AJH
1992; 5-.247S-251S
Clinical Experience With the Angiotensin II Receptor Antagonist Losartan A Preliminary Report
The nonpeptide angiotensin II (All)-receptor antagonist losartan is a selective blocker of the pressor effects of AIL It is now being evaluated as an antihypertensive drug in multicenter clinical trials in the United States and other countries. Preliminary inpatient studies have shown that after 5 days of treatment, losartan—in doses of 50,100, and 150 mg — is significantly more effective than placebo in decreasing blood pressure, and has efficacy similar to that of the angiotensin-converting enzyme (ACE) inhibitor enalapril. Large-scale dose-ranging studies in ambulatory hypertensive patients have shown that 10- and 25-mg losartan doses have brief effects in lowering blood pressure, but when given once daily, 50 mg is the minimal dose needed to produce significant day-long decreases in blood pressure. Interestingly, higher doses do not appear
B
ecause the renin-angiotensin system participates so widely in sustaining high blood pressure in hypertensive patients, blockade of this system appears to offer a logical approach to the clinical treatment of hypertension. The angiotensinconverting enzyme (ACE) inhibitors, which prevent conversion of angiotensin I (Al) to the active pressor hormone angiotensin II (All) are now in wide use. The ^-adrenergic blockers, which also are commonly used as antihypertensive agents, appear to produce at least some of their efficacy through inhibition of renin release
From the Department of Medicine, University of California, Irvine, and the VA Medical Center, Long Beach, California. Address correspondence and reprint requests to Michael A. Weber, MD, VA Medical Center, Hypertension Center W130, 5901 E. Seventh Street, Long Beach, CA 90822.
© 1992 by the American Journal of Hypertension, Inc.
to exhibit greater efficacy; however, the effects of these doses are all similar to those of enalapril (20 mg once daily). Losartan's long duration of action is documented by ratios of trough (end of 24-h dosing interval) to peak antihypertensive effects, which are consistently above 50%. Clinical experiences thus far have indicated a low incidence of adverse events. Preliminary animal and in vitro investigations have shown that losartan produces beneficial effects on cardiac function, renal function, and survival that are similar to those of ACE inhibitors. Additional studies are now under way to define more fully the cardiovascular and metabolic profiles of losartan. Am J Hypertens 1992;5:247S-251S KEY WORDS: Hypertension, angiotensin II, losartan.
from the kidney. Renin inhibitors, which block the enzymatic action of renin upon its substrate, are now in early development, but appear to offer similar therapeutic potential. ' Much interest has focused on the therapeutic effects of directly blocking All receptors. In acute clinical studies with saralasin, an intravenously administered peptide analog of All, the drug produced blood pressure decrements that correlated closely with pretreatment plasma renin activity. Losartan (DuP 753, MK 954) is a nonpeptide blocker of the angiotensin type 1 (AT^ receptor that works by a similar principle. Its basic pharmacologic properties and its actions in animal models have been previously described in detail. Figure 1 illustrates losartan's blockade of the pressor effects of AIL In the pithed rat, losartan was shown to have a dose-dependent ability to shift the pressor dose-response curve 1 2
3
4
5
0895-7061/92/$5.00
Downloaded from http://ajh.oxfordjournals.org/ at Florida Atlantic University on March 21, 2016
Michael A. Weber
248S
AJH-DECEMBER
WEBER
120-
Decreases From Baseline in SBP/DBP on 5th Day of Treatment*
O Vehicle (1 m l / k g iv) • DuP 7 5 3 ( 3 m g / k g iv) • DuP 7 5 3 ( 1 0 m g / k g iv)
80-
Placebo 50 mg losartan 100 mg losartan 150 mg losartan 10 mg enalapril
60-
40
20
Ν
6 h post Dose
24 h post Dose
20 20 18 19 18
4.7/4.9 19.5/15.3 15.3/12.2 19.4/17.8 18.2/16.1
10.0/3.6 12.0/10.3 17.5/11.9 18.9/10.8 15.3/10.3
* All treatment changes significantly different from placebo. From Nelson et al.
7
Pithed rat
0 I I I 111,
01
I
I I I I 11 Fι
1
10
I
1
Τ I I MI ;
100
1000
Angiotensin II (/*g/kg)
cacy. Studies of hospitalized patients have been com pleted; an extensive clinical development program in ambulatory outpatients is now under way.
