A Randomized, Placebo-Controlled, Double-Blind, Parallel Study of Various Doses of Losartan Potassium Compared With Enalapril Maleate in Patients With Essential Hypertension
Abstract The efficacy and safety of various doses of losartan potassium, a specific and selective angiotensin II receptor antagonist, were compared with those of placebo and enalapril maleate 20 mg in patients with mild to moderate essential hypertension in a randomized, double-blind, parallel study. We randomly allocated 576 patients at the end of a 4-week placebo baseline period to 8 weeks of once-daily double-blind treatment with losartan potassium 10, 25, 50, 100, or 150 mg, enalapril maleate 20 mg, or placebo. After 8 weeks of treatment, mean reductions from baseline in supine systolic/diastolic pressure 24 hours after dosing (trough) for losartan potassium 10, 25, 50, 100, and 150 mg, enalapril maleate 20 mg, and placebo were 7.6/7.9, 7.8/6.8, 13.0/10.1, 8.9/9.9, 10.5/9.7, 14.7/11.2, and 3.8/5.6 mm Hg, respectively. Compared with mean changes in supine diastolic pressure in the placebo group, losartan potassium 50 to 150 mg and enalapril maleate 20 mg produced clinically important and statistically significant reductions (P≤.01) in blood pressure. At 24 hours after dosing, the blood pressure changes obtained with losartan potassium 50 mg were essentially identical to those obtained with enalapril maleate 20 mg. While there was a dose-related effect with losartan potassium from 10 to 50 mg at peak (6 hours after dosing), doses of 10 and 25 mg were not consistently different from placebo 24 hours after dosing. To assess the once-daily effect of losartan potassium, trough-to-peak ratios of the mean changes in supine diastolic pressure after 8 weeks of treatment were calculated. These placebo-adjusted ratios (losartan potassium 10 mg, 78%; 25 mg, 23%; 50 mg, 60%; 100 mg, 72%; 150 mg, 49%) indicated that losartan potassium had sustained antihypertensive effects at 24 hours that were not the result of large peak effects; consequently, once-daily dosing is appropriate. In terms of safety and tolerability, there were no dose-related trends for losartan potassium with respect to the percentage of patients with any adverse experiences, serious adverse experiences, or drug-related adverse experiences or patients who withdrew because of an adverse experience. Headache was a common adverse experience for almost all the treatment groups. Dry cough was reported as an adverse experience in 8% of the enalapril maleate–treated patients compared with 3% in both the placebo- and losartan potassium 50 mg–treated groups.
- hypertension, essential
- angiotensin II
- dose-response relationship, drug
- angiotensin-converting enzyme inhibitors
The proximate mediator of the renin-angiotensin-aldosterone system (RAAS) is the octapeptide angiotensin II (Ang II), which elicits cellular responses in all target tissues by binding to specific high-affinity cell surface receptors.1 2 Ang II is an important peptide hormone in cardiovascular homeostasis and is a major determinant of long-term blood pressure control.3 4 The classic effects of Ang II such as vasoconstriction, aldosterone release, vascular and cardiac hypertrophy, and potentiation of catecholamine release result from the binding of the hormone to specific AT1 receptors.5 6
Losartan potassium (COZAAR) is the first of a new class of nonpeptide, orally active antagonists of the Ang II subtype 1 (AT1) receptor.5 6 Experimental studies indicate that losartan potassium reduces blood pressure through inhibition of the RAAS at the final definitive site of action of Ang II, the angiotensin receptor.7 8 Losartan is metabolized to an active metabolite, E-3174, which is a more potent AT1 Ang II antagonist, has a longer half-life, and appears to bind more avidly to the receptor, resulting in insurmountable antagonism.9
Clinical pharmacology studies in healthy volunteers have demonstrated dose-related blockade of Ang II–induced pressor effects after single and multiple doses of losartan potassium.10 11 12 In a preliminary report, Nelson and colleagues13 discussed the safety and antihypertensive effects of once-daily losartan potassium (50, 100, and 150 mg) in patients with essential hypertension during a 5-day in-patient trial. That study demonstrated that losartan potassium 50 mg was well tolerated and reduced blood pressure 24 hours after dosing to the same magnitude as enalapril maleate 10 mg. E-3174 has also been shown to reduce blood pressure after a single intravenous infusion in patients with hypertension.14
The present 8-week double-blind placebo-controlled trial was conducted to characterize the safety and antihypertensive dose-response relation of once-daily administration of losartan potassium compared with enalapril maleate 20 mg in patients with mild to moderate essential hypertension. Furthermore, this study was designed to assess blood pressure response at peak (6 hours after dosing) and trough (24 hours after dose).
