The Expert Committee noted that there is evidence of a favourable benefit–risk profile for the use of losartan for treatment of hypertension. The Committee therefore recommended the addition of losartan, with a square box as the representative of the pharmacological class of angiotensin-receptor blockers, to the EML for persons with hypertension, chronic heart failure with reduced ejection fraction, or chronic kidney disease who are unable tolerate angiotensin-converting-enzyme inhibitors.
Angiotensin-receptor blockers (ARBs) had not previously been considered for inclusion on the EML.
Angiotensin-converting-enzyme (ACE) inhibitors have been included on the EML since 1990, when the pharmacological class was represented by captopril. In 2003, enalapril replaced captopril as the representative ACE inhibitor. ACE inhibitors are represented by enalapril in the current EML as antihypertensive medicines and medicines used in heart failure.
Enalapril (with a square box) has been included on the EMLc for the treatment of hypertension in children since 2009.
Public health relevance
Hypertension is the leading risk factor for death worldwide (1), and the burden of hypertension disproportionately afflicts the world’s poorest countries (2–4). Hypertension contributes to coronary heart disease, myocardial infarction, stroke, chronic kidney disease and heart failure, among other conditions. There is high-quality evidence that hypertension control is both effective and cost effective in reducing the risk of these conditions.
ACE inhibitors and ARBs are widely recommended in international evidence-based guidelines for the treatment of hypertension, heart failure and chronic kidney disease (CKD), especially in persons with diabetes.
The 2014 Evidence-based guidelines for the management of high blood-pressure in adults, authored by the Eighth Joint (US) National Committee recommend the use of ARBs or ACE inhibitors as possible first-line agents for essential hypertension, alone or in combination, for all non-black populations, and as definite first-line agents for essential hypertension for persons with CKD, regardless of race (5).
The 2013 European Society of Cardiology Guidelines on diabetes, pre-diabetes and cardiovascular diseases recommend ACE inhibitors or ARBs for persons with diabetes and hypertension, especially when there is concomitant coronary artery disease, to reduce morbidity and mortality (6).
The 2013 American College of Cardiology/American Heart Association (ACC/AHA) guideline for the management of heart failure and the 2016 European Society of Cardiology (ESC) guidelines for the treatment of acute and chronic heart failure recommend the use of ARBs for reduction of morbidity and mortality in patients with heart failure and reduced ejection fraction who are ACE inhibitor-intolerant (7, 8).
The 2012 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines for evaluation and management of CKD recommend either an ARBs or ACE inhibitors for all persons with CKD with urine albumin excretion of more than 300 mg/day, to prevent and control proteinuria and consequent nephropathy (9).
The application stated that extensive high-quality data have demonstrated the efficacy of ACE inhibitors for the treatment of hypertension as well as primary and secondary prevention of cardiovascular disease (CVD) in individuals with diabetes mellitus, heart failure with reduced ejection fraction, and myocardial infarction (10–12). ARBs act on a near-identical biological pathway to ACE inhibitors, inhibiting the renin-angiotensin system by blocking renal receptors for angiotensin instead of preventing its generation in the lung.
In a systematic review of 61 studies involving more than 15 000 patients no significant difference in blood-pressure lowering was found between ACE inhibitors and ARBs (13).
A 2014 Cochrane systematic review examined nine studies with 11 007 participants and found no significant difference between ACE inhibitors and ARBs with respect to total mortality, total cardiovascular events, or cardiovascular mortality among patients with hypertension (14). A 2016 systematic review of randomized trials of more than 250 000 patients without heart failure confirmed this result, finding no significant difference with respect to all-cause mortality, cardiovascular mortality and myocardial infarction (15). In addition, relative to placebo, ARBs were significantly associated with reduced risk of multiple hypertension sequelae such as heart failure, stroke and end-stage renal disease (15).
ACE inhibitors and ARBs are efficacious in secondary prevention of morbidity and mortality in patients with existing heart failure with reduced ejection fraction. A meta-analysis of five trials involving 12 763 patients with heart failure with reduced ejection fraction found that use of an ACE inhibitor substantially decreased risk of all-cause death, readmission for heart failure, and myocardial infarction (16). Similarly, a randomized trial of the ARB valsartan in chronic heart failure found a significant reduction, relative to placebo, in mortality and morbidity signs and symptoms of heart failure, and hospitalizations for treatment (17). Another trial by the VALIANT investigators showed non-inferiority of valsartan compared with captopril among patients with post-myocardial infarction with reduced ejection fraction (18).
