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ACE inhibition in cardiovascular disease

Lynda Filer
MSc BSc(Hons) RGN PGCEA
Lecturer in Applied Biological Sciences
City University
London

Prashant Sanghani
MSc MRPharmS BPharm
Senior Directorate Pharmacist
Medical and Emergency
Bart's and The London NHS Trust
London

Initial research carried out on angiotensin-converting enzyme (ACE) inhibitors looked at their ability to treat hypertension and heart failure. The results of these trials suggested that there might be a wider benefit in reducing the risk of other cardiovascular events, including myocardial infarction and stroke.

Mode of action
ACE inhibitors work by inhibiting ACE, an enzyme that plays an important role in the renin- angiotensin-aldosterone system. ACE converts angiotensin I to angiotensin II, predominantly in the lung. Angiotensin II is a powerful vasoconstrictor that also stimulates the adrenal cortex to produce aldosterone. Aldosterone acts on the renal tubules to increase the reabsorption of sodium and water.
Angiotensin II and aldosterone contribute to increased systemic vascular resistance, circulatory congestion and, as has more recently been understood, myocardial fibrosis and hypertrophy. They also play a role in endothelial dysfunction, reducing fibrinolysis and plaque rupture.
The most obvious physiological effects of ACE inhibitors are peripheral vasodilatation, reduction in afterload and a decrease in blood ­pressure.

Heart failure
Heart failure, which has been defined as a syndrome caused by a reduction in the output of the heart, is one pathology in which ACE inhibitors have been shown to be beneficial. Heart failure is an increasing problem, and there is a need to control its symptoms, improve the quality of life, slow the progression of the disease and reduce the frequency of admissions to hospitals. 
There have been a large number of clinical trials in this area, probably because there has been a greater awareness of the underlying mechanisms causing heart failure. Left ventricular dysfunction causes activation of many neurohormonal reflexes (including the sympathetic nervous system and the renin- angiotensin-aldosterone system) that lead to heart failure. The alteration to the renin-angiotensin-aldosterone system caused by ACE inhibitors is thought to be the reason that these drugs are so effective in prolonging survival and improving quality of life in patients with heart failure.(1)

Clinical trials
The first major clinical trial that demonstrated the benefits of ACE inhibitors was the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS).(2) It demonstrated a significant reduction in mortality rates in patients with severe heart failure treated with enalapril as opposed to placebo.
The Studies of Left Ventricular dysfunction (SOLVD), designed to assess the effect of enalapril on mortality in patients with mild to moderate heart failure, found that there was a significant reduction in mortality.(3) A number of other clinical trials were conducted (see Table 1), and an overview of 32 clinical trials indicated that morbidity and mortality were significantly reduced by ACE inhibitors in a wide range of patients with heart failure.(4)

[[NIP02_table1_22]]
 
The SAVE trial suggested that treatment with ACE inhibitors might reduce the risk of cardiovascular events. The Heart Outcomes Prevention Evaluation (HOPE) trial was developed to study the effects of an ACE inhibitor, ramipril, on death from cardiovascular causes, such as myocardial infarction or stroke as a primary outcome in patients with no signs of heart failure.(8) The secondary outcomes were death from any cause (ie, heart failure) or the need for revascularisation. The study found that there was an overall reduction in myocardial infarction, stroke and death rates from cardiovascular causes.
ACE inhibitors also inhibit the degradation of bradykinin. Bradykinin is a vasodilator and therefore may contribute to the reduction in blood pressure seen with the administration of ACE inhibitors; however, it has been proposed that bradykinin may be responsible for the side-effects seen with ACE inhibitors such as a dry cough, angio-oedema and hypotension.(9)

