in patients with hf , increased raas contributes to the pathogenesis , and ace inhibitors reduce the activity of the raas by inhibiting the production of angiotensin ii .
two benchmark randomized controlled trials , namely the cooperative north scandinavian enalapril survival study7 and the studies of left ventricular dysfunction treatment trial,8 demonstrated that ace inhibitors reduce mortality and improved new york heart association class , exercise capacity and cardiac function in patients with hf with reduced ef .
subsequently , the assessment of treatment with lisinopril and survival study5 investigated whether ace inhibitors had favourable effects on the outcome of patients with hf with reduced ef in a dosedependent manner . in this trial ,
an ace inhibitor , lisinopril , at high dose ( 32.535  mg daily ) significantly decreased death or hospitalization for any cause by 12% ( p  =  0.002 ) compared with that at low dose ( 2.55  mg daily ) , but not significantly decreased death by 8% ( p  =  0.128 ) .
show that benazepril at supramaximal dose results in prolonged survival by 41% compared with that at low dose [ 95% confidence interval ( ci ) 0.360.98 , p  =  0.042 ] .
further research should reveal whether ace inhibitors at supramaximal dose reduce the mortality rate in patients with hf compared with those at high dose .
common side effects of ace inhibitors are hyperkalaemia , hypotension , cough , and impaired renal function . according to the severity of these adverse events ,
it is crucial to manage when to stop uptitration , reduce dose , or discontinue treatment .
five ace inhibitors , namely ramipril , enalapril , lisinopril , captopril , and trandolapril , are listed for the treatment of hf with reduced ef , and the starting dose and the target dose are also described in the current guidelines.3 however , it remains unclear which ace inhibitor should be administered or if there are differences between the drugs , because headtohead comparisons are still missing .
angiotensin receptor blockers would be expected to exert beneficial effects on the treatment of hf through the stronger inhibition of angiotensin ii than ace inhibitors .
the evaluation of losartan in the elderly study ii study9 showed that losartan was noninferior to captopril in reducing mortality in elderly patients with hf with reduced ef ( hazard ratio 1.13 , 95% ci 0.951.35 , p  =  0.16 ) , and the candesartan in heart failureassessment of reduction in mortality and morbidityalternative trial10 showed that candesartan reduces the risk of cardiovascular death or hospital admission for hf in patients intolerant of ace inhibitors compared to placebo ( hazard ratio 0.70 , 95% ci 0.600.81 , p  <  0.0001 ) .
subsequently , the heart failure endpoint evaluation of angiotensin ii antagonist losartan study6 revealed that losartan at high dose ( 150  mg daily ) reduced death or hospitalization for hf in patients with hf with reduced ef , compared with losartan at low dose ( 50  mg daily ) ( hazard ratio 0.90 , 95% ci 0.820.99 ; p  =  0.027 ) , indicating the doserelated therapeutic effect of arbs on the outcome of hf as well as ace inhibitors . in the swedish heart failure registry,11 the use of losartan was associated with significant increase in mortality in patients with hf compared with that of candesartan ( hazard ratio 1.43 , 95% ci 1.231.65 , p  <  0.001 ) , suggesting the different clinical effects among arbs .
common side effects of arbs are well known and include hyperkalaemia , hypotension , and impaired renal function , similar to ace inhibitors ; however , arbs are believed to be better tolerated than ace inhibitors .
reports that 29 patients ( 29% ) at supramaximaldose benazepril withdrew from this study , as did 12 patients ( 12% ) at supramaximaldose valsartan .
doserelated increase in the development of adverse events in patients receiving both benazepril and valsartan is observed , which is inconsistent with the findings of previous studies using very highdose arb.12 , 13 
  in view of these findings , arbs are considered second choice in patients with hf with reduced ef who are not tolerated to ace inhibitors or mineralocorticoid receptor antagonists in the current guidelines .
because of the different mechanism of action of ace inhibitors and arbs in blocking the raas , combination therapy of an ace inhibitor and an arb was thought to be attractive for the treatment of hf as well as the monotherapy with an arb . in the valsartan heart failure trial,14 the addition of valsartan to conventional therapy for hf resulted in a significant decrease in cardiovascular events compared to placebo ( relative risk 0.87 , 97.5% ci 0.770.97 , p  =  0.009 ) ; however , a post hoc analysis indicated increased mortality and complications in the subgroup taking an ace inhibitor , valsartan , and a betablocker .
moreover , a recent metaanalysis15 suggested that combination therapy of an ace inhibitor with an arb should not be advocated in patients with hf , because the combination does not seem to reduce mortality or hospitalization and was associated with more adverse events .
as described earlier , an ace inhibitor , lisinopril , or an arb , losartan , at high dose produced better clinical outcomes in patients with hf compared with each at low dose but did not decrease mortality significantly.5 , 6 on the other hand , he et al .
reports that supramaximal dose of benazepril or valsartan improves not only cardiac function but also survival in patients with dcm compared with the low dose of each medication,16 which indicates that ace inhibitors or arbs at supramaximaldose might produce better outcomes in patients with ef compared with those at high dose ( target dose ) .
these unique findings are derived from a singlecentre prospective , randomized , and controlled trial .
the sample size is small , but the followup period is long enough to detect the statistical difference in the outcomes of hf among the treatment groups . they should be confirmed with doubleblind multicentre randomized controlled studies .
recently , ivabradine17 and lcz696 , a combination of the new neprilysin inhibitor sacubitril ( ahu377 ) with valsartan,18 have attracted attention for the treatment of hf .
if the efficacy and safety of supramaximaldose valsartan were well acknowledged in this field , it would be helpful to investigate the appropriate dose of lcz696 more precisely .
 abstractheart failure is a major public issue , and dilated cardiomyopathy ( dcm ) is one of the common etiologies of heart failure . 
 dcm is generally progressive , and some patients with dcm need heart transplant despite optimal medical and mechanical therapy . 
 current guidelines recommend inhibitors of renin  angiotensin  
 aldosterone system , namely angiotensinconvertingenzyme ( ace ) inhibitor , angiotensin receptor blocker ( arb ) , and mineralocorticoid receptor antagonist as well as betablockers for the medical treatment of heart failure with reduced ejection fraction , including dcm . 
 furthermore , because they have beneficial effects on the outcome of heart failure in a doserelated fashion , they should be titrated to the target dose . in clinical practice , 
 the underuse and underdose of these agents matter ; however , the efficacy and safety of supramaximal dose of ace inhibitor or arb have never been investigated in the patients with dcm . in this issue of esc heart failure 
 , it is demonstrated that benazepril or valsartan at supramaximal dose improved left ventricular function and reduced cardiovascular events compared with each drug at low dose , respectively . in this editorial , 
 the current evidence concerning the use of ace inhibitor or arb in patients with hf and future prospective will be discussed . 
Angiotensinconvertingenzyme inhibitor for the treatment of heart failure
Angiotensin receptor blocker for the treatment of heart failure
Combination therapy with angiotensinconvertingenzyme inhibitor and angiotensin receptor blocker, supramaximal dose of angiotensinconvertingenzyme inhibitor or angiotensin receptor blocker and beyond
Future perspective
Conflict of interest