Journal of Human Hypertension (2000) 14, Suppl 1, S87–S90  2000 Macmillan Publishers Ltd All rights reserved 0950-9240/00 $15.00 www.nature.com/jhh Angiotensin II-receptor blockers: will they replace angiotensin-converting enzyme inhibitors in the treatment of hypertension?

NM Kaplan University of Texas, Southwestern Medical Center, Dallas, TX, USA

In the past few years, angiotensin II-receptor blockers outcome data are available, they should continue to be have become available and are being heavily marketed used primarily in patients who should receive an ACEI and increasingly used. In various ways they differ from but cannot tolerate the drug because of cough. Journal angiotensin-converting enzyme inhibitors (ACEIs). Until of Human Hypertension (2000) 14, Suppl 1, S87–S90.

Keywords: angiotensin II; angiotensin-converting enzyme inhibitors; angiotensin II-receptor blockers

Introduction tensive drug. The newness of this class has contrib- uted further to their use by those practitioners who Over the past 2 years, the greatest relative growth in are attracted to the latest fashions in medicine, sales of hypertensive drugs in the US has been while at the same time it has held back their use by among the angiotensin II-receptor blockers (ARBs) those more conservative practitioners who change (Figure 1). At the same time, sales of angiotensin- their prescribing habits only slowly, if at all. Over- converting enzyme inhibitors (ACEIs) have con- all, the marketing of this new class has overcome a tinued to increase, although they remain below both good deal of the hesitation since many more pre- diuretics and calcium antagonists in total usage. scriptions have been written than would be Similar figures have been noted in most other coun- expected if they were used only in the situation re- tries with the exception of Japan where ARBs have commended by both the US Joint National Commit- not yet been approved, most likely because none tee (JNC-6)1 and the World Health Organization/ have been developed by Japanese pharmaceutical International Society of Hypertension (WHO/ISH),2 companies. namely in those patients who cannot tolerate an The rapid growth of ARBs have occurred in large ACEI because of cough. part because of the intensive and effective marketing Part of the rapid growth in the ARB family reflects of the most recently introduced class of antihyper- the availability of a drug that has few adverse effects beyond that noted with placebo.3 Every practitioner has patients who have experienced side effects from virtually every class of antihypertensive drugs, so there is a natural inclination to use a drug that is not only new and therefore untried but also that promises better acceptability by those who have ‘been through the lot’.

Differences between ARBs and ACEIs The recommendations of both the 1997 JNC-6 and the 1999 WHO/ISH guidelines that ARBs are specifically indicated only in patients who should be given an ACEI but who cannot tolerate that choice because of a cough, may give rise to the per- ception that the two classes are essentially the same—except for the absence of cough with the ARBs. Increasingly convincing evidence shows that Figure 1 Sales of major classes of antihypertensive drugs in the they are different in a number of ways, differences US from 1986 to 1998. which may end up favouring one over the other or which may recommend they be used together for Correspondence: Dr NM Kaplan, University of Texas, Southwest- effects additive to what one alone can provide. ern Medical Center, Dallas, TX, USA Before further considerations of the clinical use of Angiotensin II-receptor blockers NM Kaplan S88 these drugs, a brief review of the fundamentals of Table 1 AT1 and AT2 receptor-mediated activities their mechanisms of action will be provided. ACEIs act to inhibit the activity of the ACE enzyme, which AT1 Receptor AT2 Receptor converts the impotent angiotensin I to the potent angiotensin II, while at the same time it breaks down Vasoconstriction Stimulation of apoptosis 4 Simulation of aldosterone Antiproliferative bradykinin to inactive fragments (Figure 2). The tra- synthesis and release ditional pathway for angiotensin synthesis, from Renal tubular sodium Embryonic differentiation and angiotensinogen to AI to AII, can be circumvented reabsorption development by non-ACE alternative pathways including that Cardiac growth Endothelial cell growth Vascular smooth muscle Vasodilation involving the enzyme chymase, which has been proliferation found in high concentrations in heart muscle. Thus Augmentation of peripheral AII may be found in blood and tissues even with noradrenergic activity effective ACE inhibition. Augmentation of central The most widely recognised functions of angio- sympathetic nervous system activity tensin II are mediated through its binding to the AT1 Stimulation of vasopressin receptor on cell membranes. The currently available release ARBs, shown as AT1RA in Figure 2, block the bind- Decreased renal blood flow ing of AII upon this receptor. As a consequence of Renal renin inhibition this blockade, circulating levels of AII, with no place to be bound, increase.5 These increased levels of cir- culating AII are then free to bind onto other AII of ACEI therapy: a dry, non-productive, hacking receptors, of which the AT2 receptor is the next best cough seen in up to 15% of patients overall. As characterised. Although most of the activities bothersome as this cough may be, preventing the mediated by the AT2 receptor appear to be beneficial continued intake of an ACEI by perhaps 5% of so that their stimulation could be useful, there may patients, the increased levels of bradykinin may also be other long-term adverse effects mediated through be beneficial in enhancing the overall effectiveness this or other AT receptors which have not yet been and benefits of ACEI therapy. recognised (Table 1). Research into the effects of Experimental evidence suggests a protective effect stimulation of the AT2 and other angiotensin recep- of bradykinin6 and a lesser effectiveness of ARBs tors is ongoing. than ACEIs in lowering blood pressure and revers- Therefore ARBs may be pharmacologically ing left ventricular hypertrophy.7 Much more superior to ACEIs by blocking the adverse effects of impressive are the data published by Gainer et al8 in whatever AII that is synthesized through non-ACE humans (Figure 3). In their study, 20 normotensive pathways. On the other hand, ARBs may be pharma- subjects and seven hypertensive patients were stud- cologically inferior to ACEIs both because they do ied while on a very low sodium diet that raised the not lead to increased levels of bradykinin and level of their renin-angiotensin activity. They because they could lead to detrimental actions received, randomly, four drugs: a placebo, an ACEI mediated through other AII receptors. (captopril, 25 mg), the ACEI with a specific bradyki- nin-receptor antagonist (icatibant acetate) and an The potential benefits of increased bradykinin The increased levels of bradykinin that are provided when ACEIs inhibit its breakdown are almost cer- tainly responsible for the most common side effect