This trial included men and women who had mild to moderate (JNC-V, stages 1 and 2) essential hypertension and were at least 21 years of age and within 30% of their ideal weight. All antihypertensive medications were withdrawn at least 7 days before the screening visit, when patients gave written informed consent to participate in the study and complete medical histories and had physical evaluations. The patient’s supine diastolic blood pressure (DBP) was >90 mm Hg at the screening visit and ≥95 mm Hg after 2 weeks of single-blind placebo therapy. After an additional 2 weeks of placebo therapy, to qualify for double-blind randomization, supine DBP was 100 to 115 mm Hg, and the two blood pressure readings during the single-blind placebo phase (weeks 2 and 4) could not differ by more than 7 mm Hg.
Patients were excluded from the study if there was any evidence of clinically significant hematologic, renal, hepatic, or gastrointestinal problems or diseases involving the cerebrovascular, autoimmune, or cardiovascular systems, including angina pectoris, secondary hypertension, congestive heart failure, or known left ventricular ejection fraction <40%. Patients were excluded from the study because of concomitant use of major psychotropic agents or antidepressant drugs or regular use of nonsteroidal anti-inflammatory agents, high-dose aspirin, or any agent that could lower blood pressure. A history of drug or alcohol abuse, prior exposure to losartan potassium, sensitivity to angiotensin-converting enzyme (ACE) inhibitors, and active treatment for diabetes mellitus were other exclusion criteria.
Forty-one clinical centers (mix of private practice and academic settings) participated in this trial, with a planned enrollment of 14 patients per site. Twelve sites enrolled fewer than 10 patients. The average enrollment across sites was 14 patients (range, 5 to 27). The study consisted of a 4-week single-blind placebo run-in period followed by an 8-week, double-blind phase in which the patients were randomized to seven parallel treatment groups: five groups treated with losartan potassium (10, 25, 50, 100, or 150 mg), one group treated with enalapril maleate 20 mg, and 1 group treated with placebo. Patients were seen at the clinic at 2-week intervals during the single-blind period, after weeks 1 and 2 of double-blind therapy, and then at 2-week intervals thereafter for the remainder of the 8-week double-blind period. Patients who satisfied the entry criteria, including a supine DBP of 100 to 115 mm Hg, were stratified by race (nonblack versus black) and randomly allocated to receive once-daily losartan potassium, enalapril maleate 20 mg, or placebo. For safety considerations, patients with a supine DBP of 110 to 115 mm Hg could enter the double-blind phase of the trial after 2 weeks on placebo.
At all clinic visits, trough supine and standing blood pressures and heart rate measurements were obtained approximately 24 hours (range, 22 to 26 hours) after the last dose of study medication. Peak blood pressure and heart rate measurements were obtained approximately 6 hours (range, 5 to 8 hours) after the last day of baseline and at weeks 4 and 8 of double-blind treatment.
After 5 minutes of rest with patients in the supine position, blood pressure was obtained at 1-minute intervals until stable, based on the criterion that none of the three consecutive supine DBP measurements could be greater than 5 mm Hg from the calculated average of the three readings. Subsequently, after 2 minutes of standing, the blood pressure was measured three times at 1-minute intervals, and the mean value was recorded.
All observed or volunteered adverse experiences were recorded at each visit and designated by the investigator as definitely, probably, or possibly drug-related; probably not drug-related; or definitely not drug-related. Standard fasting laboratory tests were performed after 2 weeks of single-blind placebo treatment and after 2, 4, and 8 weeks of double-blind treatment. A 12-lead ECG was obtained during the single-blind placebo period and 2 and 8 weeks after double-blind treatment. A complete physical examination was performed at baseline and after 8 weeks of double-blind therapy.
For nominal categorical comparisons (ie, adverse experiences and demographics), Fisher’s exact test was used. Continuous patient demographic characteristics were compared by ANOVA. The primary analysis of efficacy in this study included all patients treated in the 8-week double-blind phase of the study. Patients with at least one treatment period measurement were included. The last double-blind measurements of the withdrawn patients were carried forward to subsequent time points. Comparisons between treatment groups with respect to changes from baseline in supine blood pressures were performed with adjusted means based on an ANCOVA for a randomized block (investigators as blocks) design, with baseline blood pressure as the covariate.15 The primary comparisons of interest were the responses of losartan potassium versus placebo. For the dose-response relation analysis, linear, quadratic, and segmented (part quadratic and part constant, ie, Emax-like models) were considered. A lack-of-fit test of the hypothesis that the model fits the data was used to determine the appropriateness of each model.16 These models were used to fit both trough and peak supine DBPs (week 8 change from baseline). Categories of antihypertensive response were analyzed with a cumulative logit model for the proportions of patients within each category of response.