The application stated that, on the basis of these and other data , the 2013 ACC/AHA guideline for the management of heart failure and the 2016 ESC guidelines for the treatment of acute and chronic heart failure recommend the use of ARBs for those with heart failure and reduced ejection fraction who are ACE inhibitor-intolerant (7, 8).
Chronic kidney disease (CKD)
In patients with CKD, ACE inhibitors and ARBs may be superior to other antihypertensives in the secondary prevention of cardiovascular events because, in addition to their impact on blood pressure control, they influence other renal sequelae, such as proteinuria. A meta-analysis of the effect of monotherapy and combination therapy with ACE inhibitors and ARBs for CKD in 6181 participants (18) found that they significantly, and with equal effectiveness, reduced proteinuria compared with both placebo and calcium channel blockers (ratio of means 0.66; 95% confidence interval (CI) 0.63–0.69; and ratio of means 0.62, 95% CI 0.55–0.7, respectively) over 5–12 months. The ESC/European Association for the Study of Diabetes guidelines on diabetes, pre-diabetes, and cardiovascular disease therefore recommend ACE inhibitors and ARBs for secondary prevention of CVD in patients with these conditions (6).
ACE inhibitor-mediated inhibition of pulmonary kininase activity frequently results in cough secondary to increased bradykinin (19–21). In addition, ACE inhibitors can cause angioedema in 0.1–0.8% of individuals, with up to five times greater frequency in people of African descent (10, 11, 22, 23).
Rates of adverse events with ARBs have been assessed relative to placebo and to ACE inhibitors.
In the ONTARGET trial comparing telmisartan with ramipril, telmisartan was associated with a greater mean decrease in blood pressure but a significantly higher rate of hypotensive symptoms. However, there was a lower rate of cough (1.1% vs 4.2%) and angioedema (0.1% vs 0.3%) with telmisartan than with ramipril (10). The rate of hyperkalaemia was 3% in both groups.
The TRANSCEND investigators examined 5926 patients deemed intolerant to ACE inhibitors and showed very low rates of both cough (0.5%) and angioedema (0.07%) associated with the ARB telmisartan, with no statistically significant difference in incidence of these side-effects when compared with the placebo group (12).
Both ACE inhibitors and ARBs are contraindicated in pregnancy; in the case of ARBs this is partly because of feedback disinhibition of renin release, which could activate the fetal AT2 receptor (24). There is evidence that olmesartan may rarely produce a sprue-like enteropathy, which resolves on cessation of the drug. A French cohort trial of some 4.5 million patients on olmesartan established a number-needed-to-harm (NNH) of 12 550 for olmesartan treatment to cause one case of severe enteropathy (25); there was no increased risk in users of other ARBs.
A 2014 Cochrane systematic review found high-quality evidence supporting a lower incidence of withdrawals due to all adverse effects (WDAE) for ARBs relative to ACE inhibitors (relative risk 0.83; 95% CI 0.74–0.93), accounted for mostly by a difference in the incidence of cough (14). A 2016 meta-analysis involving more than 250 000 patients from randomized trials found the relative risk of WDAE in ARBs relative to ACE inhibitors was 0.72 (95% CI 0.85–0.81), suggesting better tolerability of ARBs (15).
Cost / cost effectiveness
Generic formulations of ARBs are now available, and the differences in costs between ARBs and ACE inhibitors is diminishing. The application notes that losartan has therefore followed the typical pattern of evolution of pricing for antihypertensives, with an 80–90% price reduction in the year after generics become available and gradual decreases in prices thereafter.
By way of comparison, the median buyer price for losartan 50 mg according to the MSH International Medical Products Price Guide (2015) was US$ 0.0181 per tablet/capsule, while that for enalapril 20 mg was US$ 0.0114 per tablet/capsule (26).
ARBs have been approved by stringent regulatory authorities including the U.S. Food & Drugs Administration, the European Medicines Agency, the Australian Therapeutic Goods Administration, the Japan Pharmaceuticals and Medical Devices Agency, and Health Canada.
1. Global health risks: mortality and burden of disease attributable to selected major risks. Geneva: World Health Organization; 2009 (http://www.who.int/healthinfo/global_burden_disease/GlobalHealthRisks_report_full.pdf, accessed 15 March 2017).
2. Lim SS, Vos T, Flaxman AD, Danaei G, Shibuya K, Adair-Rohani H et al. A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380(9859):2224–60.
3. Mills KT, Bundy JD, Kelly TN, Reed JE, Kearney PM, Reynolds K et al. Global disparities of hypertension prevalence and control: a systematic analysis of population-based studies from 90 countries. Circulation. 2016;134(6):441–50.
