Clinical review

Management: diuretics, ACE inhibitors, and nitrates

M K Davies,  C R Gibbs,  G Y H Lip. 

In the past 15 years several large scale, randomised controlled trials have revolutionised the management of patients with chronic heart failure. Although it is clear that some drugs improve symptoms, others offer both symptomatic and prognostic benefits, and the management of heart failure should be aimed at improving both quality of life and survival.

Diuretics and angiotensin converting enzyme (ACE) inhibitors, when combined with non-pharmacological measures, remain the basis of treatment in patients with congestive heart failure. Digoxin has a possible role in some of these patients, however, and the potential benefits of  blockers and spironolactone (an aldosterone antagonist) in chronic heart failure are now increasingly recognised.

	Diuretics

Top Diuretics ACE inhibitors Angiotensin receptor... Oral nitrates and hydralazine Other vasodilators

Diuretics are effective in providing symptomatic relief and remain the first line treatment, particularly in the presence of oedema. Nevertheless, there is no direct evidence that loop and thiazide diuretics confer prognostic benefit in patients with congestive heart failure.

Loop diuretics
Loop diureticsfrusemide (furosemide) and bumetanidehave a powerful diuretic action, increasing the excretion of sodium and water via their action on the ascending limb of the loop of Henle. They have a rapid onset of action (intravenously 5 minutes, orally 1-2 hours; duration of action 4-6 hours). Oral absorption of frusemide may be reduced in congestive heart failure, although the pharmacokinetics of bumetanide may allow improved bioavailability.

View larger version (19K): [in this window] [in a new window]   Diagram of nephron showing sites of action of different diuretic classes: 1=loop (eg frusemide); 2=thiazide (eg bendrofluazide); and 3=potassium sparing (eg amiloride)

Thiazide diuretics
Thiazidessuch as bendrofluazide (bendroflumethiazide)act on the cortical diluting segment of the nephron. They are often ineffective in elderly people, owing to the age related and heart failure mediated reduction in glomerular filtration rate. Hyponatraemia and hypokalaemia are commonly associated with higher doses of thiazide diuretics, and potassium supplementation, or concomitant treatment with a potassium sparing agent, is usually needed with high dose thiazide therapy.

View larger version (23K): [in this window] [in a new window]   Survival curve for randomised aldactone evaluation study (RALES) showing 30% reduction in all cause mortality when spironolactone (up to 25 mg) was added to conventional treatment in patients with severe (New York Heart Association class IV) chronic heart failure

Potassium sparing diuretics
Amiloride acts on the distal nephron, while spironolactone is a competitive aldosterone inhibitor. Potassium sparing diuretics have generally been avoided in patients receiving ACE inhibitors, owing to the potential risk of hyperkalaemia. Nevertheless, a recent randomised placebo controlled study, the randomised aldactone evaluation study (RALES), reported that hyperkalaemia is uncommon when low dose spironolactone (25 mg daily) is combined with an ACE inhibitor. Risk factors for developing hyperkalaemia include spironolactone dose >50 mg/day, high doses of ACE inhibitor, or evidence of renal impairment. It is recommended that measurement of the serum creatinine and potassium concentrations is performed within 5-7 days of the addition of a potassium sparing diuretic to an ACE inhibitor until the levels are stable, and then every one to three months.

	ACE inhibitors

Top Diuretics ACE inhibitors Angiotensin receptor... Oral nitrates and hydralazine Other vasodilators

ACE inhibitors have consistently shown beneficial effects on mortality, morbidity, and quality of life in large scale, prospective clinical trials and are indicated in all stages of symptomatic heart failure resulting from impaired left ventricular systolic function.

Mechanisms of action
ACE inhibitors inhibit the production of angiotensin II, a potent vasoconstrictor and growth promoter, and increase concentrations of the vasodilator bradykinin by inhibiting its degradation. Bradykinin has been shown to have beneficial effects associated with the release of nitric oxide and prostacyclin, which may contribute to the positive haemodynamic effects of the ACE inhibitors. Bradykinin may also be responsible, however, for some of the adverse effects, such as dry cough, hypotension, and angio-oedema.

View larger version (7488K): [in this window] [in a new window]   Front view and side view of woman with angio-oedema related to treatment with ACE inhibitors (published with permission of patient)

Clinical effects
Symptomatic left ventricular dysfunction

View larger version (22K): [in this window] [in a new window]   ACE inhibitors in left ventricular dysfunction: best benefit for ACE inhibitors in higher risk group

Doses and tolerability
ACE inhibitors should be started at a low dose and gradually titrated to the highest tolerated maintenance level. The recent prospective assessment trial of lisinopril and survival (ATLAS) randomised patients with symptomatic heart failure to low dose (2.5-5 mg daily) or high dose (32.5-35 mg daily) lisinopril, and, although there was no significant mortality difference, high dose treatment was associated with a significant reduction in the combined end point of all cause mortality and all cause admissions to hospital. Adverse effects of the ACE inhibitors include cough, dizziness, and a deterioration in renal function, although the overall incidence of hypotension and renal impairment in the CONSENSUS and SOLVD studies was only 5%. Angio-oedema related to ACE inhibitors is rare, although more common in patients of Afro-Caribbean origin than in other ethnic groups.