Patient Characteristics and Accounting
A total of 576 patients entered the double-blind phase of the study (Table 1⇓). The patients were generally similar among treatment groups with respect to sex (male, 66% overall), age (combined mean age, 53 years), race (76% white, 14% black, 10% Hispanic), and severity of hypertension (mild, 76%; moderate, 24% overall). A total of 526 patients completed the double-blind portion of the study; Table 1⇓ lists the reasons for discontinuation by treatment group. The largest percentage of patients who withdrew from the study was in the placebo group (14%). No patients withdrew because of ineffective therapy in the losartan potassium 50 or 100 mg or enalapril maleate 20 mg groups. Three patients in the placebo group discontinued for ineffective therapy. There appeared to be no dose-related reasons for discontinuation in the losartan potassium groups.
Mean Changes in Blood Pressure
The first approach used in interpreting the antihypertensive efficacy of losartan potassium was qualitative and empirical, as summarized in Fig 1⇓. This graph (mean change from baseline in trough blood pressure by week) illustrates a number of important clinical considerations such as onset of antihypertensive activity, blood pressure changes by dose, and the time to a “steady-state” blood pressure lowering. Clinically meaningful decreases in blood pressure were observed in several of the losartan potassium groups and the enalapril maleate group 1 to 2 weeks after initiation of therapy. At all double-blind visits during the trial, the trough antihypertensive efficacy of enalapril maleate 20 mg and losartan potassium 50 mg was approximately the same (within 1 mm Hg difference in supine DBP between the groups). Maximum reduction of both supine DBP and systolic blood pressure (SBP) was achieved after 3 to 6 weeks of treatment with losartan potassium.
The primary efficacy and statistical determinations were made from trough blood pressures after 8 weeks of double-blind treatment. Table 2⇓ gives the mean changes from baseline for trough and peak supine blood pressures. Significant reductions (P≤.01) in trough and peak supine DBPs occurred consistently with doses of 50 mg and above of losartan potassium and with enalapril maleate 20 mg compared with placebo. Changes in trough supine DBP for doses of losartan potassium 50 mg and above were not statistically different from the change seen with enalapril maleate 20 mg. At 24 hours after dosing, losartan potassium 25 mg did not produce a clinically meaningful reduction of DBP compared with placebo (Table 2⇓).
SBPs were significantly reduced 24 hours after dosing by losartan 50 mg or greater (P<.01) compared with placebo. The magnitude of the reduction in trough SBP with losartan potassium 50 mg was not statistically different from the response observed with enalapril maleate 20 mg (Table 2⇑).
At week 8, a somewhat steeper dose-response relation was evident at peak (6 hours after dosing) with losartan potassium 10 to 50 mg with a plateauing of the blood pressure response at doses above 50 mg (Table 2⇑, bottom). In contrast, there was a flatter dose-response relation in terms of mean changes in blood pressures 24 hours after dosing (Table 2⇑, top).
The dose-response relation of losartan potassium for reduction of trough and peak supine DBPs was characterized by an Emax type of model. This model was curvilinear to the plateau-effect point, after which no additional reduction with increasing doses was seen. The plateau-effect dose was estimated in the model along with the corresponding plateau effect. At trough, the analysis indicated that a plateau-effect reduction in supine DBP of 9.9 mm Hg would be observed with a dose of approximately 80 mg/d. At peak, the estimated plateau-effect reduction of 11.8 mm Hg would be achieved with a 50 mg/d dose of losartan potassium. Therefore, according to these models (Fig 2⇓), losartan potassium 50 to 100 mg provides the maximal reductions in supine DBP during the 24-hour period after dosing.
To assess the once-a-day effect of losartan potassium, trough-to-peak ratios of the mean changes in supine DBP were calculated. This computation is used to determine whether the effect on blood pressure reduction seen at the end of the 24-hour dosing interval is due simply to the residual of a large peak antihypertensive effect. Table 3⇓ summarizes the ratios corrected for placebo effects seen at trough and peak times. A ratio of 50% or greater is thought to be indicative of a once-daily antihypertensive agent. The calculated ratios indicate that most of the losartan potassium doses evaluated in this study have trough effects that are not the result of a large effect at peak.
