Dr Andrew Clark explains why ACE inhibitors should be prescribed for all patients with evidence of left ventricular systolic dysfunction unless contrindicated
Angiotensin-converting enzyme (ACE) inhibitors have revolutionised the treatment of chronic heart failure.
The first evidence of their potentially dramatic benefits was seen in the CONSENSUS study, published in 1987,1 which demonstrated a 40% mortality reduction in patients with severe heart failure treated with enalapril. The long-term follow-up data have now been published, suggesting that ACE inhibitor therapy increases survival time by 50%.2
Since then, studies have extended the known area of benefit to patients with mild to moderate heart failure3 and those with asymptomatic left ventricular dysfunction.4
Despite this wealth of data, ACE inhibitors are still underused in heart failure – only about 60% of patients with heart failure across Europe are receiving an ACE inhibitor.5
Chronic heart failure is now the most common cause of medical admission to hospital,6 and has a survival rate worse than most forms of cancer. We have effective treatment available, and it should be used as widely as possible.
This article discusses some of the outstanding issues relating to ACE inhibition in heart failure.
Mechanisms of action
ACE catalyses the conversion of angiotensin (Ang) I to Ang II, the active molecule. Through its interaction with its receptors, Ang II causes vasoconstriction and increases the afterload against which the heart has to work (see Figure 1, below).
|Figure 1: The renin-angiotensin-aldosterone system. Enzymes are shown in boxes with double arrows indicating the reactions they catalyse. Drugs interfering with the system are shown in green.|
In the classic haemodynamic view of heart failure, ACE inhibitors produce their beneficial effect by reducing vasoconstriction; however, they have a better effect on mortality than pure vasodilation would lead one to expect.7
The effects are predominantly mediated through reduction in the hypertrophic, growth factor effects of angiotensin II.
Who should be prescribed an ACE inhibitor?
The short answer is that anyone with significant systolic left ventricular dysfunction should be treated with an ACE inhibitor. The optimum duration of treatment is not certain, but is assumed to be lifelong.
This begs the question as to what constitutes significant left ventricular dysfunction, and how to diagnose it. There are two main groups of patients to consider:
- Those with clinical heart failure, i.e. symptoms of heart failure that respond to treatment, who have objective evidence of impairment of left ventricular systolic dysfunction
- Those with asymptomatic left ventricular dysfunction.
Both groups of patients should be treated with an ACE inhibitor. A key investigation is imaging of the left ventricle. Echocardiography is the most widely available technique, and anyone thought likely to have heart failure should have an echocardiogram performed.
A problem then is how to treat a patient found to have mild left ventricular dysfunction. A balance has to be struck, for the individual patient, between current symptoms, previous evidence of heart failure, likely outcome and possible side-effects.
ACE inhibitors post-MI
A variety of trials has demonstrated the potential benefit of ACE inhibitors after myocardial infarction (MI) (see Table 1, below), but the best way of using them remains unclear.
Table 1: Post-infarction ACE inhibitor trials*
|Trial||Year||N||Drug||Targeted?||Follow-up||Active vs Placebo|
|TRACE23||1995||1749||Trandolapril||Yes||42 months||34.7 vs 42.3
|AIRE24||1993||1986||Ramipril||Yes||15 months||17 vs 23
|SAVE25||1992||2231||Captopril||Yes||27 months||20 vs 25
|ISIS-48||1995||58050||Captopril||No||5 weeks||7.19 vs 7.69
|GISSI-39||1994||19394||Lisinopril||No||6 weeks||6.3 vs 7.1
|*ISIS and GISSI took 'all comers' following infarction, whereas the other studies targeted treatment at patients with evidence of left ventricular dysfunction. N is the number of patients in the trial; in the active vs placebo column, the percentage mortality for active and placebo groups is given, together with the relative risk reduction (RRed).|
The greatest benefit accrues to those with the greatest amount of left ventricular dysfunction. Studies that have treated all-comers (ISIS-48 and GISSI-39) have demonstrated benefit with treatment, but this has been a small gain from treating an enormous number of patients.
