Losartan in Heart Failure
Hemodynamic Effects and Tolerability
Background The aim of the present study was to assess the short- and long-term effects of multiple doses of the angiotensin II receptor antagonist losartan in heart failure.
Methods and Results A multicenter, placebo-controlled, oral, multidose (2.5, 10, 25, and 50 mg losartan once daily) double-blind comparison in patients with symptomatic heart failure and impaired left ventricular function (ejection fraction <40%). Invasive 24-hour hemodynamic assessment was performed after the first dose and after 12 weeks of treatment. Clinical status and tolerability of treatment with losartan over the 12-week period were also evaluated. One hundred fifty-four patients were enrolled, of which 134 met the protocol criterion of baseline pulmonary capillary wedge pressure ≥13 mm Hg. During short-term administration, systemic vascular resistance (SVR) (largest reduction against placebo of 197 dyne · s−1 · cm−5 at 4 hours) and blood pressure fell significantly with 50 mg, lesser decreases were seen with 25 mg, and no discernible effects were seen with 2.5 and 10 mg. After 12 weeks of treatment, similar effects were seen on SVR and blood pressure (maximal fall in SVR against placebo, 318 dyne · s−1 · cm−5 at 5 hours with 50 mg). In addition, pulmonary capillary wedge pressure fell with 2.5, 25, and 50 mg (largest reduction against placebo of 6.3 mm Hg at 6 hours with 50 mg), cardiac index rose with 25 and 50 mg, and heart rate was lower with all active treatment groups. Active treatment was well tolerated, and excess cough was not reported.
Conclusions This study showed that oral losartan administered to patients with symptomatic heart failure resulted in beneficial hemodynamic effects with short-term administration, with additional beneficial hemodynamic effects seen after 12 weeks of therapy. Clear effects were seen with both 25 and 50 mg, with the greatest effect seen with 50 mg.
Pharmacological blockade of the renin-angiotensin-aldosterone system is of proven benefit in patients with heart failure.1 Angiotensin-converting enzyme (ACE) inhibitors exert major clinical effects via inhibition of the production of the vasoconstrictor angiotensin II.2 ACE inhibitors are clearly beneficial in improving the symptomatic status in all grades of heart failure.1 3 4 5 6 ACE inhibitors also reduce mortality in severe7 and less severe8 grades of heart failure and beneficially modify the progressive left ventricular dysfunction that occurs after acute myocardial infarction.9
Losartan is a novel, orally active, nonpeptide angiotensin II receptor antagonist that specifically blocks the angiotensin II (AT1) receptor.10 11 Early studies have shown that losartan inhibits the angiotensin II–mediated pressor response in healthy subjects.12 Losartan also reduces the blood pressure response to angiotensin II in healthy subjects with a plateau in effect at doses of 80 mg and more.13 A single-dose study in patients with heart failure demonstrated beneficial vasodilator and neurohormonal effects of losartan in these patients.14
The purpose of the present study was to assess the short- and long-term hemodynamic and neurohumoral effects of several dosages of losartan in patients with symptomatic heart failure and impaired left ventricular function.
Patients with stable symptomatic heart failure (New York Heart Association [NYHA] functional classification of II to IV) and left ventricular ejection fraction (LVEF) of <40% in sinus rhythm were eligible for enrollment in this multicenter assessment of losartan. Before the study, patients were stabilized on diuretics, and digoxin, ACE inhibitors, and vasodilators were withdrawn for at least 14 and 7 days, respectively, before assessment. The protocol was approved by local ethical committees, and all patients gave written, informed consent.
Hemodynamic assessment was performed the day after placement of a balloon-tipped thermodilution catheter in the pulmonary artery and a brachial or a radial arterial line. Systemic and pulmonary arterial pressures and ECG were measured continuously throughout the study, and all measurements were made at end expiration.
After an overnight fast, the patients began a 24-hour hemodynamic assessment period, during which routine medication was withheld and light meals were administered at 2:00 and 8:00 pm. A minimum of two baseline assessments of hemodynamic parameters, 20 minutes apart with <10% variability in all parameters and mean pulmonary capillary wedge pressure (PCWP) ≥13 mm Hg, was required to enter the randomized study phase.
Patients then received 2.5, 10, 25, or 50 mg losartan or placebo PO in a randomized, double-blind fashion.
Repeat hemodynamic measurements were made at 0.5, 1, 2, 3, 4, 5, 6, 10, 12, and 24 hours after drug ingestion, after which the catheters were removed, hemostasis was secured, regular drugs were restarted, and the randomized treatment continued as a single daily administration at 8:00 am for 12 weeks.
Venous blood was drawn at baseline and at 5 and 24 hours after dose administration for measurement of aldosterone, plasma renin activity, and angiotensin II by radioimmunoassay and for measurement of norepinephrine by high-performance liquid chromatography.
After 12 weeks of randomized therapy, repeat hemodynamic and neurohormonal assessments were performed over a similar 24-hour period with the study medication being administered after two baseline measurements that showed <10% variability. Other medications were withheld during this period.
Baseline PCWP was defined in the protocol as both an entrance criterion and a primary end point. Therefore, analysis of the hemodynamic results was based on the population with baseline PCWP ≥13 mm Hg.