	Angiotensin receptor antagonists

Top Diuretics ACE inhibitors Angiotensin receptor... Oral nitrates and hydralazine Other vasodilators

Orally active angiotensin II type 1 receptor antagonists, such as losartan, represent a new class of agents that offer an alternative method of blocking the renin-angiotensin system. The effects of angiotensin II receptor antagonists on haemodynamics, neuroendocrine activity, and exercise tolerance resemble those of ACE inhibitors, although it still remains to be established fully whether these receptor antagonists are an effective substitute for ACE inhibitors in patients with chronic heart failure.

The evaluation of losartan in the elderly (ELITE) study compared losartan with captopril in patients aged 65 or over with mild to severe congestive heart failure. Although the ELITE study was designed as a tolerability study, and survival was not the primary end point, it did report a reduction in all cause mortality (4.8% v 8.7%) in patients treated with losartan. Important limitations of the ELITE study included the limited size and the relatively short follow up. However, the recently reported ELITE II mortality study failed to show that treatment with losartan was superior to captopril, although it confirmed improved tolerability with losartan.

ACE inhibitors, therefore, remain the treatment of choice in patients with left ventricular systolic dysfunction, although angiotensin II receptor antagonists are an appropriate alternative in patients who develop intolerable side effects from ACE inhibitors.

	Oral nitrates and hydralazine

Top Diuretics ACE inhibitors Angiotensin receptor... Oral nitrates and hydralazine Other vasodilators

The V-HeFT trials showed a survival benefit from combined treatment with nitrates and hydralazine in patients with symptomatic heart failure (New York Heart Association class II-III). The V-HeFT II trial also showed a modest improvement in exercise capacity, although the nitrate and hydralazine combination was less well tolerated than enalapril, owing to the dose related adverse effects (dizziness and headaches). There is no reproducible evidence of symptomatic improvement from other randomised placebo controlled trials, however, and survival rates were higher with ACE inhibitors than with the nitrate and hydralazine combination (V-HeFT II trial).

In general, oral nitrates should be considered in patients with angina and impaired left ventricular systolic function. The combination of nitrates and hydralazine is an alternative regimen in patients with severe renal impairment, in whom ACE inhibitors and angiotensin II receptor antagonists are contraindicated. Although it is rational to consider the addition of a combination of nitrates and hydralazine in patients who continue to have severe symptoms despite optimal doses of ACE inhibitors, no large scale trials have shown an additive effect of these combinations.

	Other vasodilators

Top Diuretics ACE inhibitors Angiotensin receptor... Oral nitrates and hydralazine Other vasodilators

Long acting dihydropyridine calcium channel blockers generally have neutral effects in heart failure, although others, such as diltiazem and verapamil, have negatively inotropic and chronotropic properties, with the potential to exacerbate heart failure. Two recent trials of the newer calcium channel blockers amlodipine (the prospective randomised amlodipine survival evaluation (PRAISE) trial) and felodipine (V-HeFT III) in patients with heart failure suggest that long acting calcium antagonists may have beneficial effects in non-ischaemic dilated cardiomyopathy, although further studies are in progressfor example, PRAISE II. Importantly, these studies indicate that amlodipine and felodipine seem to be safe in patients with congestive heart failure and could therefore be used to treat angina and hypertension in this group of patients.

View larger version (20K): [in this window] [in a new window]   Cumulative mortality in V-HeFT II trial: enalapril v hydralazine plus isosorbide dinitrate in patients with congestive heart failure (mild to moderate)

	Acknowledgments

The two tables on recommended doses of ACE inhibitors are adapted and reproduced with permission from Remme WJ (Eur Heart J 1997;18: 736-53). The meta-analysis table is adapted and used with permission from Garg R et al (JAMA 1995;273:1450-6). The graph showing the benefit of ACE inhibitors in left ventricular dysfunction is adapted from Davey Smith et al (BMJ 1994;308:73-4).

	Footnotes

The ABC of heart failure is edited by C R Gibbs, M K Davies, and G Y H Lip. CRG is research fellow and GYHL is consultant cardiologist and reader in medicine in the university department of medicine and the department of cardiology, City Hospital, Birmingham; MKD is consultant cardiologist in the department of cardiology, Selly Oak Hospital, Birmingham. The series will be published as a book in the spring.