Journal of Human Hypertension (1997) 11, 483–489 1997 Stockton Press. All rights reserved 0950-9240/97 $12.00 ORIGINAL ARTICLE Valsartan, a new angiotensin II antagonist for the treatment of essential hypertension: efficacy, tolerability and safety compared to an angiotensin- converting enzyme inhibitor, lisinopril HR Black1, A Graff2, D Shute3, R Stoltz4, D Ruff5, J Levine6, Y Shi7 and S Mallows7 1Rush-Presbyterian-St Luke’s Medical Center, Chicago, IL; 2Practice, Fort Lauderdale, FL; 3Metropolitan Clinic, Portland, OR; 4GFI Pharmaceutical Services Inc, Evansville, IN; 5Practice, San Antonio, TX; 6Practice, Nashville, TN; 7Cardiovascular Clinical Research, Ciba-Geigy Corporation, Summit, NJ, USA Objective: To compare the efficacy, safety and toler- reduction from baseline: valsartan 80/160 mg: 25.25 ability of valsartan to an angiotensin-converting enzyme mm Hg (CI 27.17, 23.34, P , 0.001); valsartan 80/80 mg (ACE) inhibitor, lisinopril, and placebo in patients with twice daily: 25.63 mm Hg (CI 27.51,23.75, P , 0.001); mild-to-moderate essential hypertension. lisinopril 10/20 mg: 26.93 mm Hg, (CI 28.81, 25.05, Design: A total of 734 men and women were randomised P , 0.001). There were no statistically significant differ- in this multicentre, double-blind, optional titration, par- ences between the active treatment groups at endpoint allel group trial. Volunteers received valsartan 80 mg (n of therapy. In patients requiring titration to a higher = 364), lisinopril 10 mg (n 5 187) or placebo (n = 183) dose (placebo n 5 142, valsartan 80/80 twice daily n 5 daily for 4 weeks, with subsequent titration of dose 124, valsartan 80/160 n 5 114, lisinopril 10/20 n 5 120), depending on response to treatment (valsartan 80 mg there were no significant treatment differences between titrated to valsartan 160 mg once daily or valsartan valsartan 160 mg given as a single daily dose or as 80 mg twice daily, lisinopril 10 mg titrated to lisonopril 80 mg twice daily (P 5 0.658). Both valsartan and lisino- 20 mg once daily). Patients were assessed at 4, 8 and pril produced similarly high percentages of ‘successful’ 12 weeks. responders at endpoint of therapy. A somewhat higher Main outcome measures: The primary variable was frequency of drug related cough was observed in lisino- change from baseline in mean sitting diastolic blood pril treated patients (8%) compared to valsartan (1.1%) pressure (SDBP). Other efficacy variables included sit- or placebo (0.5%). ting systolic blood pressure (SSBP) and percentage of Conclusions: Valsartan 80 mg daily, with titration to ‘successful’ responders (SDBP ,90 mm Hg or >10 160 mg daily as required, provides similar antihyperten- mm Hg reduction from baseline). sive efficacy to lisinopril 10 mg daily with titration to Results: All active treatment groups were shown to 20 mg daily. Valsartan provides a new antihypertensive demonstrate significant reductions in SDBP compared agent with comparable efficacy to lisinopril and appears to placebo at endpoint of therapy (least mean square to be associated with a reduced incidence of cough. Keywords: valsartan; angiotensin II receptor antagonist; essential hypertension; angiotensin-converting enzyme inhibitor; ACE; lisinopril Introduction angiotensin II from interaction with its cellular receptors. The renin-angiotensin system plays a fundamental ACE inhibitors have been successfully used as role in the maintenance and regulation of the extra- antihypertensive therapy for more than a decade 1 cellular fluid volume and blood pressure (BP). Con- and have been shown to be effective and well toler- trol of BP in essential hypertension can be achieved ated.2,3 However, ACE acts on substrates other than by blockade of the renin-angiotensin system. This angiotensin I and its inhibition leads to the accumu- can be done either through inhibition of angioten- lation of other polypeptides such as bradykinin and sin-converting enzyme (ACE) or by preventing substance P. These mediators are thought possibly to be responsible for the characteristic side effects 4 Correspondence: Dr Henry R Black, Department of Preventative associated with ACE inhibitor therapy. Angioneur- Medicine, St Luke’s Medical Center, 1725 W. Harrison St., Suite otic oedema is rare, but cough associated with ACE 119, Chicago, IL 60612, USA inhibitors, may occur in up to 25% of patients.5 The Received 17 February 1997; revised 10 April 1997; accepted 12 cough tends to be disturbing to many patients, with May 1997 its characteristic dryness and often disturbance of sleep.6–8 Valsartan: comparison with lisinopril HR Black et al 484 The newest class of antihypertensive agents, cebo run-in period, volunteers satisfying the angiotensin II receptor antagonists, antagonise the inclusion criteria were randomised to receive either action of angiotensin II at its AT1 cellular receptor valsartan 80 mg, (two groups), lisinopril 10 mg or site.9–11 As this mode of action does not involve placebo once daily. Randomisation