Renin-Angiotensin System RAS Drugs

1. Renin-Angiotensin System (RAS) Drugs October 2011

2. Why are we looking at this? From April 2010 to March 2011, approximately £37 million was spent on RAS drugs in the West Midlands. RAS drugs are one of the National Prescribing Centre’s key Quality, Innovation, Productivity and Prevention (QIPP) topics1 and there: “are likely to be safety and effectiveness benefits as well as cost-savings from reviewing and where appropriate, revising prescribing of ACE inhibitors and ARBs” “has been progress on this topic in only a minority of localities, despite it being one of the Better Care, Better Value (BCBV) national indicators.” is a prescribing comparator available to support this QIPP topic http://www.nhsbsa.nhs.uk/PrescriptionServices/3332.aspx Cost of losartan has recently decreased considerably as a result of the introduction of low-cost generic formulations 2

3. What are RAS drugs? Angiotensin converting enzyme inhibitors (ACEi) inhibit the conversion of angiotensin I to angiotensin II. Frequently prescribed ACEi include: enalapril maleate lisinopril perindopril erbumine or perindopril arginine ramipril Angiotensin receptor blockers (ARBs*) block actions of angiotensin II mediated by the AT1 receptor. Frequently prescribed ARBs include: losartan candesartan telmisartan valsartan Renin inhibitors inhibit renin directly. Aliskiren is currently the only available renin inhibitor *also known as angiotensin II receptor antagonists (A2RAs) 3 Notes for presenters ACEi inhibit angiotensin converting enzyme. This enzyme converts angiotensin I to the active mediator angiotensin II, a potent vasoconstrictor that also causes vascular growth and aldosterone release. There are currently more than 10 ACEi available in the UK including enalapril, lisinopril, perindopril and ramipril. ARBs are receptor antagonists that block type 1 angiotensin II (AT1) receptors on bloods vessels and other tissues (e.g. heart). There are currently seven ARBs available in the UK including candesartan, losartan, telmisartan and valsartan. Renin inhibitors are a new class of drugs that also target the renin-angiotensin system. Currently, the only available renin inhibitor is aliskiren. This presentation will focus on ACEi and ARBs (direct renin inhibitors will not be discussed). Notes for presenters ACEi inhibit angiotensin converting enzyme. This enzyme converts angiotensin I to the active mediator angiotensin II, a potent vasoconstrictor that also causes vascular growth and aldosterone release. There are currently more than 10 ACEi available in the UK including enalapril, lisinopril, perindopril and ramipril. ARBs are receptor antagonists that block type 1 angiotensin II (AT1) receptors on bloods vessels and other tissues (e.g. heart). There are currently seven ARBs available in the UK including candesartan, losartan, telmisartan and valsartan. Renin inhibitors are a new class of drugs that also target the renin-angiotensin system. Currently, the only available renin inhibitor is aliskiren. This presentation will focus on ACEi and ARBs (direct renin inhibitors will not be discussed).

4. For what conditions are ACEi and ARBs used? Used for a range of conditions. Licensed indications for different ACEi and ARBs vary. All ACEi and ARBs are licensed for the treatment of hypertension. Variously indicated for the treatment of other conditions including: Heart Failure Prophylaxis of cardiovascular (CV ) events in patients at high risk Secondary prevention after myocardial infarction (MI) Diabetic nephropathy 4 Notes for presenters Although ACEi and ARBs work at different steps of the renin-angiotensin system, they are broadly indicated for similar conditions. The exact licensed indication varies from drug to drug. All ACEi and ARBs are licensed for the treatment of hypertension Variously indicated for the treatment of other conditions including heart failure, prevention of cardiovascular events in patients at high risk, secondary prevention post-MI and diabetic nephropathy Notes for presenters Although ACEi and ARBs work at different steps of the renin-angiotensin system, they are broadly indicated for similar conditions. The exact licensed indication varies from drug to drug. All ACEi and ARBs are licensed for the treatment of hypertension Variously indicated for the treatment of other conditions including heart failure, prevention of cardiovascular events in patients at high risk, secondary prevention post-MI and diabetic nephropathy

