. . and Losartan Was No Better Than Placebo
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Journal of Human Hypertension (1999) 13, 649–650 1999 Stockton Press. All rights reserved 0950-9240/99 $15.00 http://www.stockton-press.co.uk/jhh EDITORIAL . And losartan was no better than placebo The United States Food and Drug Administration dose of 50 mg, the recommendation of the manufac- (FDA) has established stringent criteria to determine turer is not to uptitrate but rather to add a low dose efficacy and safety of antihypertensive drugs.1 diuretic.8 When looking back on the history of Although efficacy still merely needs to be defined hypertension, it is distinctly unusual to market an with regard to the surrogate end-point, ie, blood antihypertensive drug in just one strength. However, pressure (and not with regard to morbidity and there are substantial data that up-titration from 50 mortality), all antihypertensive drugs must be able to 100 or even 150 mg with losartan does little if to lower blood pressure and to do so over the full anything to increase antihypertensive efficacy.9 dosing interval which is, in most instances, 24 What then are the reasons for losartan’s shallow hours. Thus, we can be reassured that several stat- dose response curve and its relative loss of efficacy istically highly significant studies have documented at the end of the dosing interval? that losartan’s antihypertensive efficacy was greater Losartan exerts most of its antihypertensive effect than placebo and that this also was true at the end through its metabolite EXP 3174 and needs to be of the dosing interval. How then, is it possible that converted by the liver to this active metabolite. in the study of Mallion et al2 the antihypertensive Unfortunately, losartan and its active metabolite efficacy of losartan during the last 6 h of a 24-h cycle EXP 3174 compete for the same AII-1 receptors. The was not different from placebo and that it was sig- efficacy of losartan alone on blood pressure is con- nificantly inferior to telmisartan? siderably less marked than that of EXP 3174. Thus, Several points need to be discussed before we can by occupying the receptor, the weak antagonist los- draw any conclusions: (1) The effects of losartan artan may prevent the more powerful EXP 3174 from were, indeed, numerically different from placebo, exerting its full antihypertensive effect. In contrast, although this difference did not reach statistical sig- with most other angiotensin receptor antagonists the nificance. Indeed, a reduction of 6 mm Hg in dia- active compound binds directly with the AII-1 stolic pressure was observed with losartan in clinic receptor and can exert its full antihypertensive measurements, but this was merely 2.5 mm Hg bet- power. It is not surprising, therefore, that some of ter than placebo. With a greater number of patients, these compounds are more powerful and have a the difference might have become statistically sig- more prolonged duration of action than losartan. nificant although still not necessarily clinically rel- Clearly, the differences between, ie, telmisartan evant. Also, the FDA requires that clinic blood and losartan as documented in the thorough study pressure levels and not 24-h ambulatory blood of Mallion et al2 are relatively small, and the clinical pressure monitoring are used to establish efficacy. significance of such a difference in the blood press- Conceivably, losartan which has a relatively short ure lowering potency remains to be determined. half-life, may provide a less comprehensive cover- Possibly a twice-a-day dosing of losartan could age of a 24-h period than other longer acting angio- improve blood pressure control during the last 6 h of 3 tensin receptor inhibitors, such as telmisartan. a 24-h period. However, good blood pressure control (2) Several other comparative studies also docu- during these last 6 h is particularly important 4,5 6 mented that irbesartan, candesartan and valsar- because of the excessive risk of cardiovascular 7 tan have greater antihypertensive efficacy than los- events that have been documented during this time artan. (3) In contrast to most other angiotensin period, ie, the early morning hours. All other factors receptor inhibitors, losartan seems to have a very being equal, a compound that has more powerful shallow dose response curve. In patients whose and longer lasting antihypertensive efficacy when blood pressure insufficiently responds to the starting given once a day, such as telmisartan, should be pre- ferred over one that seems to lose part of its antihy- Correspondence: Dr FH Messerli, Ochsner Clinic, 1514 Jefferson pertensive efficacy at the end of the dosing interval, Highway, New Orleans, LA 70121, USA such as losartan. And losartan was no better than placebo FH Messerli 650 Franz H Messerli 4 Kassler-Taub K et al. Comparative efficacy of two angi- Department of Internal Medicine otensin II receptor antagonists, irbesartan and losartan Section on Hypertensive Diseases in mild-to-moderate hypertension. Irbesartan/Losartan Ochsner Clinic and Alton Ochsner Medical Study Investigators. Am J Hypertens 1998; 11(4 Pt 1): Foundation 445–453. 5 Oparil S et al, on behalf of the Irbesartan/Losartan New Orleans, LA, USA Study Investigators. An elective-titration study of the comparative effectiveness of two angiotensin II-recep- tor blockers, irbesartan and losartan. Clin Ther 1998; References 20: 398–409. 6 Andersson OK, Neldam S. The antihypertensive effect 1 Division of cardio-renal drug products. Proposed and tolerability of candesartan cilexetil, a new gener- guidelines for the clinical evaluation of antihyperten- ation angiotensin II antagonist, in comparison with sive drugs. Draft 5/09/88. Report by the United States losartan. Blood Pressure 1998; 7: 53–59. Food and Drug Administration. 7 Hedner T et al. A comparison of the angiotensin II 2 Mallion JM, Siche JP, Lacourciere Y, and the Telmisar- antagonists valsartan and losartan in the treatment of tan Blood Pressure Monitoring Group. ABPM compari- essential hypertension. Am J Hypertens 1999; 12: son of the antihypertensive profiles of the selective 414–417. angiotensin II receptor antagonists telmisartan and los- 8 Bunt T. Problems with interpreting the data in Kassler- artan in patients with mild-to-moderate hypertension. Taub et al’s article comparing irbesartan and losartan. J Hum Hypertens 1999; 13: 657–664. Am J Hypertens 1999; 12(1 Pt 1): 79–81. 3 Messerli FH, Grossman E, Weber MA, Brunner HR. 9 Gradman AH et al. A randomized, placebo-controlled, Angiotensin II receptor inhibition. In: Messerli FH double-blind, parallel study of various doses of losar- (ed). The ABCs of Antihypertensive Therapy. 2nd edi- tan potassium compared with enalapril maleate in tion. Authors’ Publishing House and Raven Press: New patients with essential hypertension. Hypertension York, 1999; (in press). 1995; 25: 1345–1350..