was stratified by inhibition of the converting enzyme this class would age (,65 years and >65 years) to provide compara- be anticipated to be effective an antihypertensive ble age distributions for each of the four treatment devoid of the characteristic ACE inhibitor associated groups within each centre. side effects. After 4 weeks on starting dose, those with a mean Valsartan is a new, orally active, potent, selective SDBP >90 mm Hg and no symptoms of orthostatic and specific angiotensin II receptor antagonist.12 It hypotension had their dose of trial medication has already been shown to be effective and well tol- titrated upwards according to the following dosage erated when given as a single daily dose of 80 mg schedules: valsartan 80 mg titrated to valsartan regardless of age, sex or race of the study subject.13 160 mg once daily or to valsartan 80 mg twice daily; Valsartan demonstrates relatively simple pharma- lisinopril 10 mg titrated to lisinopril 20 mg once cokinetics and is not dependent on metabolism for daily; placebo to placebo. All other volunteers con- its activity. It is rapidly absorbed from the gastro- tinued their initial treatment regimen. intestinal tract with peak plasma valsartan levels To maintain blinding following titration, all vol- occurring approximately 2 h after ingestion. It has unteers took two tablets per day, one at approxi- an elimination half-life of around 9 h and undergoes mately 8 am and one at approximately 8 pm (active little metabolism with the majority excreted as or matching placebo, depending on the dosage unchanged compound in urine and bile.14,15 regimen). No medication was taken on the day of The purpose of the current optional titration trial the visit, prior to assessment, to provide trough was to evaluate different treatment regimens for val- measurement of BP. sartan in a clinical setting compared to usual treat- After the placebo run-in period, volunteers were ment regimens with lisinopril. The efficacy, safety seen at 4-week intervals for 12 weeks. At each visit, and tolerability of valsartan 80 mg once daily and sitting systolic (SSBP) and SDBP were measured in valsartan 160 mg daily administered either as a sin- accordance with WHO guidelines (three measure- gle dose or as 80 mg twice daily were compared to ments after 5 min resting, one measurement in the lisinopril 10 or 20 mg once a day and placebo over standing position after at least 2 min a 12-week period. equilibration.)11 All measurements were to the near- est 2 mm Hg. Phase V (disappearance of the Korot- Materials and methods koff sound) was used for the measurement of DBP in the dominant arm by the same clinician using the Volunteers same mercury sphygmomanometer in the same vol- Men and women aged 21–80, with stage I–III dia- unteer. stolic essential hypertension, were eligible to par- Pulse rate was also measured at each visit and a ticipate in the study. Stage I–III hypertension was physical examination was performed. In addition, defined as sitting diastolic blood pressure (SDBP) the occurrence and details of any adverse experi- >95 mm Hg and <115 mm Hg after 2 to 4 week pla- ences were recorded at each visit. Standard labora- cebo run-in period. The most important exclusion tory analyses (haematology, blood chemistry, criteria were presence of symptomatic heart failure; urinalysis) were carried out at baseline and at the myocardial infarction, hypertensive encephalopathy final visit (12 weeks). or cerebrovascular accident within the preceding 6 The use of concomitant medication with the months; second or third degree heart block; con- potential to interfere with the assessment of trial comitant angina pectoris; clinically relevant endpoints was prohibited throughout the trial. arrhythmias; clinically significant valvular heart dis- These concomitant medications included other anti- ease; significant hepatic disease and/or renal impair- hypertensive drugs, antiarrhythmic drugs, anti- ment, and insulin-dependent diabetes. Women of anginal or heart failure medication, antidepressants, child-bearing potential were required to use an psychotrophic drugs (except for hypnotics and anxi- effective form of contraception and to have negative olytics if the need was present before the trial), and pregnancy tests throughout the trial. anti-inflammatory drugs apart from aspirin at a All volunteers gave written consent to participate maximum daily dose of 325 mg. Oestrogen replace- in the study which was approved by the relevant ment therapy and thyroid replacement medications local Institutional Review Boards. The study was were excluded unless the patient had been main- conducted according to the revised Declaration of tained on a stable dose for at least 6 months prior Helsinki and Good Clinical Practice requirements. to study entry. Volunteers could be withdrawn from the trial if The primary efficacy variable was the change from either the patient or the investigator felt it was in baseline in mean SDBP.