Valsartan, a New Angiotensin II Antagonist for the Treatment

Home , Lisinopril, Valsartan

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: ؊5.25 ability of valsartan to an angiotensin-converting enzyme mm Hg (CI ؊7.17, ؊3.34, P Ͻ 0.001); valsartan 80/80 mg ;(ACE) inhibitor, lisinopril, and placebo in patients with twice daily: ؊5.63 mm Hg (CI ؊7.51,؊3.75, P Ͻ 0.001) ,mild-to-moderate essential hypertension. lisinopril 10/20 mg: ؊6.93 mm Hg, (CI ؊8.81, ؊5.05 Design: A total of 734 men and women were randomised P Ͻ 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 ؍ valsartan 80/80 twice daily n ,142 ؍ or placebo (n = 183) dose (placebo n (187 ؍ lisinopril 10 mg (n ,(364 = ,(120 ؍ lisinopril 10/20 n ,114 ؍ daily for 4 weeks, with subsequent titration of dose 124, valsartan 80/160 n 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 -Both valsartan and lisino .(0.658 ؍ mg twice daily, lisinopril 10 mg titrated to lisonopril 80 mg twice daily (P 80 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 Ͻ90 mm Hg or у10 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 (Ͻ65 years and у65 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 у90 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- у95 mm Hg and р115 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. Other efficacy variables the volunteer’s best interest to discontinue partici- included change in SSBP and the presence of a ‘suc- Ͻ pation in the trial. cessful’ response, defined as mean SDBP 90 mm Hg or у10 mm Hg decrease from baseline. The criteria for tolerability were incidence and Study design type of adverse experiences, significant changes or The study was a multicentre, randomised, double- trends in physical findings, pulse rate and changes blind, parallel group trial. After a 2 to 4 week pla- in clinical laboratory parameters. Particular atten- Valsartan: comparison with lisinopril HR Black et al 485 tion was paid to incidence of cough, and clinically The mean duration of treatment, defined as the significant symptomatic postural decreases in BP, number of days from randomisation date to the last defined as a decrease of у20 mm Hg in SBP and/or known medication date (inclusive), was comparable a decrease of у10 mm Hg in DBP, accompanied by for all four groups (81 days for valsartan 80/160 once symptoms of cerebral hypoperfusion, after a pos- daily; 82.2 days for valsartan 80/80 twice daily; 81.3 tural change from sitting to standing for 2 min.16 days for lisinopril 10/20 once daily; and 76.8 days for placebo). Statistical methodology There were a total of 90 premature discontinuations during the trial. Most discontinuations were We calculated that at least 180 patients per treat- due to an adverse experience or unsatisfactory thera- ment group would be required to detect a treatment peutic response with the highest proportion for both difference of 3 mm Hg in mean SDBP between the seen in the placebo group. The remainder were due groups with 90% power, assuming a standard devi- to non-compliance, withdrawal of consent, and lost ation of SDBP of 8 mm Hg. to follow-up. All randomised volunteers (n = 734) The primary dataset used included all randomised were included in the endpoint dataset, 665 volun- patients with a baseline measurement and at least teers were included in the assessable volunteer data- one post-treatment observation (the intent-to-treat set. Of the 69 volunteers excluded from the clini- dataset). In addition, an acceptable patient dataset cally assessable volunteer efficacy analysis, 18 were was used for analyses which included all random- due to protocol violations. ised volunteers with assessable data who took trial medication for at least 25 days but excluded major protocol violators. For analyses at 4- and 12-week Efficacy time points, all randomised volunteers with a baseline measurement and a measurement at the time All active treatments were significantly superior to point under analysis were included. To avoid poten- placebo in reducing SDBP and SSBP at all time tial analysis problems due to small centres, for each points post dose. Results are given below for the variable small centres were pooled to provide at intent-to-treat dataset unless otherwise stated. How- least 2 randomised patients with available measure- ever, results using the acceptable volunteer dataset ments per treatment group for each dataset. were comparable. Mean SDBP and SSBP were compared by means All three active treatment groups showed signifi- of a two-way analysis of covariance (with treatment cantly greater lowering of mean SDBP compared to group and trial centre as factors and baseline as placebo at endpoint (least mean square change from covariate). Both treatment-by-centre and treatment- baseline: −8.29 mm Hg for valsartan 80/160 once by-baseline interactions were included in the model. daily, −8.67 mm Hg for valsartan 80/80 twice daily, The proportion of successful responders was ana- −9.97 mm Hg for lisinopril 10/20 once daily, −3.04 lysed by means of a one-way logistic model with mm Hg for placebo). Table 2 shows the between- treatment as the factor. All statistical tests were two- treatment contrasts and shows that the differences sided. Bonferroni’s multiple comparison procedure compared to placebo reached statistical significance was used to maintain an overall significance level for all active treatments (P Ͻ 0.001). The three active р 0.05. The significance level for each of the pair- treatment groups produced comparable efficacy in wise comparisons was 0.025. reducing mean SDBP with no statistically significant For all safety and tolerability parameters, sum- differences between active treatments at endpoint mary statistics were used. Frequency of adverse of therapy. experiences by dosage were based on the total daily In the subset of volunteers who were titrated from dose received by the volunteer at the time any valsartan 80 to either valsartan 160 once daily (n = adverse experience began. 114) or valsartan 80 twice daily (n = 124) there was no difference (P = 0.896) between the two regimens Results of valsartan 160 mg at endpoint (least mean square reduction in SDBP from baseline −7.90 mm Hg for Patients valsartan 80 twice daily and −7.76 mm Hg for valsar- A total of 734 hypertensives were randomised into tan 160 once daily). each of the four treatment groups: valsartan 80/160 Figures 1 and 2 show the least mean square once daily (n = 177), valsartan 80/80 twice daily (n reductions in BP at 4 and 12 weeks. At 4 weeks, = 187), lisinopril 10/20 once daily (n = 187) and pla- when volunteers were receiving either valsartan cebo (n = 183). A total of 644 patients completed the 80 mg once daily, lisinopril 10 mg once daily or pla- 12-week study period. Demographics and baseline cebo, both active treatments were significantly data were similar in the four treatment groups with superior in lowering SDBP compared to placebo no statistically significant differences with respect (least mean square change from baseline: valsartan to any of the demographic and medical history vari- 80 mg, −7.12 mm Hg; lisinopril 10 mg, −7.47 mm Hg; ables (Table 1). Approximately 40% were women placebo, −3.23 mm Hg). The estimated treatment dif- and 14% black subjects. The number of patients ferences compared to placebo were −3.89 mm Hg for requiring titration at 4 weeks was highest in the pla- valsartan 80 mg (CI −5.40, −2.38; P Ͻ 0.001) and cebo group (n = 142) compared with valsartan 80/80 −4.24 mm Hg for lisinopril 10 mg (CI −5.98, −2.51; twice daily (n = 124), valsartan 80/160 (n = 114) and P Ͻ 0.001). There was no significant difference lisinopril 10/20 (n = 120). between the efficacy of valsartan 80 mg once daily Valsartan: comparison with lisinopril HR Black et al 486 Table 1 Patient demographics and baseline data