Angiotensin II receptor blockers
A newer class of drugs, angiotensin II receptor blockers, block the receptor sites to which angiotensin II binds. There are two receptor sites identified at present - AT1 and AT2. The present group of drugs blocks AT1 receptor sites. They are thought to have the same beneficial effects as ACE inhibitors but without the adverse effects related to bradykinin.
Clinical trials have been carried out to establish whether angiotensin II receptor blockers are as effective as ACE inhibitors in treating heart failure. The Evaluation of Losartan in the Elderly (ELITE) study compared the angiotensin II receptor blocker losartan with the ACE inhibitor captopril.(10) The results showed that the effects on renal function as measured by creatinine elevation were similar for both groups of drugs, but the risks of hospitalisation or death were lower within the group treated with losartan. 
However, a larger study - ELITE II - found that there was no statistical difference for the primary endpoint of mortality between losartan and captopril. Losartan was, however, better tolerated.(11)
The Valsartan Heart Failure Trial (Val-Heft) has been designed to investigate the effects that the angiotensin receptor blocker (valsartan) will have on mortality and morbidity in patients with heart failure, in combination with ACE inhibitors.(12) The preliminary results suggest that there is significant reduction in morbidity and mortality.(13) We await publication of the complete study.

Conclusion
Clinical trials support the use of ACE inhibitors as first-line treatment for patients with heart failure and postmyocardial infarction (AIRE), and even for patients with cardiovascular risk factors without heart failure (HOPE). Clinical trials using angiotensin II receptor blockers have, so far, supported their use only in combination with ACE inhibitors.

[[NIP02_pp_24]]

References

  1. Lonn E, McKelvie R. Drug ­treatment in heart failure. BMJ 2000;320:1188-92.
  2. 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(23):1429-35.
  3. The Studies of Left Ventricular Dysfunction (SOLVD) Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991;325(5):293-302.
  4. Garg R, Yusuf S, for the Collaborative Group on ACE Inhibitor Trials. Overview of randomised trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. JAMA 1995;273(18):1450-6.
  5. 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(5):303-10.
  6. Pfeffer MA, Braunwald E, Moye LA, et al, on behalf of the SAVE ­investigators. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after ­myocardial infarction. Results of the Survival and Ventricular Enlargement (SAVE) Trial. N Engl J Med 1992; 327(10):669-77.
  7. The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lancet 1993;342:821-8.
  8. The Heart Outcomes Prevention Evaluation Study Investigators. Effects of angiotensin-converting enzyme inhibitor, ramipril, on ­cardiovascular events in high risk patients. N Engl J Med 2000;342(3):145-53.
  9. Davies MK, Gibbs CR, Lip GYH. ABC of heart failure. Management: diuretics, ACE inhibitors, and nitrates. BMJ 2000;320:428-31.
  10. Pitt B, Segal R, Martinez FA, et al. Randomised trial of losartan versus captopril in patients over 65 with heart failure (Evaluation of Losartan in the Elderly Study, ELITE). Lancet 1997;349:747-52.
  11. Pitt B, Poole-Wilson PA, Segal R, et al. Effects of losartan versus ­captopril on mortality in patients with ­symptomatic heart failure: rationale, design and baseline characteristics of patients in the Losartan Heart Failure Survival Study (ELITE II). J Card Failure 1999;5(2):146-54.
  12. Cohn JN, Tognoni G, Glazer RD, et al. Rationale and design of the Valsartan Heart Failure Trial: a large multinational trial to assess the effects of valsartan, an angiotensin-receptor blocker on morbidity and mortality in chronic congestive heart failure. J Card Failure 1999;5:155-60.
  13. Cohn JN,Tognoni G for the Val-HeFT Investigators. Effect of the angiotensin receptor blocker valsartan on morbidity and mortality in heart ­failure: the Valsartan Heart Failure Trial (Val-HeFT). Circulation 2000;102(21):2672-B.

Resources
British Heart Foundation
W:www.bhf.org.uk

Heartlink
W:www.heartlink.org.uk

Further reading
Department of Health.
Coronary heart disease: emerging findings report.
London: DoH; 1998

Department of Health.
National Service Framework for coronary heart disease.
London: DoH; 2000
(www.doh.gov.uk/nsf/coronary.htm)