Hospital Experience The principal trial of losartan's antihypertensive efficacy in hospitalized patients is sum marized in Table l . All patients had in-hospital dia stolic blood pressure levels of at least 95 mm Hg immedi Increase in diastolic pressure (mmHg) ately before treatment. In this dose-ranging study, the 120 patients were randomly allocated into five treatment groups, each with approximately 20 patients. Three of 100 0 Vehicle (1 m l / k g iv) these groups were given losartan in once-daily doses of • DuP 7 5 3 ( 1 0 m g / k g iv) either 50, 100, or 150 mg. There were two control 80 groups. One control group received placebo, while the other group served as a positive control and was treated 60with the ACE inhibitor enalapril, 10 mg daily. Treat ment lasted for five full days. 40The treatment effects were measured by comparing the blood pressure values on day 5 with those obtained 20during the pretreatment baseline. The results are shown in Table 1. The values are given at 6 h after dosing, 0 Pithed rat which represents the presumed peak effect of losartan, Τ •Τ;n| ' I—I I I I Im I I I I I I I I MM|— and 24 h after dosing, which is denned as the trough 100 001 0.1 1 10 effect. Compared with placebo, each of the three groups Norepinephrine (/ig/kg) receiving losartan, as well as the enalapril group, had significantly greater decreases in systolic and diastolic FIGURE 1. The effects of the All-receptor antagonist losartan blood pressures both at peak and at trough. (DuP 753) on diastolic blood pressure responses to infusions of All and norepinephrine in the pithed rat. Data adapted from Wong etThis relatively short-term inpatient experience estab lished that losartan given in once-daily doses of 50,100, al. or 150 mg produced significant antihypertensive effects that were sustained throughout the day. There were no significant differences among the four actively treated of All to the right. The specificity of this blocking ac groups. Thus, it appeared that the 50-mg losartan dose tion was confirmed in parallel studies (Figure 1) in was as effective as the higher doses and that each of which losartan had no impact on the pressor effects of these doses produced antihypertensive effects similar to norepinephrine. those of enalapril. 6
5
EARLY
CLINICAL
EXPERIENCE
Losartan is readily absorbed when taken orally in humans. It appears to have a long duration of action; once-daily doses produce 24-h antihypertensive effi-
Outpatient Experience The preliminary findings from the first large-scale multicenter trial outpatient study with losartan are summarized in Table 2 7 This trial was performed in hypertensive patients, free of treatment
Downloaded from http://ajh.oxfordjournals.org/ at Florida Atlantic University on March 21, 2016
Η
0.01
5, NO. 12, PART 2
TABLE 1. LOSARTAN IN HOSPITALIZED WHITE HYPERTENSIVE PATIENTS (DBP > 95 mm Hg)
Increase in diastolic pressure ( m m H g )
100-
1992-VOL
AJH-DECEMBER
1992-VOL
5, NO. 12, PART 2
CLINICAL EXPERIENCE
TABLE 2. EFFECTS OF LOSARTAN ON OUTPATIENT HYPERTENSIVE PATIENTS (SUPINE DBP > 100 mm Hg) Decreases From Baseline in SBP/DBP After 8 Weeks Treatment
Mean baseline: 157/104
Trough
Peak
69 71 74 68 82 76 71
3.9/5.7 7.3/7.3 7.7/7.0 13.4*/10.5* 9.8*/10.1* 10.7*/9.8* 13.7*/11.2*
1.1/4.9 9.P/7.0
H.479.8*
14.6*/12.1* 13.0*/10.6* 12.8*/12.4* 17.8715.8*
mm Hg.
* Significant. From Nelson E, et al.
