ACP Brief Fall 2006 prioritization. Angiotensin II Receptor Blockers (ARBs) for Proteinuria, Hypertension (HTN) and Congestive Heart Failure (CHF)

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1 ACP Brief Fall 2006 prioritization Angiotensin II Receptor Blockers (ARBs) for Proteinuria, Hypertension (HTN) and Congestive Heart Failure (CHF) Background This topic was submitted by BC PharmaCare during the Fall 2006 call for new HTA topics. Currently, ARBs are funded by PharmaCare as Limited Coverage through Special Authority for those patients who develop cough on angiotensin converting enzyme inhibitors (ACEIs). Information from an HTA report would be useful in developing their future policy regarding the coverage of ARBs. Research questions would include a review of the comparative effectiveness of ARBs (including versus other drugs such as ACEIs) in the treatment of HTN, CHF and proteinuria. Cost-effectiveness is also of interest to them. Disease Burden In Canada, the prevalence of HTN is approximately 6,500,000 patients. 1 For patients 35 years of age and over, the prevalence of CHF is at least 533,310 in Canada. 2 Approximately 44,000 of patients 18 years or older with type 1 diabetes in Canada developed proteinuria. 3,4 Prevalence estimates for proteinuria associated with type 2 diabetes would be expected to be higher. Alternatives There are six ARB products available in Canada: candesartan (Atacand ), eprosartan (Teveten ), irbesartan (Avapro ), temisartan (Micardis ), valsartan (Diovan, Diovan-HCT ), and losartan (Fortzaar, Hyzaar ). Alternative therapies include diuretics, beta-blockers and ACEIs for treatment of HTN, CHF and proteinuria. 2,5,6 Dihydropyridine calcium channel blockers (CCBs) (e.g. amlodipine) are also used to treat HTN and CHF. 1 Clinical Impact HTN ARBs are efficacious in improving cardiovascular outcomes in patients with HTN and related conditions, such as CHF and type 2 diabetes with nephropathy. For example, the Losartan Intervention for Endpoints (LIFE) trial demonstrated a significant reduction in stroke with losartan. Death and myocardial infarction (MI) were also reduced among diabetic patients. 7 However, such effects have not been consistently reported in the literature. For example, a meta-analysis of three major outcome trials of ARBs in patients with HTN reported an increase in risk of MI (RRR 1.12; 95% CI 1.01 to 1.26, p=0.041) but a decrease in new onset diabetes mellitus (RRR 0.80; 95% CI ; p< ) and no significant change in all-cause mortality (RRR 0.96; 95% CI 0.88 to 1.06; p=0.45) when compared with placebo and alternative therapies, such as beta-blocker atenolol and amlodipine. 9 1

2 Proteinuria Several studies have found ARBs to be effective in reducing albuminuria and the progression of renal disease from microalbuminaria to macroalbuminaria. Losartan and irbesartan have also demonstrated some anti-proteinuric effects leading to cardiovascular and renoprotective effects, such as delay in need for dialysis or kidney transplantation by several years. 10 CHF No differences in mortality between losartan and captopril among CHF patients were found in a systematic review. As well, there were no differences in mortality between candesartan and placebo in CHF patients who stopped taking ACEIs because of adverse effects. Candesartan however had a beneficial effect on the progression of CHF symptoms. 11 The lower adverse event profile of ARBs may result in improved quality of life in patients with HTN or CHF, compared with placebo and standard therapies (ACEIs, beta-blockers, CCBs, and diuretics). 12 Budget Impact Assuming that a daily dosage of ARBs and ACEIs is applicable to all three treatment populations (e.g. HTN, CHF and proteinuria) and that an estimated 30% of 1,000 patients with HTN are treated with ARBs (e.g. losartan) due to intolerance to ACEinhibitors, the cost of these drugs for one year (single daily dose of losartan 25-50mg) would be C$120,600. The cost of treating HTN with ACEIs (e.g. generic captopril) for one year (daily dose of mg) for the remainder of the population would range between C$163,800 and C$230,300. As a result, the total cost per 1,000 patients would range between C$284,400 and C$350,900 per year. Should evidence support more patients with HTN, proteinuria and/or CHF using ARBs instead of ACEIs (e.g. 60% of 1,000 patients with HTN, CHF and/or proteinuria), the treatment cost with losartan for one year (single daily dose 25-50mg) per 600 patients would be C$241,200. The cost of ACEI treatment for the remainder of the population would range between C$93,600 and C$131,600. Under the second scenario, the total cost for treating patients with HTN, CHF and/or proteinuria per 1,000 patients would range between C$334,800 and C$372,800 per year. Net budget impact estimates for the all populations are summarized in Table I. 2