Randomised volunteers Valsartan Valsartan Lisinopril Placebo 80/160 once daily 80/80 twice daily 10/20 once daily n = 177 n = 187 n = 187 n = 183

Sex (% female) 40% 39% 40% 38% Race (%) White 84% 82% 79% 81% Black 12% 14% 14% 15% Other 4% 4% 6% 4% Age in years (s.d.) 53.49 (11.07) 53.43 (11.06) 53.86 (10.71) 54.03 (11.78) Weight in pounds (s.d.) 199.02 (43.12) 201.44 (43.56) 198.50 (45.2) 204.1 (39.48) Height in inches (s.d.) 67.39 (4.53) 67.84 (4.23) 67.58 (4.27) 67.78 (3.81) Mean SSBP in mm Hg (s.d.) 153.64 (14.95) 154.27 (14.95) 153.93 (14.94) 154.13 (14.39) Mean SDBP in mm Hg (s.d.) 100.81 (4.41) 101.66 (4.83) 100.99 (4.45) 100.93 (4.37) Duration of hypertension 10.27 (9.47) 9.18 (8.12) 9.39 (8.51) 10.23 (9.72) in years (s.d.) Antihypertensive medication 79% 71% 79% 78% in past 3 months (%)

Table 2 Between treatment contrasts for the difference in least square mean change from baseline in SDBP and SSBP at endpoint of therapy (all randomised patients)