7
istics, low doses of losartan do not possess sufficient duration of action to produce significant effects 24 h after administration. Low doses given more frequently, perhaps twice daily, could possibly produce meaningful antihypertensive efficacy. In considering the trough data, it appears that the 50-mg losartan dose is pivotal in the antihypertensive action of this drug: lower doses seem ineffective, whereas higher doses may be redundant. The effective duration of action of losartan in doses of 50 mg or higher is confirmed by the ratio of the trough and peak blood pressure effects. After subtraction of the placebo effect, the 50-, 100-, and 150-mg doses had 63, 74, and 5 2 % trough:peak ratios, respectively. Thus, at least half of the drug's peak antihypertensive efficacy was still present at the end of the dosing interval. There was no meaningful difference between placebo and lo sartan in the incidence of adverse events during the 8 weeks of this study. These findings with losartan have been confirmed in preliminary studies using ambulatory blood pressure monitoring. Initial, but incomplete, analysis of this work has shown that losartan—in doses of 50 mg once daily, 50 mg twice daily, or 100 mg once d a i l y — produces consistent reductions in blood pressure throughout the 24-h observation period. The effects are similar for both diastolic and systolic blood pressures. 8
for at least 3 weeks, whose supine diastolic blood pres sures were at least 190 mm Hg at the end of a placebo period. The average baseline blood pressure for these patients was 157/104 mm Hg. As shown in Table 2, the patients were randomly allocated into seven groups with between 68 and 82 patients in each: five of the groups received losartan in doses of 10, 25, 50, 100, or 150 mg. One group received placebo, and the seventh received the ACE inhibitor enalapril in a 20-mg dose. All medications were administered as a single daily dose; active treatment lasted for 8 weeks. The trough data indicate that neither the 10- nor the 25-mg dose of losartan produced blood pressure changes that were different from placebo. However, the 50-mg dose, as well as the higher losartan doses, all significantly decreased both systolic and diastolic blood pressures. Of interest, the reductions produced by the 50-mg losartan dose were at least equal to those pro duced by the higher doses. Thus, as with the in-hospital experience, a dose of 50 mg may define the upper end of the dose-response relationship for losartan. Blood pressure measurements at peak (6 h after dos ing) are also shown in Table 2. Unlike the trough effects, the 10- and 25-mg losartan doses produced significantly greater blood pressure decrements than placebo. The 50-mg dose appears to be more effective than either of the two lower doses, although further dosage increases did not amplify the peak blood pressure changes. Ena lapril at 20 mg had similar antihypertensive effects to those found with the 50-mg or higher doses of losartan at trough. It is noteworthy that the peak data appear to describe a clear dose-response curve in the range of 10 to 50 mg. Peak data often demonstrate a dose-response curve more clearly than do trough data. This suggests that the low doses of losartan can produce hemodynamic effects but, presumably because of pharmacokinetic character
8
FURTHER OPPORTUNITIES Losartan and other potential All-receptor antagonists will be compared clinically with the ACE inhibitors in future studies, because these two drug classes work largely by blocking the renin-angiotensin system. Sub stantial and still-growing experience with the ACE in hibitors has shown that beyond their effects on blood pressure, these drugs have important actions in critical organs such as the heart and kidneys. The ACE inhibi tors have been shown to cause regression of left ventric ular hypertrophy and to improve both systolic and dia stolic left ventricular function. They have also been shown to reduce renal glomerular hypertension, pre vent nephropathy, and preserve renal function. Clearly, it is relevant to determine whether losartan also exhibits these important clinical attributes. Although major clinical studies have not yet been undertaken, results from animal or in vitro research have produced some interesting findings. An important effect of losartan on renal physiology, shown in Figure 2, derives from a study that focused on the actions of the All-receptor antagonist on glomerular afferent and ef ferent arterioles in the isolated perfused hydronephrotic kidney. As shown in Figure 2, All produced marked vasoconstrictor effects in these vessels, reducing their diameters by approximately one-third. Losartan antago nized the vasoconstrictor actions of All and restored vascular diameter to baseline values in a dose-depen9
Downloaded from http://ajh.oxfordjournals.org/ at Florida Atlantic University on March 21, 2016
Placebo 10 mg losartan 25 mg losartan 50 mg losartan 100 mg losartan 150 mg losartan 20 mg enalapril
Ν
249S
250S
WEBER
AJH-DECEMBER
1992-VOL
ANG II
FIGURE 2. The effects of losartan (DuP 753) on renal afferent and ef.
"
.
.
ANG II
Afferent Arteriolar
ferent arteriolar diameters during All infusion in isolated perfused hydronephrotic kidneys. Data adapted from Loutzenhiser et al. f
5, NO. 12, PART 2
Diameter (microns)
9
10
ously hypertensive rat, a model that also has an in creased likelihood of strokes, renal failure, heart failure, and early death. After 12 weeks, more than 8 0 % of the rats treated with losartan were still alive, whereas only about 2 0 % of the group receiving a placebo had survived. 13
IMPLICATIONS
11
1 2
The clinical experience with losartan thus far has estab lished that it is an effective antihypertensive agent. It appears to be well tolerated. There is a dose-effect rela tionship for the drug's antihypertensive actions at peak (approximately 6 h after administration) in the dosage range of 10 to 50 mg. When effects are judged at trough (which is the usual criterion for determining antihyper tensive efficacy), the once-daily, 50-mg dose of losartan appears to be both the minimally and potentially the maximally effective dose. If confirmed, this finding would lead to simplicity in prescribing for this drug: A single daily dose could be recommended for routine clinical use. Additional studies, which are ongoing, are required to measure the efficacy and safety of losartan in combina tion with other classes of antihypertensive agents. It will be necessary to define the doses of losartan that would provide optimal efficacy in combination with com-
TABLE 3. POST-INF ARCT CHF IN THE SPRAGUE-DAWLEY RAT Control Mean aortic pressure Right atrial pressure (mm Hg) Left ventricular end-diastolic pressure (mm Hg) End-diastolic volume index (mL/kg) Venous compliance (mL/mm Hg/kg) Ν From Ray a et al.
