Prescribing Review - Prescribing of Drugs Affecting the Renin-Angiotensin System


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Prescribing of cardiovascular drugs has increased by 82% since 2000, when the National Service Framework for Coronary Heart Disease was published. This trend has been matched by increased prescribing of drugs acting on the renin-angiotensin system - that is, ACE inhibitors (ACEIs) and angiotensin-II receptor antagonists (ARAs). In Prescribing Costs in Primary Care, the National Audit Office estimated that £67 million could be saved by increasing the use of generic ACEIs in place of ARAs, which are more expensive and offer no advantage for most patients.¹ ACEIs currently account for 72% of prescribing but the proportion of prescriptions for ARAs has been increasing steadily (Chart 1). In the last three years, increases in cost have been limited by the introduction of generic ramipril, the leading ACEI (Chart 2). However, growth in prescribing of ARAs, which are more expensive than ACEIs, has continued to exert upward pressure on costs and ARAs now account for 65% of total costs for this class. There is also a trend for increased prescribing of perindopril which, even generically, is more expensive than ramipril (see Prescribing Data).

Although the licensed indications vary, ACEIs and ARAs are primarily prescribed for the treatment of hypertension and heart failure and for secondary prevention of cardiovascular events post-myocardial infarction.

Hypertension

The National Institute for Health and Clinical Excellence (NICE) clinical guideline on the management of hypertension, updated in 2006, states that hypertension should be treated as part of the overall management of cardiovascular risk in individual patients.² There is no evidence of clinically significant differences in overall efficacy between or within the various classes of antihypertensive drugs with the exception of beta-blockers, which reduce the risk of major events less effectively. The choice of initial treatment should therefore be made according to individual patient factors (e.g. age, comorbidity, ethnicity), the nature of adverse effects and cost. NICE recommends that initial treatment for patients aged over 55 years, or for those of African or Caribbean descent of any age, should be either a thiazide diuretic (D) or a calcium channel blocker (C). In patients under 55 years, the drug of first choice is an ACEI (A); if this is not tolerated, an ARA is appropriate. ACEIs are also the drugs of first choice to lower blood pressure (BP) in patients with diabetes who have microalbuminuria or proteinuria.³ If combinations of two drugs are indicated, the recommended regimens are A+C or A+D; if three are needed, the recommended regimen is A+C+D. Combinations of four drugs may include a second diuretic, a beta-blocker or an alpha-blocker; specialist advice should also be considered. In clinical trials, about half of patients required treatment with more than one antihypertensive to achieve target BP.

ACEIs are preferred to ARAs because the long-term outcome data are stronger for ACEIs, they cost less, and there is no convincing evidence of clinical advantage. A meta-analysis of 48 clinical trials and 13 observational studies which compared ACEIs and ARAs found no consistent differences in BP control; as monotherapy they were both effective in about 55% of patients.⁴ In these trials, reported rates of discontinuation due to adverse events varied between 1% and 41% for both ACEIs and ARAs and the data were of variable quality. The odds ratio for withdrawal due to adverse events for ARAs vs. ACEIs was 0.51 (95%CI 0.38 - 0.70) (median withdrawal rate 3.7% vs. 8.0%). The incidence of adverse effects was similar overall but cough was more frequent with ACEIs than ARAs. This difference was greater in clinical trials when patients were asked about it directly (9.9 vs. 3.2%) than was reported in cohort studies (1.7 vs. 0.6%). NICE's economic model of the cost effectiveness of treatment assumed, based on expert opinion, that ACEIs would account for 80% of prescribing and ARAs for 20%. However, it should be noted that this not an evidence-based assumption. Chart 3 shows that the percentage of items for ACEIs ranges from 68% to 78% across Strategic Health Authorities.

Clinical trials show that combining an ACEI and an ARA offers a further reduction in BP compared with monotherapy but the effect is small (3 - 4/2 - 3 mmHg)5 and is probably also achievable by titrating the ACEI to the target dose. The adverse effects associated with long-term combined treatment have not been adequately quantified.⁵ It is therefore preferable to add an antihypertensive from another class when target BP is not achieved with an ACEI.

Post myocardial infarction
Early treatment with an ACEI after acute myocardial infarction (MI) reduces mortality and reinfarction by approximately 10 - 20% (depending on left ventricular function) during the first 2 - 5 years, with a 10% reduction in all-cause mortality over 12 years.¹³ NICE guidance recommends treatment with an ACEI, a beta-blocker, aspirin and a statin.¹⁴ An ACEI should be initiated early after MI and the dose titrated as recommended for heart failure; treatment should continue indefinitely whether or not the patient is symptomatic. Patients who had an MI more than a year previously and are symptomatic should be treated according to NICE guidance on heart failure management; if they are asymptomatic, they should be offered an ACEI even if left ventricular function is preserved. NICE restricts the role of ARAs to intolerance of an ACEI; combined treatment is not recommended for routine use. There is no difference in efficacy between different ACEIs or between the ACEIs and ARAs in preventing recurrent MI or death after acute MI.¹⁵ The VALIANT trial compared valsartan and captopril separately and in combination post-myocardial infarction.¹⁶ The incidence of adverse events leading to treatment discontinuation was significantly lower with valsartan than captopril or combined treatment (5.8 vs. 7.7 and 9.0% respectively) but the difference in the incidence of cough leading to discontinuation was small (valsartan 0.6% vs. captopril 2.5%).

