treated patients . in the larger madit - crt , published in 2009 , the use of crt combined with an icd in asymptomatic or mildly symptomatic patients with heart failure and a reduced ejection fraction and wide qrs complex was associated with 34% reduction in the risk of death or heart failure events , as compared with the use of an icd alone .
this benefit was driven by 41% reduction in the risk of heart failure events , a finding that was evident primarily in subgroup of patients with a qrs duration of 150 msec or more .
similarly , the raft trial , published in 2010 , found the addition of crt to an icd and optimal medical therapy reduced rates of death and hospitalization for hf among patients with mild - to - moderate hf , a reduced lv ef , and a wide qrs complex over a period of 40 months of follow - up .
the echocardiographic studies from reverse , madit - crt , and care - hf showed substantial improvements in lv size and function , lvef , rv function , left atrial size and mitral regurgitation severity in patients treated with crt compared with icd only .
these findings were strongly concordant with and predictive of the primary outcome of death or a hf event and suggest a compelling cardiac structural and functional mechanism by which crt therapy improves outcomes .
these results suggest that in the long term , crt lowers the risk of hf - related adverse clinical events and prevents or reduces the progression of disease by reverse lv remodelling .
four trials have studied the effect of crt on rates of death among patients with hf .
care - hf and companion included patients with moderate to - severe nyha class iii and ambulatory class iv hf .
raft and madit - crt included less symptomatic patients with nyha class ii and iii in the raft and nyha class i or ii in the madit - crt .
the raft trial found a significant reduction in the rate of death from any cause associated with the use of crt in addition to icd and optimal medical therapy .
the relative risk of death was reduced by 25% , resulting in an absolute mortality reduction of 6 percentage points at 5 years .
possible reasons for the differences in mortality rates between raft and madit crt are that raft had longer follow up period and that patients had slightly more advanced disease with a slightly lower ef and a higher proportion of the raft patients and ischemic heart disease . although reverse was not designed as a morbidity and mortality trial , its 5-year follow - up confirmed the raft findings that crt in mild hf patients over a longer treatment period provided benefits in morbidity and mortality .
this positive impact on mortality was in fact predicted by the reverse authors in their 2009 publication as they observed a delay in time to first hf hospitalization in the active crt group in the 24 months follow - up .
however , the investigators were not blinded to the follow - up cohort and this could represent a potential bias to the results . like the madit - crt ,
the positive reverse findings were greatest in patients with a qrs width of more than 150 msecs , left bundle branch block ( lbbb ) , and of non - ischemic aetiology .
in fact , this finding was confirmed in a meta - analysis of five randomized controlled trials . a detailed
non - invasive 3-dimensional electrocardiographic mapping , in 33 consecutive crt candidates , demonstrated that patients with lbbb had uniform patterns of activation , whereas in patients with nonspecific interventricular conduction delay , conduction patterns were highly variable .
left ventricular electrical uncoupling was consistently elevated in all lbbb patients , and properly identified clinical crt responders . among the 419 patients , 51 ( 12.2% ) experienced 63 lv lead - related complications .
most events occurred within the first 3 months of implant with a rate of 7.9% ( 95% ci : 5.710.9% ) , and a rate of 12.5% ( 95% ci : 9.616.2% ) at 5 years .
the majority were due to lv lead dislodgment ( n  =  33 ) and/or diaphragmatic stimulation ( n  =  10 ) .
over the course of the 5-year follow - up , 132 of the 419 patients ( 31.5% ) underwent device replacement .
these findings were relatively fewer than the 16% complication rate ( lv 11% , rv 5% ) reported in nyhaclass iii and iv patients with 6-month follow - up and comparable to the reported european crt survey with 1-year follow - up ( 10.3% ) . despite the low mortality rates , the cost effective analysis from reverse showed that compared with crt - off , 0.94 life years or 0.80 qalys were gained in the crt on group at an additional cost of  11,455 - yielding an incremental cost - effectiveness ratio of  14,278 per quality - adjusted life year ( qaly ) gained . at a threshold of  33,000 (  30,000 ) per qaly
in the usa 5 million individuals - from a total population of nearly 294 million - have hf . in europe
asymptomatic left ventricular dysfunction is estimated to have at least the same prevalence as congestive hf .
overt hf symptoms generally follow the asymptomatic phase and are linked to increased morbidity and mortality .
the clinical efficacy of crt in patients with moderate to severe hf has been established in a number of trials .
in contrast , for patients with asymptomatic or mildly symptomatic hf , crt represents a relatively novel treatment option .
evidence on the efficacy of crt in this patient group has recently been demonstrated with the publication of the reverse and madit - crt trials .
the long term follow up confirmed the initial findings of reverse by showing that cardiac reverse remodelling lowers hf related events and mortality rates with longer follow up time . the possibility of long - lasting benefit of crt on hf progression outweighs the risk , as the complication rate related to crt remained acceptable after 5 years .
however , these results are exclusive to patients with lbbb and wide qrs complex more than 150 milliseconds , emphasizing a specific electrophysiological process that takes place in crt responders .
the role of cardiac resynchronization therapy ( crt ) in patients presenting with mild manifestations of heart failure ( hf ) , depressed left ventricular ejection fraction ( lv ef ) , and wide qrs complex , has been addressed in four previous trials : miracle icd ii,1 madit - crt,2 raft,3 and reverse.4 the consistent observed benefits in reverse cardiac remodelling and reduction of heart failure adverse events have resulted in guideline recommendations for crt in nyha class ii patients . 
 the guidelines also recommend further studies to determine whether survival is increased by crt in patients with mild symptoms . 
 the 5-year analysis of the resynchronization reverses remodeling systolic left ventricular ( reverse ) trial , which was designed prospectively for 5-year follow - up to specifically assess the long term benefits of crt , were recently published in the european heart journal.5