4. Olsen MH, Angell SY, Asma S, Boutouyrie P, Burger D, Chirinos JA et al. A call to action and a lifecourse strategy to address the global burden of raised blood pressure on current and future generations: the Lancet Commission on hypertension. Lancet. 2016;388(10060):2665–712.
5. James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, Handler J et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014;311(5):507–20.
6. Ryden L, Grant PJ, Anker SD, Berne C, Cosentino F, Danchin N et al. ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD: the Task Force on Diabetes, Pre-diabetes, and Cardiovascular Diseases of the European Society of Cardiology (ESC) and developed in collaboration with the European Association for the Study of Diabetes (EASD). Eur Heart J. 2013;34(39):3035–87.
7. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH et al. 2013 ACCF/AHA guideline for the management of heart failure: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation. 2013;128(16):1810–52.
8. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Rev Esp Cardiol (Engl Ed). 2016;69(12):1167.
9. Stevens PE, Levin A. Evaluation and management of chronic kidney disease: synopsis of the Kidney Disease: Improving Global Outcomes 2012 clinical practice guideline. Ann Intern Med. 2013;158(11):825–30.
10. Yusuf S, Teo KK, Pogue J, Dyal L, Copland I, Schumacher H et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med. 2008;358(15):1547–59.
11. Kostis JB, Kim HJ, Rusnak J, Casale T, Kaplan A, Corren J et al. Incidence and characteristics of angioedema associated with enalapril. Arch Intern Med. 2005;165(14):1637–42.
12. Yusuf S, Teo K, Anderson C, Pogue J, Dyal L, Copland I et al. Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trial. Lancet. 2008;372(9644):1174–83.
13. Matchar DB, McCrory DC, Orlando LA, Patel MR, Patel UD, Patwardhan MB et al. Systematic review: comparative effectiveness of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers for treating essential hypertension. Ann Intern Med. 2008;148(1):16–29.
14. Li EC, Heran BS, Wright JM. Angiotensin converting enzyme (ACE) inhibitors versus angiotensin receptor blockers for primary hypertension. Cochrane Database Syst Rev. 2014;(8):CD009096.
15. Bangalore S, Fakheri R, Toklu B, Ogedegbe G, Weintraub H, Messerli FH. Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in patients without heart failure? insights from 254,301 patients from randomized trials. Mayo Clin Proc. 2016;91(1):51–60.
16. Flather MD, Yusuf S, Kober L, Pfeffer M, Hall A, Murray G et al. Long-term ACE-inhibitor therapy in patients with heart failure or left-ventricular dysfunction: a systematic overview of data from individual patients. ACE-Inhibitor Myocardial Infarction Collaborative Group. Lancet. 2000;355(9215):1575–81.
17. Cohn JN, Tognoni G. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med. 2001;345(23):1667–75.
18. Kunz R, Friedrich C, Wolbers M, Mann JF. Meta-analysis: effect of monotherapy and combination therapy with inhibitors of the renin angiotensin system on proteinuria in renal disease. Ann Intern Med. 2008;148(1):30–48.
19. Israili ZH, Hall WD. Cough and angioneurotic edema associated with angiotensin-converting enzyme inhibitor therapy. A review of the literature and pathophysiology. Ann Intern Med. 1992;117(3):234–42.
20. Wood R. Bronchospasm and cough as adverse reactions to the ACE inhibitors captopril, enalapril and lisinopril. A controlled retrospective cohort study. Br J Clin Pharmacol. 1995;39(3):265–70.
21. Woo KS, Nicholls MG. High prevalence of persistent cough with angiotensin converting enzyme inhibitors in Chinese. Br J Clin Pharmacol. 1995;40(2):141–4.
22. Brown NJ, Ray WA, Snowden M, Griffin MR. Black Americans have an increased rate of angiotensin converting enzyme inhibitor-associated angioedema. Clin Pharmacol Ther. 1996;60(1):8–13.
23. Gibbs CR, Lip GY, Beevers DG. Angioedema due to ACE inhibitors: increased risk in patients of African origin. Br J Clin Pharmacol. 1999;48(6):861–5.
24. Goodfriend TL, Elliott ME, Catt KJ. Angiotensin receptors and their antagonists. N Engl J Med. 1996;334(25):1649–54.
25. Basson M, Mezzarobba M, Weill A, Ricordeau P, Allemand H, Alla F et al. Severe intestinal malabsorption associated with olmesartan: a French nationwide observational cohort study. Gut. 2016;65(10):1664–9.
26. International Medical Products Price Guide. Arlington, VA: Management Sciences for Health; 2015 (http://mshpriceguide.org/en/drug-search-page-2/, accessed 15 March 2017).