11
Values are mean ± SEM. * Significantly different compared to control.
107 2.3 26.7 2.71 2.27
±3 ±0.1 ±1.5 ±0.10 ±0.06 9
Captopril 94 2.1 15.8 2.18 3.02
±5 ±0.4 ±2.2* ±0.15* ±0.21* 9
100 mg Losartan Once Daily 97 1.9 14.2 2.03 2.80
±6 ±0.2 ± 3.0* ± 0.17* ±0.18* 10
Downloaded from http://ajh.oxfordjournals.org/ at Florida Atlantic University on March 21, 2016
dent fashion. This action of losartan appears to be analo gous to the effects of ACE inhibitors in decreasing glo merular hypertension and protecting against renal dysfunction. Table 3 summarizes an important study comparing the effects of losartan and the ACE inhibitor captopril in the experimental post-infarct model of congestive heart failure in the Sprague-Dawley rat. It is evident that losartan's effects on such key measurements as left ven tricular end-diastolic pressure and volume index, as well as other hemodynamic variables, are virtually identical to those of captopril. Since captopril has proven clinical efficacy in the management of congestive heart failure, these early findings provide a clear incentive for study ing losartan in humans with congestive heart failure. Other investigational work with potential clinical rele vance has been performed in the sodium-loaded Dahl S rat. This model becomes hypertensive and develops marked susceptibility to renal failure, strokes, and early death. As shown in Figure 3 , the rats treated with losartan during a 10-week study appeared to do mark edly better than those receiving placebo. Indeed, about 7 0 % of the losartan-treated rats were still alive at the end of the study, whereas only 3 0 % of the rats in the control group were still alive. A similar study has been performed in the spontane
AJH-DECEMBER
1992-VOL
5, NO. 12, PART 2
CLINICAL EXPERIENCE
251S
REFERENCES 100DuP
80
% Survival
60
753
Η
Weber MA, Neutel JM, Smith DHG, Graettinger WF: Circulatory and extracirculatory effects of angiotensinconverting enzyme inhibition. Am Heart J 1992; 123:1414-1420.
2.
Weber MA, Neutel JM, Essinger I, et al: Assessment of renin dependency of hypertension with a dipeptide renin inhibitor. Circulation 1990;81:1768-1774.
3.
Case DB, Wallace JM, Keim HJ, et al: Usefulness and limitations of saralasin, a weak competitive agonist of angiotensin II, for evaluating the renin and sodium fac tors in hypertensive patients. Am J Med 1976;60:825836.
4.
Laragh JH, Smith RD: Symposium: nonpeptide angio tensin II receptor antagonists: a new concept for pharma cologic control of the renin system. Am J Hypertens 1991;4:271S-353S.
5.
Wong PC, Price WA, Chiu AT, et al: In vivo pharmacol ogy of DuP 753. Am J Hypertens 1991;4(suppl):288S298S.
6.
Nelson E, Merrill D, Sweet C: Proceedings of the 5th European Meeting on Hypertension, Milan, Italy, 1991. Abstract 512.
Η Control
40 Η
20-
π—I 4
Γ 6
10
Weeks
FIGURE 3. Survival of sodium-loaded Dahl S rats during treat 7. Nelson E, Arcuri K, Ikeda L, Snavely D, Sweet C: Effi ment with losartan (DuP 753) or placebo. Data adapted from von cacy and safety of losartan in patients with essential hy Lutterotti et al. pertension. Am J Hypertens 1992;5:19A. 12
monly used drugs such as the diuretics. These are almost certain to be lower than monotherapy. Clinicians will also await the results of studies testing combinations of losartan with newer drug classes, including calcium channel blockers. Practitioners also will want to evaluate the safety and side-effect profile of losartan; many will be curious to learn whether the problem of occasional cough, which has been reported with the ACE inhibitors, can be avoided with this newer renin-angiotensin system blocker. These answers will come as large-scale studies with this drug develop further. Finally, because of our awareness that clinical high blood pressure is frequently associated with concomi tant cardiovascular and metabolic risk factors, it will be necessary to characterize fully losartan's clinical profile. Reports in early animal studies of losartan's beneficial effects on renal function, cardiac function, and survival provide a strong stimulus for clinical studies that are about to get under way.
8.
Data on file, Merck Sharpe Dohme Research Labora tories.
9.