Clinical and Laboratory Safety
The safety of losartan potassium was characterized by evaluating the incidence of clinical and laboratory adverse experiences and mean changes in pulse, body weight, ECG parameters, and laboratory test results. There were no dose-related trends for losartan potassium with respect to the percentage of patients with any adverse experiences, serious adverse experiences, or drug-related adverse experiences (as assessed by the study investigator) or withdrawal because of an adverse experience.
Table 4⇓ gives the most common clinical adverse experiences occurring during the study (incidence >4% in any one treatment group). Headache (10% to 20% incidence) was the most common adverse experience for all treatment groups except for enalapril maleate 20 mg. A significantly lower proportion of patients experienced nausea in the losartan potassium 50 and 150 mg groups compared with the placebo group (P≤.05). Although some other statistically significant differences existed among the losartan potassium treatment groups with respect to upper respiratory infection and nasal congestion, they did not appear to be dose-related. Cough was recorded as an adverse experience in 8% of the enalapril-treated patients compared with 3% in both the placebo and losartan potassium 50 mg groups, respectively.
Four patients experienced adverse events that were considered serious. Three of the patients received losartan potassium therapy (one received losartan 10 mg; the other two, losartan 150 mg); one patient received placebo. Of the three patients receiving losartan therapy, only one patient’s serious adverse experiences were considered by the investigator to be possibly study drug–related (losartan 10 mg, angina pectoris, edema, and exertional dyspnea). Both serious adverse events experienced by the two patients receiving losartan 150 mg (chest pain and infectious hepatitis A) were not considered drug-related.
No dose-related trends were apparent for the percentage of patients with any laboratory adverse experiences, serious adverse experiences, or drug-related adverse experiences or who withdrew because of an adverse experience. The most common laboratory adverse experiences (patient incidence >3% in any one treatment group) that occurred during the study were elevated serum ALT and uric acid levels. No dose-related trends were apparent for either of these laboratory adverse experiences.
There were no significant mean changes from baseline for pulse, body weight, or ECG measurements after 8 weeks of treatment in any of the groups. Mean changes from baseline for various laboratory measurements were also evaluated. No clinically significant trends were evident for hematology, serum creatinine, potassium, ALT, or AST test results after 8 weeks of treatment.
Losartan potassium is the first of a new class of orally active, nonpeptide, AT1 selective Ang II receptor antagonists to be evaluated in patients with essential hypertension. With any new agent, a thorough evaluation of the dose-response curve for the drug in reducing blood pressure is crucial in determinations of the dose to be selected for in-depth phase III evaluation for safety and efficacy. The major finding of this trial was that there were important clinically and statistically significant reductions (P≤.01) in trough and peak supine SBPs and DBPs with losartan potassium 50 mg compared with placebo. Doses of losartan potassium above 50 mg provided no additional mean reduction in blood pressure. Furthermore, a smooth blood pressure profile with losartan potassium 50 mg was apparent. On the basis of an analysis of trough-to-peak ratios, the blood pressure reduction 24 hours after dosing was not the result of excessive reduction at peak 6 hours after dosing.
The blood pressure change at trough with losartan potassium 50 mg was not significantly different from that observed with enalapril maleate 20 mg. The comparison of the efficacy of losartan potassium to that of enalapril maleate 20 mg, an ACE inhibitor,17 is of interest not only because it can provide a more vigorous assessment of losartan potassium as a novel therapeutic agent but also because ACE inhibitors may be nonspecific in their effect, lowering blood pressure by reducing Ang II levels18 and altering bradykinin metabolism.19 In contrast, losartan potassium is a pure receptor antagonist that does not alter the vasodilator response to bradykinin in the human forearm.20 It was shown in this trial that enalapril maleate produced a larger decrease in blood pressure at peak than losartan potassium.
The reason for the larger peak fall in blood pressure with enalapril maleate is not entirely understood but may be bradykinin-induced vasodilation. In contrast, the smooth blood pressure profile with losartan potassium may be due to the slow conversion of losartan potassium into its active metabolite E-3174. While there were no reports of orthostatic symptoms in this trial, one could speculate that a drug with a smoother and slower onset of action might be expected to show fewer adverse experiences related to excessive lowering of blood pressure. However, E-3174 did not abruptly reduce blood pressure when infused into patients with essential hypertension.14 In Japanese patients with 24-hour ambulatory blood pressure monitoring, Tsunoda et al21 showed that losartan potassium induced a gradual, smooth onset of action.