A pragmatic approach is to target treatment at those patients with most to gain; the next problem is how to identify them.
Any patient who develops symptoms or signs of heart failure following their infarct, and any with significant left ventricular dysfunction on imaging should be treated. A corollary of this approach is that all patients should have some form of imaging following an infarct.
Which ACE inhibitor?
The number of ACE inhibitors available on the market continues to rise, with different manufacturers making very plausible claims as to why theirs is the best: differential tissue binding, differential excretion routes, first-pass metabolism, and so on.
While these arguments may appear seductive (and while it seems very likely that there is a 'class effect') there is firm mortality evidence to support the use of captopril, enalapril, trandolapril, lisinopril and ramipril. These ACE inhibitors should be used in the treatment of heart failure.
What dose of ACE inhibitor?
Many patients are started on a low dose of an ACE inhibitor, only for the dose never to be titrated up. Does this matter?
Two studies have tried to answer the question of dose of ACE inhibitor: NETWORK10 and ATLAS.11
In NETWORK, there was no significant difference in outcomes between patients treated with high- and low-dose enalapril.
The ATLAS study (3164 patients) showed a reduction in the combined endpoint of death and total hospitalisation in the group of patients treated with high dose (32.5–35mg/day) lisinopril compared with low dose (2.5–5mg/day). Further comparative studies are unlikely to be forthcoming.
High dose thus seems to be the better option. For each of the ACE inhibitors it is prudent to use the doses used in mortality trials as the target to aim for, and not accept treatment with low doses unless the patient has proved intolerant of higher doses.
ACE inhibitors vs ARBs
There has been much debate about the relative merits of ACE inhibition and angiotensin receptor antagonism. Figure 1 (above) indicates how the two drug types might differ. Conventional ACE inhibitors are not pure inhibitors of Ang II production and hence of AT1 receptor activation.
- Other enzymes, particularly chymase, catalyse the conversion of Ang I to Ang II, leading to continued production of Ang II despite ACE inibitor treatment.
- Reducing the amount of Ang II reduces the interaction with the AT2 receptor, which is potentially beneficial.
- A newly described enzyme, ACE2, catalyses the production of Ang1-9 (Ang II is Ang1-8). ACE reacts with this to produce Ang1-7 and Ang1-5. The biological roles of these fragments are unknown, but Ang1-7 at least is a vasodilator. Hence ACE inhibition may be deleterious.
On the other hand, ACE catalyses the breakdown of the vasodilator bradykinin. Some of the beneficial effect of ACE inhibition may be due to bradykinin potentiation.
Angiotensin receptor blockers (ARBs or 'sartans') will have different effects. They inhibit the interaction between Ang II and the AT1 receptor only. This causes an increase in the amount of Ang II interaction with the 'good' AT2 receptor. There is no escape phenomenon as there is with chymase in the case of ACE inhibition. On the other hand, there is no effect on bradykinin metabolism.
Two related questions arise: is angiotensin receptor antagonism better than ACE inhibition; and is there any benefit from dual inhibition?
The ELITE studies have addressed the first issue. The original ELITE study12 sought to establish the tolerability of the ARB, losartan, compared with captopril, in a group of older patients with heart failure. It was not powered as a mortality study, but had the unexpected finding that there was a reduction in mortality in the losartan group.
ELITE II13 was therefore conducted, powered to detect a difference in mortality. A total of 3152 patients aged 60 years or more with an ejection fraction of 40% or less were randomised to losartan (50mg once daily) or captopril (50mg three times daily).
At follow-up of 555 days, there was no significant difference in all-cause mortality (11.7 vs 10.4% annual mortality) between the two treatment groups. Indeed, in all the groups analysed, captopril appeared to produce better results. However, significantly fewer patients in the losartan group discontinued study treatment because of adverse effects (9.7 vs 14.7%, P<0.001), including cough (0.3 vs 2.7%).
The question of combination treatment has not yet been answered. On theoretical grounds, combination treatment seems attractive. The ValHeFT study14 examined the effect of valsartan in addition to normal treatment. This showed no effect on overall mortality, but a reduction in hospitalisation for heart failure. The majority of this effect was seen in patients not taking an ACE inhibitor.