5. NICE guidelines NICE recommends the use of ACEi or ARBs in: Hypertension (CG127, 2011)2 Heart failure (CG108, 2010)3 Type 2 diabetes (CG87, 2009)4 Chronic kidney disease (CKD, CG73, 2008)5 MI: secondary prevention (CG48, 2007)6 The NICE guidelines for heart failure, type 2 diabetes, CKD and MI secondary prevention recommend: ACEi as first-line agents where angiotensin blockade is required ARBs only for patients who are intolerant or allergic to ACEi In the recently updated NICE hypertension guideline: An ACEi or a low cost ARB are recommended if a renin-angiotensin drug is required. If an ACE inhibitor is prescribed and is not tolerated, offer a low-cost ARB. 5 Notes for presenters This slide shows the relevant NICE guidance that is applicable when ACEi or ARBs are prescribed. NICE recommends the use of ACEi or ARBs in hypertension, heart failure, type 2 diabetes, chronic kidney disease and post MI. In all but one of these guidelines (the recently updated hypertension guideline), NICE recommend ACEi as the first-line agents if a renin-angiotensin drug is required. ARBs should only be used if patients are intolerant or allergic to ACEi (see slide 15 to 18 for further detail). In the recently updated NICE hypertension guideline, an ACEi or a low cost ARB are recommended if a renin-angiotensin drug is required (see slide 14 for further detail). Notes for presenters This slide shows the relevant NICE guidance that is applicable when ACEi or ARBs are prescribed. NICE recommends the use of ACEi or ARBs in hypertension, heart failure, type 2 diabetes, chronic kidney disease and post MI. In all but one of these guidelines (the recently updated hypertension guideline), NICE recommend ACEi as the first-line agents if a renin-angiotensin drug is required. ARBs should only be used if patients are intolerant or allergic to ACEi (see slide 15 to 18 for further detail). In the recently updated NICE hypertension guideline, an ACEi or a low cost ARB are recommended if a renin-angiotensin drug is required (see slide 14 for further detail).

6. What is the evidence for the efficacy of ACEi vs. ARBs? Larger evidence base for ACEi vs. ARBs No robust evidence that ARBs more effective than ACEi for any indication. For some conditions, better evidence for efficacy with ACEi than ARBs. Systematic reviews have found ACEi reduce morbidity and/or mortality vs. placebo in: hypertension7 heart failure8, stable ischaemic heart disease9,and diabetic kidney disease10 Evidence for benefit of ARBs on morbidity and mortality vs. placebo is less consistent. A meta-analysis (2011) of 37 RCTs of patients with a variety of conditions, found11: compared with placebo, ARBs associated with a significantly lower risk of stroke, heart failure and new onset diabetes. compared with placebo or active treatment, no beneficial effect on MI, CV mortality or all-cause mortality. 6 Notes for presenters ACEi have been on the market for longer than ARBs and consequently ACEi have a larger evidence base than ARBs. There is no robust evidence that ARBs are more effective than ACEi for any indication. For some conditions there is better evidence for efficacy with ACEi than ARBs. Systematic reviews and meta-analyses have demonstrated that ACEi reduce cardiovascular morbidity and/or mortality in hypertension, heart failure, stable ischaemic heart disease and diabetic kidney disease. The evidence that ARBs reduce CV morbidity and mortality has been less clear. There is concern that ARBs may be less effective than ACEi inhibitors in preventing MI. A recently published meta-analysis evaluated cardiovascular outcomes and other outcomes associated with ARBs. The analysis included 37 RCTs (total of 147,020 participants) with a variety of conditions (e.g. acute MI, atrial fibrillation, coronary artery disease, type 1 or type 2 diabetes, heart failure , hypertension, nephropathy, renal impairment and stroke). Compared with placebo, ARBs were associated with a significantly lower risk of stroke , heart failure (RR 0.85, 0.79 to 0.92) and new onset diabetes (RR 0.90, 0.85 to 0.94)). However, there was no significant difference in the relative risk of MI, all-cause mortality, cardiovascular mortality or angina compared with placebo, or active comparators. Notes for presenters ACEi have been on the market for longer than ARBs and consequently ACEi have a larger evidence base than ARBs. There is no robust evidence that ARBs are more effective than ACEi for any indication. For some conditions there is better evidence for efficacy with ACEi than ARBs. Systematic reviews and meta-analyses have demonstrated that ACEi reduce cardiovascular morbidity and/or mortality in hypertension, heart failure, stable ischaemic heart disease and diabetic kidney disease. The evidence that ARBs reduce CV morbidity and mortality has been less clear. There is concern that ARBs may be less effective than ACEi inhibitors in preventing MI. A recently published meta-analysis evaluated cardiovascular outcomes and other outcomes associated with ARBs. The analysis included 37 RCTs (total of 147,020 participants) with a variety of conditions (e.g. acute MI, atrial fibrillation, coronary artery disease, type 1 or type 2 diabetes, heart failure , hypertension, nephropathy, renal impairment and stroke). Compared with placebo, ARBs were associated with a significantly lower risk of stroke , heart failure (RR 0.85, 0.79 to 0.92) and new onset diabetes (RR 0.90, 0.85 to 0.94)). However, there was no significant difference in the relative risk of MI, all-cause mortality, cardiovascular mortality or angina compared with placebo, or active comparators.