Figure 3 The acute changes in mean arterial pressure in seven hypertensive subjects given placebo, the ARB losartan, the ACE inhibitor captopril with the bradykinin inhibitor icatibant, and Figure 2 The renin-angiotensin system with the site of blockade the ACE inhibitor alone. (Reproduced with permission from 8 of the AT1-receptor (AT1RA). Gainer et al, 1998 ).

Journal of Human Hypertension Angiotensin II-receptor blockers NM Kaplan S89 ARB (losartan, 75 mg). As seen in Figure 3, captopril Side effects with ARBs alone lowered the blood pressure the most whereas captopril plus bradykinin-receptor antagonist was Lastly, ARBs are not entirely benign and free of side less effective and equal to the effect of the ARB effects despite the data from initial observations. alone. These data are in keeping with an extra effect With larger experience, angioneurotic oedema was of the ACEI that is provided by the rise in brady- attributed to the ARB losartan in 13 cases through 20 kinin that accompanies its action. Without the extra the Netherlands Pharmacovigilance Foundation. boost from bradykinin, the ACEI is no more effective One case of dysgeusia has also been attributed to 21 than the ARB. losartan. Only time will tell whether more side These data are short-term and in subjects with an effects will surface with larger exposure to these activated renin-angiotensin system. They do, none- agents. theless, serve as support for an additional benefit from the rise in bradykinin that accompanies the Conclusion action of an ACEI. Long-term randomised controlled trials comparing one or another ACEI versus one or As for now, the recommendation of both the US another ARB in patients with hypertension, renal JNC-6 and the WHOISH seem appropriate: use ARBs damage or heart failure are in progress. When they only in those who need an ACEI but who develop a are published, we will know whether one or another cough. In the near future, much more evidence will is better or whether they should be used together. be forthcoming to either expand or restrict the use of Until such data becomes available, the current re- this interesting new class of antihypertensive drugs. commendation—use an ARB only if cough pre- cludes use of an ACEI—seems appropriate. References The long experience with ACEIs 1 Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. This recommendation is made not on the expec- The Sixth Report of the Joint National Committee on tation that ACEIs will turn out to be better than Prevention, Detection, Evaluation, and Treatment of ARBs but rather on the certainty that ACEIs provide High Blood Pressure (JNC-VI). Arch Intern Med 1997; numerous benefits based upon the immense 20-year 157: 2413–2446. experience with them, benefits which have not yet 2 Guidelines Subcommittee. 1999 World Health Organi- zation-International Society of Hypertension Guide- been clearly documented with ARBs which have lines for the management of hypertension. J Hypertens been available for less than 5 years. 1999; 17: 151–183. These benefits of ACEIs, which have not yet been 3 Kaplan NM. Treatment of hypertension: drug therapy. shown to accrue to ARBs, include those shown in In: Clinical Hypertension, 7th Edition. Williams & Table 2. Whether or not these multiple beneficial Wilkins: Baltimore, 1998; pp 181–263. effects of ACEIs will be seen with ARBs is simply 4 Johnston CI, Risvanis J. Preclinical pharmacology of not yet known. One comparative trial in elderly angiotensin II receptor antagonists. Update and out- patients with heart failure found, quite by surprise, standing issues. Am J Hypertens 1997; 10: 306S–310S. a lower mortality rate in those treated with the ARB 5 Goldberg MR et al. Biochemical effects of losartan, a losartan than those treated with the ACEI capto- nonpeptide angiotensin II receptor antagonist, on the 17 18 renin-angiotensin-aldosterone system in hypertensive pril. A larger trial, ELITE II, found no difference. patients. Hypertension 1995; 25: 37–46. One cross-over trial comparing an ACEI 6 Madeddu P et al. Renovascular hypertension in brady-