Loutzenhiser R, Epstein M, Hayashi K, et al: Character ization of the renal microvascular effects of angiotensin II antagonist, DuP 753: studies in isolated perfused hydronephrotic kidneys. Am J Hypertens 1991;4(suppl): 309S-314S.
10.
Bochicchio T, Sandoval G, Ron O, et al: Fosinopril pre vents hyperfiltration and decreases proteinuria in posttransplant hypertensives. Kidney Int 1990;38:873-879.
11.
Raya TE, Fonken SJ, Lee RW, et al: Hemodynamic effects of direct angiotensin II blockade compared to converting enzyme inhibition in rat model of heart failure. Am J Hypertens 1991;4(suppl):334S-340S.
12.
von Lutterotti N, Camargo JF, Mueller FB, et al: Angio tensin II receptor antagonist markedly reduces mortality in salt-loaded Dahl S rats. Am J Hypertens 1991;4 (suppl):346S-349S.
13.
Camargo JF, von Lutterotti N, Pecker MS, et al: DuP 753 increases survival in spontaneously hypertensive strokeprone rats fed a high sodium diet. Am J Hypertens 1991;4(suppl):341S-345S.
Downloaded from http://ajh.oxfordjournals.org/ at Florida Atlantic University on March 21, 2016
1.
1992; 5-.247S-251S
Clinical Experience With the Angiotensin II Receptor Antagonist Losartan A Preliminary Report
The nonpeptide angiotensin II (All)-receptor antagonist losartan is a selective blocker of the pressor effects of AIL It is now being evaluated as an antihypertensive drug in multicenter clinical trials in the United States and other countries. Preliminary inpatient studies have shown that after 5 days of treatment, losartan—in doses of 50,100, and 150 mg — is significantly more effective than placebo in decreasing blood pressure, and has efficacy similar to that of the angiotensin-converting enzyme (ACE) inhibitor enalapril. Large-scale dose-ranging studies in ambulatory hypertensive patients have shown that 10- and 25-mg losartan doses have brief effects in lowering blood pressure, but when given once daily, 50 mg is the minimal dose needed to produce significant day-long decreases in blood pressure. Interestingly, higher doses do not appear
B
ecause the renin-angiotensin system participates so widely in sustaining high blood pressure in hypertensive patients, blockade of this system appears to offer a logical approach to the clinical treatment of hypertension. The angiotensinconverting enzyme (ACE) inhibitors, which prevent conversion of angiotensin I (Al) to the active pressor hormone angiotensin II (All) are now in wide use. The ^-adrenergic blockers, which also are commonly used as antihypertensive agents, appear to produce at least some of their efficacy through inhibition of renin release
From the Department of Medicine, University of California, Irvine, and the VA Medical Center, Long Beach, California. Address correspondence and reprint requests to Michael A. Weber, MD, VA Medical Center, Hypertension Center W130, 5901 E. Seventh Street, Long Beach, CA 90822.
© 1992 by the American Journal of Hypertension, Inc.
to exhibit greater efficacy; however, the effects of these doses are all similar to those of enalapril (20 mg once daily). Losartan's long duration of action is documented by ratios of trough (end of 24-h dosing interval) to peak antihypertensive effects, which are consistently above 50%. Clinical experiences thus far have indicated a low incidence of adverse events. Preliminary animal and in vitro investigations have shown that losartan produces beneficial effects on cardiac function, renal function, and survival that are similar to those of ACE inhibitors. Additional studies are now under way to define more fully the cardiovascular and metabolic profiles of losartan. Am J Hypertens 1992;5:247S-251S KEY WORDS: Hypertension, angiotensin II, losartan.
from the kidney. Renin inhibitors, which block the enzymatic action of renin upon its substrate, are now in early development, but appear to offer similar therapeutic potential. ' Much interest has focused on the therapeutic effects of directly blocking All receptors. In acute clinical studies with saralasin, an intravenously administered peptide analog of All, the drug produced blood pressure decrements that correlated closely with pretreatment plasma renin activity. Losartan (DuP 753, MK 954) is a nonpeptide blocker of the angiotensin type 1 (AT^ receptor that works by a similar principle. Its basic pharmacologic properties and its actions in animal models have been previously described in detail. Figure 1 illustrates losartan's blockade of the pressor effects of AIL In the pithed rat, losartan was shown to have a dose-dependent ability to shift the pressor dose-response curve 1 2
3
4
5
0895-7061/92/$5.00
Downloaded from http://ajh.oxfordjournals.org/ at Florida Atlantic University on March 21, 2016
Michael A. Weber
248S
AJH-DECEMBER
WEBER
120-
Decreases From Baseline in SBP/DBP on 5th Day of Treatment*
O Vehicle (1 m l / k g iv) • DuP 7 5 3 ( 3 m g / k g iv) • DuP 7 5 3 ( 1 0 m g / k g iv)
80-
Placebo 50 mg losartan 100 mg losartan 150 mg losartan 10 mg enalapril
60-
40
20
Ν
6 h post Dose
24 h post Dose
20 20 18 19 18
4.7/4.9 19.5/15.3 15.3/12.2 19.4/17.8 18.2/16.1
10.0/3.6 12.0/10.3 17.5/11.9 18.9/10.8 15.3/10.3
* All treatment changes significantly different from placebo. From Nelson et al.