More worryingly, there appeared to be an adverse effect with valsartan on outcome in those patients taking a beta-blocker. Given the definitive evidence in favour of beta-blockers, the role of ARBs remains in doubt.
The conclusion from ELITE II and ValHeFT must be that ACE inhibitors continue to be the first-line treatment for heart failure. Where a patient is intolerant of ACE inhibitors, then treatment with an ARB is appropriate.
ACE inhibitors and aspirin interaction
An unresolved issue with ACE inhibitors is their interaction with aspirin. Many heart failure patients will be on aspirin, although there is no evidence that it is beneficial in heart failure. Pretreatment with aspirin prevents the beneficial haemodynamic effects of ACE inhibitors.15, 16
There is some evidence to suggest an interaction between aspirin and ACE in clinical studies: the benefit from ACE inhibitors is less in those patients taking aspirin in the HOPE study,17 for example, and aspirin may worsen the physiology of heart failure.18
The WATCH study19 will answer the question as to whether aspirin should be used: in the meanwhile, it is certainly worth stopping aspirin where it is proving difficult to control heart failure.
Spironolactone and ACE inhibitors
The RALES study20 demonstrated a survival benefit for patients with NYHA class III symptoms treated with the aldosterone antagonist spironolactone.
Both spironolactone and ACE inhibitors cause potassium retention. In the RALES study, around 95% of the patients were taking ACE inhibitors, but there was no difference between spironolactone and placebo groups in the incidence of serious hyperkalaemia. In only 3 of 822 patients was the spironolactone stopped.
Despite these reassuring data, hyperkalaemia is a serious concern, and potassium should be measured within 48 hours of introducing spironolactone and after a further week.
Diastolic heart failure
All the studies discussed so far involved patients with systolic heart failure, i.e. a major abnormality of systolic function. Epidemiological evidence is controversial, but some studies have suggested that in up to half of all patients with heart failure the cause is diastolic dysfunction.
There have been no clinical studies to test the effects of different treatments on survival in diastolic heart failure. There are ongoing clinical trials designed to test the effects of interference with the renin-angiotensin system in diastolic heart failure, such as PEP-CHF21 and the CHARM study.22
Until these studies report, it is difficult to know what treatment to recommend for diastolic heart failure. Such patients should be offered the opportunity to take part in clinical trials.
ACE inhibitors are one of the great success stories of cardiology. They should be prescribed for all patients with evidence of left ventricular systolic dysfunction unless contraindicated, or side-effects intervene.
The ACE inhibitor used, and the target dose, should be one shown to be beneficial in clinical trials. Where an ACE inhibitor is not tolerated, then an ARB is appropriate therapy.
There are unresolved issues relating to the relative roles of ACE inhibition and angiotensin receptor antagonism, particularly in patients who are taking (as most patients should be) a beta-blocker. The interaction with aspirin is also a concern.
The largest area of concern in heart failure management remains the management of diastolic heart failure, where there is no evidence from clinical trials to guide treatment. This is likely to be the next area of advance in heart failure therapy.
Clinical trial acronyms
Trandolapril Cardiac Evaluation
|AIRE||Acute Infarction Ramipril Efficacy|
|SAVE||Survival and Ventricular Enlargement|
|ISIS||International Study of Infarct Survival|
|RALES||Randomized Aldactone Evaluation Study|
|CONSENSUS||Cooperative North Scandinavian Enalapril Survival Study|
|NETWORK||(Not an acronym)|
|ATLAS||Assessment of Treatment with Lisinopril and Survival|
|ELITE||Evaluation of Losartan in the Elderly|
|ValHeFT||Valsartan Heart Failure Trial|
|HOPE||Heart Outcomes Prevention Evaluation Study|
|WATCH||Warfarin and Antiplatelet Therapy in Chronic Heart Failure|
|GISSI||Gruppo Italiano per lo Studio della Sopravvivenza nell'infarto Miocardico|
|CHARM||Candesartan in Heart Failure – Assessment of Reduction in Mortality and Morbidity|
|PEP-CHF||Perindopril for Elderly People with Chronic Heart Failure|
- The CONSENSUS trial study group. Effects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med 1987; 316:1429-35.