7. Efficacy of ACEi vs. ARBs continued ONTARGET – largest RCT comparing ACEi vs. ARB12 Double-blind non-inferiority RCT, compared ramipril 10 mg/day (n = 8,576) with telmisartan 80 mg/day (n = 8,542) or both (n = 8,502) in patients with vascular disease or diabetes but not heart failure. Primary outcome: composite of CV death, MI, stroke or heart failure hospitalisation After a median follow-up of 56 months, no difference in primary outcome between groups Telmisartan non-inferior to ramipiril, 16.5% ramipril vs.16.7% telmisartan (relative risk [RR] 1.01, 95% CI 0.94 to 1.09). 16.3% with combination (RR compared with ramipril 0.99, 95% CI 0.92 to 1.07) 7 Notes for presenters ONTARGET is to date, the largest RCT that has compared an ACEi with an ARB. ONTARGET was a double-blind RCT that included over 25,000 patients aged over 55 years with vascular disease or diabetes but without heart failure. Patients were randomised to receive either ramipril, telmisartan or both drugs (combination therapy). After a median follow up of 56 months, there was no significant difference between the treatment groups in the primary outcome, a composite of CV death, MI, stroke, or hospitalisation for heart failure. Telmisartan was deemed to be non-inferior to ramipril. A primary outcome event occurred in 16.5% of patients in the ramipril group, 16.7% in the telmisartan group and 16.3% in the combination group. Notes for presenters ONTARGET is to date, the largest RCT that has compared an ACEi with an ARB. ONTARGET was a double-blind RCT that included over 25,000 patients aged over 55 years with vascular disease or diabetes but without heart failure. Patients were randomised to receive either ramipril, telmisartan or both drugs (combination therapy). After a median follow up of 56 months, there was no significant difference between the treatment groups in the primary outcome, a composite of CV death, MI, stroke, or hospitalisation for heart failure. Telmisartan was deemed to be non-inferior to ramipril. A primary outcome event occurred in 16.5% of patients in the ramipril group, 16.7% in the telmisartan group and 16.3% in the combination group.

8. Safety and tolerability of ACEi vs. ARBs No evidence that ARBs are safer than ACEi for any indication Both ACEi and ARBs are generally well tolerated. Adverse effects with both drug classes include17: hypotension, angioedema, worsening of renal function, hyperkalaemia ACEi may cause persistent dry cough in a minority of patients17 In ONTARGET, 4.2% of patients taking an ACEi discontinued because of cough vs. 1.1% of patients taking an ARB12 Other causes of cough (e.g. heart failure) should always be considered before discontinuing an ACEi ACEi and ARBs have similar monitoring requirements (renal function)17 ACEi and ARBs contraindicated in pregnancy18, not recommended for breastfeeding mothers19 8 Notes for presenters There is no good evidence that ARBs are safer than ACEi for any indication Both ACEi and ARBs are generally well tolerated and have a relatively low incidence of adverse effects. Adverse effects with both drug classes include hypotension, renal impairment In a minority of patients ACEi may cause a persistent dry cough. It usually develops one week to a few months after starting treatment. ARBs are less likely to cause cough as they do not inhibit the breakdown of bradykinin, and other kinins. In the ONTARGET study, 4.2% of patients in the ACEi arm stopped their treatment (ramipril) because of intractable cough compared with 1.1% in the arm taking an ARB (telmisartan). Other causes of cough (e.g. heart failure) should always be considered before discontinuing an ACEi ACEi and ARBs have similar monitoring requirements (renal function) The MHRA have advised that ACEi and ARBs should not be used at any stage of pregnancy as they may adversely effect fetal and neonatal blood pressure control and renal function. Skull defects have also been reported. Use in women who are planning pregnancy should be avoided unless absolutely necessary, in which case the potential risks and benefits should be discussed. ACEi and ARBS are not recommended for use by breastfeeding mothers. In mothers who are breastfeeding older infants, the use of captopril, enalapril, or quinapril may be considered if an ACEi is necessary for the mother. Careful follow-up of the infant for possible signs of hypotension is recommended. Notes for presenters There is no good evidence that ARBs are safer than ACEi for any indication Both ACEi and ARBs are generally well tolerated and have a relatively low incidence of adverse effects. Adverse effects with both drug classes include hypotension, renal impairment In a minority of patients ACEi may cause a persistent dry cough. It usually develops one week to a few months after starting treatment. ARBs are less likely to cause cough as they do not inhibit the breakdown of bradykinin, and other kinins. In the ONTARGET study, 4.2% of patients in the ACEi arm stopped their treatment (ramipril) because of intractable cough compared with 1.1% in the arm taking an ARB (telmisartan). Other causes of cough (e.g. heart failure) should always be considered before discontinuing an ACEi ACEi and ARBs have similar monitoring requirements (renal function) The MHRA have advised that ACEi and ARBs should not be used at any stage of pregnancy as they may adversely effect fetal and neonatal blood pressure control and renal function. Skull defects have also been reported. Use in women who are planning pregnancy should be avoided unless absolutely necessary, in which case the potential risks and benefits should be discussed. ACEi and ARBS are not recommended for use by breastfeeding mothers. In mothers who are breastfeeding older infants, the use of captopril, enalapril, or quinapril may be considered if an ACEi is necessary for the mother. Careful follow-up of the infant for possible signs of hypotension is recommended.