7
Pithed rat
0 I I I 111,
01
I
I I I I 11 Fι
1
10
I
1
Τ I I MI ;
100
1000
Angiotensin II (/*g/kg)
cacy. Studies of hospitalized patients have been com pleted; an extensive clinical development program in ambulatory outpatients is now under way.
Hospital Experience The principal trial of losartan's antihypertensive efficacy in hospitalized patients is sum marized in Table l . All patients had in-hospital dia stolic blood pressure levels of at least 95 mm Hg immedi Increase in diastolic pressure (mmHg) ately before treatment. In this dose-ranging study, the 120 patients were randomly allocated into five treatment groups, each with approximately 20 patients. Three of 100 0 Vehicle (1 m l / k g iv) these groups were given losartan in once-daily doses of • DuP 7 5 3 ( 1 0 m g / k g iv) either 50, 100, or 150 mg. There were two control 80 groups. One control group received placebo, while the other group served as a positive control and was treated 60with the ACE inhibitor enalapril, 10 mg daily. Treat ment lasted for five full days. 40The treatment effects were measured by comparing the blood pressure values on day 5 with those obtained 20during the pretreatment baseline. The results are shown in Table 1. The values are given at 6 h after dosing, 0 Pithed rat which represents the presumed peak effect of losartan, Τ •Τ;n| ' I—I I I I Im I I I I I I I I MM|— and 24 h after dosing, which is denned as the trough 100 001 0.1 1 10 effect. Compared with placebo, each of the three groups Norepinephrine (/ig/kg) receiving losartan, as well as the enalapril group, had significantly greater decreases in systolic and diastolic FIGURE 1. The effects of the All-receptor antagonist losartan blood pressures both at peak and at trough. (DuP 753) on diastolic blood pressure responses to infusions of All and norepinephrine in the pithed rat. Data adapted from Wong etThis relatively short-term inpatient experience estab lished that losartan given in once-daily doses of 50,100, al. or 150 mg produced significant antihypertensive effects that were sustained throughout the day. There were no significant differences among the four actively treated of All to the right. The specificity of this blocking ac groups. Thus, it appeared that the 50-mg losartan dose tion was confirmed in parallel studies (Figure 1) in was as effective as the higher doses and that each of which losartan had no impact on the pressor effects of these doses produced antihypertensive effects similar to norepinephrine. those of enalapril. 6
5
EARLY
CLINICAL
EXPERIENCE
Losartan is readily absorbed when taken orally in humans. It appears to have a long duration of action; once-daily doses produce 24-h antihypertensive effi-
Outpatient Experience The preliminary findings from the first large-scale multicenter trial outpatient study with losartan are summarized in Table 2 7 This trial was performed in hypertensive patients, free of treatment
Downloaded from http://ajh.oxfordjournals.org/ at Florida Atlantic University on March 21, 2016
Η
0.01
5, NO. 12, PART 2
TABLE 1. LOSARTAN IN HOSPITALIZED WHITE HYPERTENSIVE PATIENTS (DBP > 95 mm Hg)
Increase in diastolic pressure ( m m H g )
100-
1992-VOL
AJH-DECEMBER
1992-VOL
5, NO. 12, PART 2
CLINICAL EXPERIENCE
TABLE 2. EFFECTS OF LOSARTAN ON OUTPATIENT HYPERTENSIVE PATIENTS (SUPINE DBP > 100 mm Hg) Decreases From Baseline in SBP/DBP After 8 Weeks Treatment
Mean baseline: 157/104
Trough
Peak
69 71 74 68 82 76 71
3.9/5.7 7.3/7.3 7.7/7.0 13.4*/10.5* 9.8*/10.1* 10.7*/9.8* 13.7*/11.2*
1.1/4.9 9.P/7.0
H.479.8*
14.6*/12.1* 13.0*/10.6* 12.8*/12.4* 17.8715.8*
mm Hg.
* Significant. From Nelson E, et al.