Treatment contrasts SDBP SSBP

Estimated Conﬁdence P-value Estimated Conﬁdence P-value difference interval difference interval (mm Hg) (97.5%) (mm Hg) (97.5%)

VAL 80/160 once −5.25 (−7.17, −3.34) Ͻ0.001 −8.96 (−12.4, −5.55) Ͻ0.001 daily vs placebo VAL 80/80 twice −5.63 (−7.51, −3.75) Ͻ0.001 −7.19 (−10.5, −3.86) Ͻ0.001 daily vs placebo LIS 10/20 once −6.93 (−8.81, −5.05) Ͻ0.001 −10.98 (−14.3, −7.65) Ͻ0.001 daily vs placebo VAL 80/160 once daily 1.68 (−0.24, 3.59) 0.0496 2.02 (−1.38, 5.43) 0.182 vs LIS 10/20 once daily VAL 80/80 twice daily 1.30 (−0.58, 3.18) 0.121 3.79 (0.47, 7.12) 0.011 vs LIS 10/20 once daily VAL 80/80 twice daily −0.38 (−2.30, 1.54) 0.658 1.77 (−1.64, 5.17) 0.244 vs VAL 80/160 once daily

VAL = valsartan; LIS = lisinopril.

compared to lisinopril 10 mg once daily (estimated (Table 3). In the between-treatment comparison for difference 0.35 mm Hg; CI − 1.15, 1.86; P = 0.599). successful responders, there were no significant dif- Results at 12 weeks of therapy were similar to the ferences between active treatment groups at any data for 4 weeks; all active treatments were again time point apart from a slightly higher percentage of significantly superior to placebo (P Ͻ 0.001) with no responders in the lisinopril 10/20 group compared significant differences between active treatment to the valsartan 80/160 group at endpoint (P = 0.012) groups. and at 12 weeks (P = 0.018). No statistically signifi- Results for mean SSBP were similar to the find- cant treatment differences between the two valsartan ings for mean SDBP (Figures 1 and 2). All active titrated sub-groups was detected (P = 0.481). treatments were superior to placebo in lowering SSBP at endpoint (Table 2). There were no statisti- Tolerability and safety cally significant differences between active treatment groups at endpoint, with the exception of a The overall frequency of adverse experiences, small difference between the lisinopril 10/20 once regardless of relationship to trial medication, was daily and valsartan 80/80 twice daily group (P = similar for those taking valsartan (all doses, 62.6%), 0.011). However, the small difference in SSBP in lisinopril (all doses, 58.3%) and placebo (63.4%). favour of lisinopril but with comparable SDBP When individual dose groups were compared the reduction is unlikely to be of major clinical rel- frequency was also comparable between the groups evance. (valsartan 80 mg, 45.3%; lisinopril 10 mg, 45.5%; The percentage of ‘successful’ responders was sig- valsartan 160 mg, 49.2%; lisinopril 20 mg, 50.0%). nificantly superior for all active treatment groups Table 4 shows the frequency of adverse experi- compared to placebo at all time points (P Ͻ 0.001) ences considered trial drug related. More cases of Valsartan: comparison with lisinopril HR Black et al 487

Figure 1 Least mean square change in BP from baseline (mm Hg) in all randomised volunteers at 4 weeks (n = 364 for valsartan 80 once daily; n = 187 for lisinopril 10 once daily; n = 183 for placebo).