3 Table I Annual Drug Costs (C$) based on incidence/prevalence for each population* Population ARBs ACE-inhibitors Total HTN (70%-37.5mg daily) 589M 1,065M 1,654M 589M 1,497M 2,086M 1,568M 601M 2,168M 1,568M 855M 2,423M CHF (70%-37.5mg daily) 64M 88M 152M 64M 123M 187M 1,286M 50M 1,336M 1,286M 70M 1,356M Proteinuria (70%-37.5mg daily) 5M 7M 12M 5M 10 15M 11M 4M 15M 11M 6M 17M * drug costs only, does not include dispensing fees. Economic Impact A cost-effectiveness analysis estimated expected values for outcomes of interest of irbesartan and amlodipine in the treatment of Canadian patients with diabetic nephropathy and HTN from a third-party payers perspective. Based on a Markov modelling, irbesartan was dominant over both standard care and amlodipine because it both lowered medical costs and led to greater life expectancy. 13 No economic evaluations comparing ARBs therapy alone with alternative therapies in patients with CHF and/or proteinuria were found. ARBs therapy may be associated with decreased direct medical costs, such as fewer hospital admissions and physician visits, and increased life expectancy and quality of life when compared with alternative therapies, such as ACEIs, CCBs and betablockers. Economic benefits in terms of reduced indirect costs (e.g. productivity) may also be possible should serious cardiac events be reduced, compared to alternative therapies. 3

4 Evidence Three systematic reviews 8,10,11, one meta-analysis 9 and one RCT 7 evaluated the effects of monotherapy treatment with ARBs compared with alternative therapies in patients with HTN, CHF and/or proteinuria. One CEA from a Canadian perspective 13 and QoL study 14 } were retrieved. References 1. High blood pressure [document online]. In: Prevention of risk factors: high blood pressure (hypertension) [web site]. Ottawa: Heart and Stoke Foundation; Available: (accessed 2006 Sep 27). 2. Congestive heart failure (CHF): percentage of CHF patients who received discharge instructions regarding symptoms of worsening heart failure. In: National Quality Measures Clearinghouse [web site]. Rockville (MD): Agency for Healthcare Research and Quality (AHRQ); Available: (accessed 2006 Sep 27). 3. Millar WJ, Young TK. Tracking diabetes: prevalence, incidence and risk factors. Health Rep 2003;14(3): Appendix B: general information diabetes mellitus. In: Diabetes in Canada: national statistics and opportunities for improved surveillance, prevention, and control. Ottawa: Public Health Agency of Canada; Available: (accessed 2006 Sep 27). 5. Campbell NRC. Hypertension. In: Gray J, editor. Therapeutic choices. 4th edition. Ottawa: Canadian Pharmacists Association; p Belenkie I. Congestive heart failure. In: Gray J, editor. Therapeutic choices. 4th edition. Ottawa: Canadian Pharmacists Association; p Massie BM, McPhee SJ. Systemic hypertension. In: Tierney LM, McPhee SJ, Papadakis MA, editors. Current medical diagnosis and treatment. 44th edition. New York: Lange Medical Books, McGraw-Hill; p McDonald MA, Simpson SH, Ezekowitz JA, Gyenes G, Tsuyuki RT. Angiotensin receptor blockers and risk of myocardial infarction: systematic review. BMJ 2005;331(7521): Cheung BM, Cheung GT, Lauder IJ, Lau CP, Kumana CR. Meta-analysis of large outcome trials of angiotensin receptor blockers in hypertension. J Hum Hypertens 2006;20(1): Burnier M, Zanchi A. Blockade of the renin-angiotensin-aldosterone system: a key therapeutic strategy to reduce renal and cardiovascular events in patients with diabetes. J Hypertens 2006;24(1): Angiotensin II receptor antagonists and heart failure: angiotensin-converting-enzyme inhibitors remain the first-line option. Prescrire Int 2005;14(79): Weber MA. Angiotensin-II receptor blockers for hypertension and heart failure: quality of life and outcomes. Manag Care Interface 2005;18(2):

5 13. Coyle D, Rodby RA. Economic evaluation of the use of irbesartan and amlodipine in the treatment of diabetic nephropathy in patients with hypertension in Canada. Can J Cardiol 2004;20(1): Carides GW, Shahinfar S, Dasbach EJ, Keane WF, Gerth WC, Alexander CM, et al. The impact of losartan on the lifetime incidence of end-stage renal disease and costs in patients with type 2 diabetes and nephropathy. PharmacoEconomics 2006;24(6):

HTN: 80 mg once daily 23,f 80 mg once daily 23,f Hypertension 40, 80 mg $82.66 (80 mg once daily) HTN: 8-32 mg daily in one or two divided doses 1

HTN: 80 mg once daily 23,f 80 mg once daily 23,f Hypertension 40, 80 mg $82.66 (80 mg once daily) HTN: 8-32 mg daily in one or two divided doses 1 Detail-Document #260301 This Detail-Document accompanies the related article published in PHARMACIST S LETTER / PRESCRIBER S LETTER March 2010 ~ Volume 26 ~ Number 260301 Comparison of Angiotensin Receptor