7
istics, low doses of losartan do not possess sufficient duration of action to produce significant effects 24 h after administration. Low doses given more frequently, perhaps twice daily, could possibly produce meaningful antihypertensive efficacy. In considering the trough data, it appears that the 50-mg losartan dose is pivotal in the antihypertensive action of this drug: lower doses seem ineffective, whereas higher doses may be redundant. The effective duration of action of losartan in doses of 50 mg or higher is confirmed by the ratio of the trough and peak blood pressure effects. After subtraction of the placebo effect, the 50-, 100-, and 150-mg doses had 63, 74, and 5 2 % trough:peak ratios, respectively. Thus, at least half of the drug's peak antihypertensive efficacy was still present at the end of the dosing interval. There was no meaningful difference between placebo and lo sartan in the incidence of adverse events during the 8 weeks of this study. These findings with losartan have been confirmed in preliminary studies using ambulatory blood pressure monitoring. Initial, but incomplete, analysis of this work has shown that losartan—in doses of 50 mg once daily, 50 mg twice daily, or 100 mg once d a i l y — produces consistent reductions in blood pressure throughout the 24-h observation period. The effects are similar for both diastolic and systolic blood pressures. 8
for at least 3 weeks, whose supine diastolic blood pres sures were at least 190 mm Hg at the end of a placebo period. The average baseline blood pressure for these patients was 157/104 mm Hg. As shown in Table 2, the patients were randomly allocated into seven groups with between 68 and 82 patients in each: five of the groups received losartan in doses of 10, 25, 50, 100, or 150 mg. One group received placebo, and the seventh received the ACE inhibitor enalapril in a 20-mg dose. All medications were administered as a single daily dose; active treatment lasted for 8 weeks. The trough data indicate that neither the 10- nor the 25-mg dose of losartan produced blood pressure changes that were different from placebo. However, the 50-mg dose, as well as the higher losartan doses, all significantly decreased both systolic and diastolic blood pressures. Of interest, the reductions produced by the 50-mg losartan dose were at least equal to those pro duced by the higher doses. Thus, as with the in-hospital experience, a dose of 50 mg may define the upper end of the dose-response relationship for losartan. Blood pressure measurements at peak (6 h after dos ing) are also shown in Table 2. Unlike the trough effects, the 10- and 25-mg losartan doses produced significantly greater blood pressure decrements than placebo. The 50-mg dose appears to be more effective than either of the two lower doses, although further dosage increases did not amplify the peak blood pressure changes. Ena lapril at 20 mg had similar antihypertensive effects to those found with the 50-mg or higher doses of losartan at trough. It is noteworthy that the peak data appear to describe a clear dose-response curve in the range of 10 to 50 mg. Peak data often demonstrate a dose-response curve more clearly than do trough data. This suggests that the low doses of losartan can produce hemodynamic effects but, presumably because of pharmacokinetic character
8
FURTHER OPPORTUNITIES Losartan and other potential All-receptor antagonists will be compared clinically with the ACE inhibitors in future studies, because these two drug classes work largely by blocking the renin-angiotensin system. Sub stantial and still-growing experience with the ACE in hibitors has shown that beyond their effects on blood pressure, these drugs have important actions in critical organs such as the heart and kidneys. The ACE inhibi tors have been shown to cause regression of left ventric ular hypertrophy and to improve both systolic and dia stolic left ventricular function. They have also been shown to reduce renal glomerular hypertension, pre vent nephropathy, and preserve renal function. Clearly, it is relevant to determine whether losartan also exhibits these important clinical attributes. Although major clinical studies have not yet been undertaken, results from animal or in vitro research have produced some interesting findings. An important effect of losartan on renal physiology, shown in Figure 2, derives from a study that focused on the actions of the All-receptor antagonist on glomerular afferent and ef ferent arterioles in the isolated perfused hydronephrotic kidney. As shown in Figure 2, All produced marked vasoconstrictor effects in these vessels, reducing their diameters by approximately one-third. Losartan antago nized the vasoconstrictor actions of All and restored vascular diameter to baseline values in a dose-depen9
Downloaded from http://ajh.oxfordjournals.org/ at Florida Atlantic University on March 21, 2016
Placebo 10 mg losartan 25 mg losartan 50 mg losartan 100 mg losartan 150 mg losartan 20 mg enalapril
Ν
249S
250S
WEBER
AJH-DECEMBER
1992-VOL
ANG II
FIGURE 2. The effects of losartan (DuP 753) on renal afferent and ef.
"
.
.