- Swedberg K, Kjekshus J, Snapinn S, CONSENSUS investigators. Long-term survival in severe heart failure in patients treated with enalapril; ten year follow-up of CONSENSUS I. Eur Heart J 1999; 20: 136-9.
- The SOLVD investigators. Effects of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991; 352: 293-302.
- Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. The SOLVD Investigators. N Engl J Med 1992; 327: 685-91.
- Witte K, Thackray S, Clark AL, Cooklin M, Cleland JGF. Clinical trials update. Eur J Heart Failure 2000: 2: 455-60.
- Parameshwar J, Poole-Wilson PA, Sutton GC. Heart failure in a district general hospital. Br Heart J 1990; 64: 57-8.
- Cohn JN, Johnson G, Ziesche S et al. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med 1991; 325: 303-10.
- ISIS-4: a randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58,050 patients with suspected acute myocardial infarction. ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group. Lancet 1995; 345: 669-85.
- GISSI-3: effects of lisinopril and transdermal glyceryl trinitrate singly and together on 6-week mortality and ventricular function after acute myocardial infarction. Gruppo Italiano per lo Studio della Sopravvivenza nell'infarto Miocardico. Lancet 1994; 343: 1115-22.
- The NETWORK Investigators. Clinical outcome with enalapril in symptomatic chronic heart failure; a dose comparison. Eur Heart J 1998; 19: 481-9.
- Packer M, Poole-Wilson PA, Armstrong PW et al, on behalf of the ATLAS Study Group. Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. Circulation 1999; 100: 2312-18.
- Pitt B, Segal R, Martinez FA et al. Randomised trial of losartan versus captopril in patients over 65 with heart failure. Lancet 1997; 349: 747-52.
- Pitt B, Poole-Wilson PA, Segal R et al on behalf of the ELITE II investigators. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomised trial – the Losartan Heart Failure Survival Study ELITE II. Lancet 2000; 355: 1582-7.
- Cohn J. The ValHeFT study. Presentation at American Heart Association Meeting, 2000.
- Spaulding C, Charbonnier B, Cohen-Solal A et al. Acute hemodynamic interaction of aspirin and ticlopidine with enalapril: results of a double-blind, randomized comparative trial. Circulation 1998; 98: 757-65.
- Hall D, Zeitler H, Rudolph W. Counteraction of the vasodilator effects of enalapril by aspirin in severe heart failure. J Am Coll Cardiol 1992; 20: 1549-55.
- The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 2000; 342: 145-53.
- Guazzi M, Pontone G, Agostoni P. Aspirin worsens exercise performance and pulmonary gas exchange in patients with heart failure who are taking angiotensin-converting enzyme inhibitors. Am Heart J 1999; 138: 254-60.
- The WASH study Steering Committee and Investigators. The WASH study (Warfarin/Aspirin study in Heart Failure) rationale, design and end-points. Eur J Heart Fail 1999; 1: 95-9.
- Pitt B, Zannad F, Remme WJ et al, for the Randomized Aldactone Evaluation Study Investigators. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999; 341: 709-17.
- Cleland JG, Tendera M, Adamus J et al. Perindopril for elderly people with chronic heart failure: the PEP-CHF study. The PEP investigators. Eur J Heart Fail 1999; 1: 211-17.
- Swedberg K, Pfeffer M, Granger C et al. Candesartan in heart failure – assessment of reduction in mortality and morbidity (CHARM): rationale and design. Charm-Programme Investigators. J Card Fail 1999; 5: 276-82.
- Kober L, Torp-Pedersen C, Carlsen JE et al. A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 1995; 333: 1670-6.
- Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators. Lancet 1993; 342: 821-8.
- Pfeffer MA, Braunwald E, Moye LA et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction – results of the Survival and Ventricular Enlargement trial. N Engl J Med 1992; 327: 669-77.