Figure 2 Least mean square change in BP from baseline (mm Hg) in all randomised volunteers at 12 weeks (n = 162 for valsartan 80/160 once daily; n = 172 for valsartan 80/80 twice daily; n = 172 for lisinopril 10/20 once daily; n = 153 for placebo). Valsartan: comparison with lisinopril HR Black et al 488 Table 3 Between treatment comparisons in the percentage of treated patients (15 patients, 8.0%) compared to val- ‘successful’ responders sartan (four patients, 1.1%) and placebo (one patient, 0.5%). Furthermore, when the individual Treatment Endpoint Week 12 Week 4 Valsartan group (%) (%) (%) treated dose groups were compared, cough occurred in a titrated higher percentage of patients in the lisinopril 10 mg volunteers (11 patients, 5.9%) group and lisinopril 20 mg (five (%) patients, 4.2%) groups than all other dose groups. For three volunteers on lisinopril, the cough was of Placebo 21.3 22.2 19.7 sufficient severity to justify premature discontinu- VAL 80/160 44.1* 46.3* ation from the trial. No other clinically significant once daily trends were observed for the remaining adverse VAL 80/80 48.7* 49.4* experiences. twice daily Overall, a greater percentage of those in the pla- LIS 10/20 57.2* 59.3* once daily cebo group (16 volunteers, 8.7%) reported serious VAL 80 41.5* adverse experiences and/or discontinued prema- once daily turely due to an adverse experience than those LIS 10 43.3* receiving valsartan (14 volunteers, 3.8%) or lisino- once daily pril (eight volunteers, 4.3%). Headache was the VAL 80 titrated 35.1 most frequently reported adverse experience to 160 once daily resulting in premature termination. In the lisinopril VAL 80 titrated 39.5 group, cough was the most frequently reported to 80 twice daily adverse experience resulting in premature termination in three patients (1.6%). No one discontinued Ͻ *Significantly superior to placebo, P 0.001. treatment due to cough in the valsartan or the placebo groups. trial drug related adverse experiences were reported Of the adverse experiences that led to discontinu- in those taking lisinopril (all doses: 27.8%) than val- ation of therapy and were judged by the investigator sartan (all doses: 22.8%) or placebo (19.1%). For lis- to be at least possibly related to trial treatment, inopril there was a slightly higher incidence of drug seven cases occurred with valsartan (three patients related adverse experiences with the 20 mg dose with headache, one lightheadedness, one shortness (24.2%) compared to 10 mg (19.3%). For valsartan of breath, one rash, one fatigue); six cases with lisin- no such dose related increase was seen with 15.7% opril (three patients with cough, one chest pain, one of volunteers reporting a drug related adverse nausea/dizziness, one fatigue) and six cases with experience on valsartan 80 mg compared to 14.3% placebo (four patients with headache, one vomiting, on valsartan 160 mg. The most frequently reported one fatigue). trial drug related adverse experience in the valsartan Sitting and standing pulse and body weight move- and placebo treatment groups was headache and ments did not show any clinically significant differ- fatigue (7.7% headache, 2.2% fatigue for valsartan ences between treatment groups at any time points. all doses; 9.3% headache, 1.6% fatigue on placebo; Upon review of orthostatic changes in BP, physi- 3.2% headache, 3.7% fatigue for lisinopril all cal examination findings, group mean values for doses). haematology and chemistry laboratory values, fre- For lisinopril the most frequently reported drug quency distribution of changes from baseline to lab- related adverse experience was cough. Trial drug oratory values at endpoint and individual laboratory related cough occurred more frequently in lisinopril values during the double-blind treatment period, no

Table 4 Incidence of most frequently reported adverse experiences considered at least possibly related to trial treatment

Valsartan Lisinopril Placebo All doses 80 mg 160 mg All 10 mg 20 mg All doses doses

Total patients n ϭ 364 n ϭ 238 n ϭ 364 n ϭ 187 n ϭ 120 n ϭ 187 n ϭ 183 With adverse experience 15.7% 14.3% 22.8% 19.3% 24.2% 27.8% 19.1%

Headache 4.7% 5.5% 7.7% 1.6% 4.2% 3.2% 9.3% Viral infection 0% 0.4% 0.3% 0% 0% 0% 0% Upper respiratory 0% 0.8% 0.5% 0% 0% 0% 0% tract infection Fatigue 0.8% 2.1% 2.2% 2.1% 3.3% 3.7% 1.6% Back pain 0.3% 0% 0.3% 0% 0% 0% 0% Diarrhoea 0.8% 1.3% 1.6% 1.1% 2.5% 2.1% 1.1% Coughing 0.5% 0.8% 1.1% 5.9% 4.2% 8.0% 0.5% Dizziness 0.8% 0.4% 1.1% 1.6% 3.3% 3.7% 1.6% Sinusitis 0% 0.4% 0.3% 0.5% 0.8% 1.1% 0% Valsartan: comparison with lisinopril HR Black et al 489 clinically important trends were observed for any of staff without whom the present study would not the parameters assessed. have been possible. References Conclusions 1 Sealey JE, Laragh JH. The renin-angiotensin-aldo- sterone system for normal regulation of blood pressure This is the first reported study comparing the effi- and sodium and potassium homeostasis. In: Brenner cacy and tolerability of a new antihypertensive BM, Laragh JH), (eds). Hypertension. Raven Press Ltd: agent valsartan with lisinopril and placebo. 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