(lisinopril) against an ARB (losartan) in 25 non-dia- kinin B2-receptor knockout mice. Hypertension 1998; betic hypertensives found an improvement in insu- 32: 502–509. lin sensitivity with the ACEI but not with the ARB. 7 Gillies LK, Werstiuk ES, Lee RMKW. Cross-over study On the other hand, an improvement in insulin sensi- comparing effects of treatment with an angiotensin tivity was found in a study of 5 hypertensive men converting enzyme inhibitor and an angiotensin II type given losartan for 6 weeks.19 Obviously more data 1 receptor antagonist on cardiovascular changes in are needed. hypertension. J Hypertens 1998; 16: 477–486. 8 Gainer JV et al. Effect of bradykinin-receptor blockade on the response to angiotensin-converting-enzyme inhibition in normotensive and hypertensive subjects. Table 2 The proven benefits of ACEIs that have not yet been N Engl J Med 1998; 339: 1285–1292. found with ARBs 9 Franz IW, Tonnesmann U, Mu¨ ller JFM. Time course of complete normalization of left ventricular hypertrophy Regression of LVH (Franz et al, 1998)9 during long-term antihypertensive therapy with angio- Prevention of ventricular remodelling and improvement of tensin converting enzyme inhibitors. Am J Hypertens haemodynamics post-MI (van den Heuvel et al, 1997)10 11 1998; 11: 631–639. Reduction of recurrent MI (Pfeffer et al, 1992) 10 van den Heuvel AFM et al. Long-term anti-ischemic Reduction of morbidity and mortality in CHF (Swedberg et al, 1999)12 effects of angiotensin converting enzyme inhibition in Improvement of endothelial dysfunction (Koh et al, 1999)13 patients after myocardial infarction. J Am Coll Cardiol Slow progression of diabetic nephropathy (Lewis et al, 1997; 30: 400–405. 1993)14 11 Pfeffer MA et al. Effect of captopril on mortality and Improvement in peripheral neuropathy in normotensive morbidity in patients with left ventricular dysfunction diabetics (Malik et al, 1998)15 after myocardial infarction. Results of the survival and Increased insulin sensitivity (Fogari et al, 1998)16 ventricular enlargement trial. The SAVE Investigators. N Engl J Med 1992; 327: 669–677.

Journal of Human Hypertension Angiotensin II-receptor blockers NM Kaplan S90 12 Swedberg K, Kjekshus J, Snapinn S, for the CONSEN- diabetic hypertensive patients. Br J Clin Pharmacol SUS Investigators. Long-term survival in severe heart 1998; 46: 467–471. failure in patients treated with enalapril. Ten year 17 Pitt B et al. Randomised trial of losartan versus captop- follow-up of CONSENSUS I. Eur Heart J 1999; 20: ril in patients over 65 with heart failure (Evaluation of 136–139. Losartan in the Elderly Study, ELITE). Lancet 1997; 13 Koh KK et al. Mechanism by which quinapril 349: 747–752. improves vascular function in coronary artery disease. 18 Pitt B et al. Losartan heart failure survival study— Am J Cardiol 1999; 83: 327–331. ELITE II. Circulation 1999; 100 (Suppl I): I-782. 14 Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect 19 Moan A et al. Effects of losartan on insulin sensitivity of angiotensin-converting-enzyme inhibition on dia- in severe hypertension: connections through sympath- betic nephropathy. N Engl J Med 1993; 329: 1456– etic nervous system activity? J Hum Hypertens 1995; 1462. 9 (Suppl 5): S45–S50. 15 Malik RA et al. Effect of angiotensin-converting- 20 van Rijnsoever EW, Kwee-Zuiderwijk WJM, Feenstra J. enzyme (ACE) inhibitor trandolapril on human dia- Angioneurotic edema attributed to the use of losartan. betic neuropathy: randomised double-blind controlled Arch Intern Med 1998; 158: 2063–2065. trial. Lancet 1998; 352: 1978–1981. 21 Heeringa M, van Puijenbroek EP. Reversible dysgeusia 16 Fogari R et al. Comparative effects of lisinopril and attributed to losartan. Ann Intern Med 1998; 129: 72. losartan on insulin sensitivity in the treatment of non-

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