The dose-response relation of losartan potassium was evaluated with various statistical models. An Emax model provided the best fit, predicting that a dose of approximately 80 mg was at the plateau of the dose-response relation. The results of this analysis also support the selection of losartan potassium in once-daily doses of 50 to 100 mg to provide optimal reductions in supine DBP during the 24-hour postdosing interval. The calculated trough-to-peak ratios for losartan potassium 50 and 100 mg further indicate that the antihypertensive effects seen 24 hours after dosing were not simply the result of large residual peak effects. These data support a once-daily dosing regimen for losartan potassium.
Losartan potassium appeared to be well tolerated in this study. There were no dose-related trends for losartan potassium with respect to the percentage of patients with any adverse experiences, serious adverse experiences, or drug-related adverse experiences or who withdrew because of an adverse experience. There were no apparent differences in the safety profiles observed between subjects treated with enalapril maleate and with various doses of losartan potassium. More patients in a placebo group had nausea as an adverse experience compared with the losartan groups. While there was a statistical difference, it was not clinically important.
In conclusion, after 8 weeks of administration, once-daily dosing with losartan potassium 50, 100, or 150 mg in patients with mild to moderate essential hypertension produced reductions in SBP and DBP throughout the 24-hour dosing interval that differed significantly from those in the placebo group. These changes were not statistically significantly different from the changes seen with enalapril maleate 20 mg. Losartan potassium doses below 50 mg did not consistently produce clinically meaningful reductions in trough (24 hours after dosing) supine blood pressure. Maximal antihypertensive effect of losartan potassium 50 to 150 mg/d was attained 4 to 6 weeks after initiation of therapy and was maintained during the rest of the 8 weeks of treatment. Losartan potassium was well tolerated as evidenced by clinical and laboratory safety profiles that, except for decreased cough, were comparable to those observed with enalapril maleate 20 mg.
We acknowledge the participation of the following clinical investigators: Vinod K. Bansal, MD, Maywood, Ill; David Bernstein, MD, Clearwater, Fla; Glen Bidwell, MD, Franklin, Va; Steven C. Bowman, MD, Safety Harbor, Fla; Richard Byyny, MD, Denver, Co; Albert A. Carr, MD, Augusta, Ga; Steven Chrysant, MD, Oklahoma City, OK; Edward Conradi, MD, Charleston, SC; Neil Cutler, MD, Beverly Hills, Calif; Jahangir Cyrus, MD, Louisville, Ky; Robert C. Davidson, MD, Seattle, Wash; Timothy Fagan, MD, Tucson, Ariz; Roy M. Fleischmann, MD, Dallas, Tex; John Fillingim, MD, Savannah, Ga; Alan Gradman, MD, Pittsburgh, Pa; Gordon P. Guthrie, MD, Lexington, Ky; Bruce Hamilton, MD, Baltimore, Md; Theodore Herman, MD, Buffalo, NY; Kenneth Lasseter, MD, Miami, Fla; Martin Lester, MD, Mobile, Ala; Andrew J. Lewin, MD, Los Angeles, Calif; George Lewis, MD, New Brunswick, Mass; James H. MacKay, MD, Portland, Ore; David McCarron, MD, Portland, Ore; F. Gilbert McMahon, MD, New Orleans, La; James Mersey, MD, Baltimore, Md; John Morledge, MD, Madison, Wis; Patrick Mulrow, MD, Toledo, Ohio; Ann Nafziger, MD, Cooperstown, NY; Suzanne Oparil, MD, Birmingham, Ala; Arturo Pascual, MD, Detroit, Mich; Susan Steigerwalt, MD, Detroit, Mich; James L. Pool, MD, Houston, Tex; J. Howard Pratt, MD, Indianapolis, Ind; Robert Reeves, MD, Olympia, Wash; Dennis Ruff, MD, San Antonio, Tex; Alexander M. Shepherd, MD, San Antonio, Tex; Melvin J. Tonkon, MD, Anaheim, Calif; Raymond Townsend, MD, Galveston, Tex; David Wallin, MD, New Orleans, La; Donald J. Weidler, MD, PhD, Miami, Fla; and Nathaniel Winer, MD, Kansas City, Mo.
- Received December 19, 1994.
- Revision received January 13, 1995.
- Accepted January 13, 1995.
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