Prescription items for drugs affecting the renin-angiotensin system have increased by 85% in the last 5 years to 12.4 million items, whereas cost has decreased by 7% to £103 million. Prescribing of ACEIs has increased by 68% (to 8.9 million items), whilst cost has decreased by 51% (to £36 million). ACEIs now account for 72% of prescribed drugs affecting the renin-angiotensin system but only 35% of the cost. Ramipril represents 45% of all ACEI items and 19% of cost, while lisinopril accounts for 25% of ACEI items and 9% of cost. Whereas prescribing of ramipril has risen by 147%, its cost has fallen by 72%. Prescribing of ramipril is predominantly in the form of capsules (94% of items and 83% of the cost), which are cheaper than tablets. Perindopril accounts for 16% of ACEI items (1.4 million) but 57% of cost (£20.4 million). The patent on perindopril erbumine (Coversyl) expired in June 2003 and generic versions of perindopril erbumine have been available in the UK since July 2007. The manufacturers of Coversyl have announced that it is to be discontinued and replaced with Coversyl Arginine which has a different equivalent dose (2mg perindopril erbumine is equivalent to 2.5mg perindopril arginine). For patients taking Coversyl, prescribers will have two choices: either to prescribe perindopril erbumine as the generic product so patients stay on the same dose and formulation, or switch patients to Coversyl Arginine with the appropriate dose change. Prescribing of ARAs has increased by 145% (to 3.5 million items) with cost rising by 80% (to £67 million). At present there are no generic presentations of ARAs. The most frequently prescribed ARA is candesartan (28% of items and 21% of cost). This represents an increase in prescribing of over 250% and an increase in spending of 137%. 23% of ARA items are for losartan (25% of cost).

REFERENCES

1. National Audit Office. Prescribing Costs in Primary Care. May 2007
2. NICE. Management of hypertension in adults in primary care. Clinical Guideline 34; June 2006
3. NICE. Management of type 2 diabetes. Management of blood pressure and blood lipids. Inherited Clinical Guideline H. October 2002
4. Matchar DB, McCrory DC, Orlando LA et al. Systematic review: comparative effectiveness of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers for treating essential hypertension. Ann Inter Med 2008;148:16-29
5. Doulton TW, He FJ, MacGregor GA. Systematic review of combined angiotensin-converting enzyme inhibition and angiotensin receptor blockade in hypertension. Hypertension 2005;45:880-6
6. NICE. Management of chronic heart failure in adults in primary and secondary care. Clinical Guideline 5. July 2003
7. National Prescribing Centre. Chronic heart failure: overview of diagnosis and drug treatment in primary care. MeReC Bulletin 2008;18 (3).
8. Flather MD, Yusuf S, Køber L et al for the ACE-inhibitor Myocardial Infarction Collaborative Group. Long-term ACE inhibitor therapy in patients with heart failure or left-ventricular dysfunction: a systematic overview of data from individual patients. Lancet 2000;355:1575–81
9. Lee VC, Rhew DC, Dylan M et al. Meta-analysis: angiotensin receptor blockers in chronic heart failure and high-risk acute myocardial infarction. Ann Intern Med 2004;141:693–704
10. Pitt B, Poole-Wilson PA, Segal R et al. 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
11. McMurray JJV, Östergren J, Swedberg K et al. Effects of candesartan in patients with chronic heart failure and reduced left ventricular function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet 2003;362:767–71
12. Cohn JN, Tognoni G for the Valsartan Heart Failure Trial Investigators. A randomised trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med 2001;345:1667–75
13. Cooper A, Skinner J, Nherera L et al. Clinical Guidelines and Evidence Review for Post Myocardial Infarction: Secondary prevention in primary and secondary care for patients following a myocardial infarction. London: National Collaborating Centre for Primary Care and Royal College of General Practitioners. 2007
14. NICE. Secondary prevention in primary and secondary care for patients following a myocardial infarction Clinical Guideline 48. May 2007
15. Hansen ML, Glslason GH, Køber L et al. Different angiotensin-converting enzyme inhibitors have similar clinical efficacy after myocardial infarction. Br J Clin Pharmacol 2007;65:217-23
16. Pfeffer MA, McMurray JJ, Velazquez EJ et al. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med 2003;349:1893-906
    

• The National Audit office estimates that £67 million could be saved by increasing the use of generic ACEIs in place of ARAs.
• ACEIs are preferred to ARAs for hypertension, heart failure and secondary prevention after MI because the long-term outcome data is stronger for ACEI.
• For the treatment of hypertension, the first choice in people aged over 55 years, or those of African or Caribbean descent of any age, is either a thiazide diuretic or a calcium blocker. In patients under 55 years, the first choice is an ACEI or ARA.
• For the treatment of heart failure, initial treatment should be with an ACEI (or ARA, if not tolerated), a beta-blocker and a diuretic.
• For post MI, the recommended drug regimen is an ACEI, a beta-blocker, aspirin and a statin.
• The incidence of adverse effects is similar between ACEIs and ARAs except for cough, which is more frequent with ACEIs.