9. Safety and tolerability of ACEi and ARBs continued Concern that ARBs may increase risk of cancer A meta-analysis found a small increased risk of cancers with ARBs vs. non-ARBs20 EMA and FDA have reviewed evidence and concluded that the evidence does not support any increased risk of cancer with ARBs20,21 Concern that olmesartan may increase CV death risk Two studies found higher rate of fatal CV events with olmesartan vs. placebo22 FDA have stated that benefits of olmesartan outweigh potential risks22 9 Notes for presenters There has been some concern that ARBs may be associated with a small increase in the risk of cancer after a meta-analysis found a small increased risk of new cancers (particularly lung cancer) with ARBs compared with non-ARB comparators. The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recently reviewed all available data on the risk of cancer (including the meta-analysis) and concluded that “the evidence does not support any increased risk of cancer in patients using these medicines”. It found that the patients in the trials included in the meta-analysis were not followed up for long enough to clearly establish a link between ARBs and cancer, information on the risk of cancer before treatment was lacking, and there was a risk of publication bias (studies that showed a link between ARBs and cancer were more likely to have been included in the analysis). The American Food and Drug Administration (FDA) recently conducted a meta-analysis of 31 RCTs that enrolled a total of 84,461 patients taking ARBs and 71,355 patients taking non-ARB comparators. Average follow-up was 39 months. The rate of incident cancer was 1.82 per 100 patient-years in the ARB group and 1.84 per 100 patient-years in the non-ARB comparator group. The relative risk of incident cancer in patients taking ARBs was 0.99 (95% CI 0.92 to 1.06) demonstrating no significant difference between the groups. Concerns have arisen that olmesartan may increase risk of cardiovascular death after two studies (ROADMAP and ORIENT) found higher rate of cardiovascular death among patients taking olmesartan, compared with those taking placebo. The trials aimed to show whether olmesartan would slow progression of kidney disease in patients with type 2 diabetes. After reviewing the two studies, the FDA has determined that the benefits of olmesartan continue to outweigh its potential risks when used for the treatment of patients with high blood pressure according to the label. Notes for presenters There has been some concern that ARBs may be associated with a small increase in the risk of cancer after a meta-analysis found a small increased risk of new cancers (particularly lung cancer) with ARBs compared with non-ARB comparators. The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recently reviewed all available data on the risk of cancer (including the meta-analysis) and concluded that “the evidence does not support any increased risk of cancer in patients using these medicines”. It found that the patients in the trials included in the meta-analysis were not followed up for long enough to clearly establish a link between ARBs and cancer, information on the risk of cancer before treatment was lacking, and there was a risk of publication bias (studies that showed a link between ARBs and cancer were more likely to have been included in the analysis). The American Food and Drug Administration (FDA) recently conducted a meta-analysis of 31 RCTs that enrolled a total of 84,461 patients taking ARBs and 71,355 patients taking non-ARB comparators. Average follow-up was 39 months. The rate of incident cancer was 1.82 per 100 patient-years in the ARB group and 1.84 per 100 patient-years in the non-ARB comparator group. The relative risk of incident cancer in patients taking ARBs was 0.99 (95% CI 0.92 to 1.06) demonstrating no significant difference between the groups. Concerns have arisen that olmesartan may increase risk of cardiovascular death after two studies (ROADMAP and ORIENT) found higher rate of cardiovascular death among patients taking olmesartan, compared with those taking placebo. The trials aimed to show whether olmesartan would slow progression of kidney disease in patients with type 2 diabetes. After reviewing the two studies, the FDA has determined that the benefits of olmesartan continue to outweigh its potential risks when used for the treatment of patients with high blood pressure according to the label.

10. Annual Cost of Treatment