ANG II
Afferent Arteriolar
ferent arteriolar diameters during All infusion in isolated perfused hydronephrotic kidneys. Data adapted from Loutzenhiser et al. f
5, NO. 12, PART 2
Diameter (microns)
9
10
ously hypertensive rat, a model that also has an in creased likelihood of strokes, renal failure, heart failure, and early death. After 12 weeks, more than 8 0 % of the rats treated with losartan were still alive, whereas only about 2 0 % of the group receiving a placebo had survived. 13
IMPLICATIONS
11
1 2
The clinical experience with losartan thus far has estab lished that it is an effective antihypertensive agent. It appears to be well tolerated. There is a dose-effect rela tionship for the drug's antihypertensive actions at peak (approximately 6 h after administration) in the dosage range of 10 to 50 mg. When effects are judged at trough (which is the usual criterion for determining antihyper tensive efficacy), the once-daily, 50-mg dose of losartan appears to be both the minimally and potentially the maximally effective dose. If confirmed, this finding would lead to simplicity in prescribing for this drug: A single daily dose could be recommended for routine clinical use. Additional studies, which are ongoing, are required to measure the efficacy and safety of losartan in combina tion with other classes of antihypertensive agents. It will be necessary to define the doses of losartan that would provide optimal efficacy in combination with com-
TABLE 3. POST-INF ARCT CHF IN THE SPRAGUE-DAWLEY RAT Control Mean aortic pressure Right atrial pressure (mm Hg) Left ventricular end-diastolic pressure (mm Hg) End-diastolic volume index (mL/kg) Venous compliance (mL/mm Hg/kg) Ν From Ray a et al.
11
Values are mean ± SEM. * Significantly different compared to control.
107 2.3 26.7 2.71 2.27
±3 ±0.1 ±1.5 ±0.10 ±0.06 9
Captopril 94 2.1 15.8 2.18 3.02
±5 ±0.4 ±2.2* ±0.15* ±0.21* 9
100 mg Losartan Once Daily 97 1.9 14.2 2.03 2.80
±6 ±0.2 ± 3.0* ± 0.17* ±0.18* 10
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dent fashion. This action of losartan appears to be analo gous to the effects of ACE inhibitors in decreasing glo merular hypertension and protecting against renal dysfunction. Table 3 summarizes an important study comparing the effects of losartan and the ACE inhibitor captopril in the experimental post-infarct model of congestive heart failure in the Sprague-Dawley rat. It is evident that losartan's effects on such key measurements as left ven tricular end-diastolic pressure and volume index, as well as other hemodynamic variables, are virtually identical to those of captopril. Since captopril has proven clinical efficacy in the management of congestive heart failure, these early findings provide a clear incentive for study ing losartan in humans with congestive heart failure. Other investigational work with potential clinical rele vance has been performed in the sodium-loaded Dahl S rat. This model becomes hypertensive and develops marked susceptibility to renal failure, strokes, and early death. As shown in Figure 3 , the rats treated with losartan during a 10-week study appeared to do mark edly better than those receiving placebo. Indeed, about 7 0 % of the losartan-treated rats were still alive at the end of the study, whereas only 3 0 % of the rats in the control group were still alive. A similar study has been performed in the spontane
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CLINICAL EXPERIENCE
251S
REFERENCES 100DuP
80
% Survival
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753
Η
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Η Control
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20-
π—I 4
Γ 6
10
Weeks
FIGURE 3. Survival of sodium-loaded Dahl S rats during treat 7. Nelson E, Arcuri K, Ikeda L, Snavely D, Sweet C: Effi ment with losartan (DuP 753) or placebo. Data adapted from von cacy and safety of losartan in patients with essential hy Lutterotti et al. pertension. Am J Hypertens 1992;5:19A. 12
monly used drugs such as the diuretics. These are almost certain to be lower than monotherapy. Clinicians will also await the results of studies testing combinations of losartan with newer drug classes, including calcium channel blockers. Practitioners also will want to evaluate the safety and side-effect profile of losartan; many will be curious to learn whether the problem of occasional cough, which has been reported with the ACE inhibitors, can be avoided with this newer renin-angiotensin system blocker. These answers will come as large-scale studies with this drug develop further. Finally, because of our awareness that clinical high blood pressure is frequently associated with concomi tant cardiovascular and metabolic risk factors, it will be necessary to characterize fully losartan's clinical profile. Reports in early animal studies of losartan's beneficial effects on renal function, cardiac function, and survival provide a strong stimulus for clinical studies that are about to get under way.
8.
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Camargo JF, von Lutterotti N, Pecker MS, et al: DuP 753 increases survival in spontaneously hypertensive strokeprone rats fed a high sodium diet. Am J Hypertens 1991;4(suppl):341S-345S.
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