All data are shown as mean±SD. Baseline hemodynamic measurements are based on two consecutive measurements, and the primary measurement is change from pretreatment baseline values. All pairwise comparisons presented are between a losartan group and a placebo group and were based on an ANCOVA model where baseline levels were included as a covariate and investigator’s site (national [US] versus international) as a blocking effect.
Adverse experience results are based on all patients randomized into the study.
Based on 28 patients per group, the study had 80% power to detect a between-group difference of 3.5 mm Hg in PCWP, a 250 dyne · s−1 · cm−5 difference in systemic vascular resistance (SVR), or a 0.25 L · min−1 · m−2 difference in cardiac index (CI). Sample size calculations were based on a two-tailed test, at the 5% α level, with no multiplicity adjustments. The observed SDs during the long-term phase of the study were moderately higher than the ones used in the sample size calculations.
Of 154 patients who entered the randomized double-blind phase of the study, 134 met the entrance criterion of baseline PCWP ≥13 mm Hg. Characteristics of these patients were similar in all treatment groups except for PCWP, which was higher in the placebo and 10-mg groups (Table 1⇓). On average, LVEF was 24%, and 66% of patients were NYHA functional class II, 30% were class III, and 4% were class IV. Before the study, 88% of patients were stabilized on diuretics and 58% were stabilized on cardiac glycosides. Overall, 43% of patients were previously treated with ACE inhibitors, and there was no statistical significant difference between groups in frequency of prior treatment with ACE inhibitors.
Trial medications were well tolerated over the 12-week period. Overall adverse experiences occurred with a similar frequency in all groups (66%, placebo; 58%, 2.5 mg losartan; 55%, 10 mg losartan; 56%, 25 mg losartan; and 59%, 50 mg losartan [P=NS]). Exacerbation of heart failure was seen more often in placebo (24%), 2.5 mg losartan (13%), and 10 mg losartan (21.1%) than 25 mg losartan (3%) and 50 mg losartan (4%) groups (P<.05 for 25 mg versus 10 mg and placebo). Hypotension occurred only in the 25- and 50-mg groups (9% and 11%, respectively) but was usually a first-dose phenomenon, was generally asymptomatic or well tolerated, and did not result in discontinuation of trial medication. Three deaths occurred during the study, 2 in the 2.5-mg group and 1 in the 10-mg group; none of the deaths were considered to be due to trial medication. There were no differences between the active treatment groups and placebo in the incidence of cough or renal function adverse experiences.
Symptoms of exertional dyspnea more often improved than worsened after 12 weeks in the 50-mg (52% improved and 9% worsened) and 25-mg (48% and 10%, respectively) groups. Although in the placebo and 10-mg groups a greater number of patients reported worsening dyspnea (26% and 20%, respectively), these differences did not achieve statistical significance. Cardiothoracic ratio at 12 weeks decreased from pretreatment baseline in the 25-mg (0.008 decrease) and 50-mg (0.01 decrease) groups but increased by 0.019 in the placebo group (P<.05 placebo versus 50-mg group).
The hemodynamic effects of losartan were evaluated in patients who fulfilled the entry criterion. One hundred thirty-four patients had stable baseline parameters and a PCWP ≥13 mm/kg. One of these patients exhibited an exaggerated hemodynamic response thought to be due to factors other than trial medication and was excluded from the analysis. Therefore, hemodynamic data were available for the short-term and 12-week periods in 133 and 118 patients, respectively. There was a significant imbalance between groups in baseline PCWP.
During short-term administration, SVR decreased in the 50 mg losartan group and was significantly lower than placebo from 2 through 10 hours, with the largest reduction of 197 dyne · s−1 · cm−5 at 4 hours (Fig 1⇓). SVR also fell with 25 mg but to a lesser degree and failed to achieve statistical significance, whereas no discernible effect was seen with 10 or 2.5 mg.
After 12 weeks of therapy baseline, SVR tended to be lower in the 25- and 50-mg groups with significant further decreases seen in both groups sustained up to 10 to 12 hours after losartan administration. The largest reduction against placebo was 318 dyne · s−1 · cm−5 at 5 hours in the 50-mg group. The SD of the changes from pretreatment baseline levels ranged from 200 to 400 dyne · s−1 · cm−5 for all treatment groups at all time points.
PCWP decreased during short-term administration of trial medication in all groups (Fig 2⇓). Although there was a tendency for a greater decrease in the 25- and 50-mg groups than the placebo or 2.5- or 10-mg group, no statistically significant difference was observed between the losartan and placebo groups.
After 12 weeks of therapy baseline, PCWP was 5.0 mm Hg lower than the pretreatment baseline in the 50-mg group and was significantly (P<.01) lower than time-matched placebo values from baseline through 12 hours with a maximal reduction of 6.3 mm Hg at 6 hours after the dose. Patients in the 25-mg group had baseline levels similar to placebo, but PCWP decreased consistently below the placebo levels during hours 2 through 12, with a significant reduction (P<.05) at 6 hours. Patients in the 2.5- and 10-mg groups also tended to have a lower PCWP than patients in the placebo group, with statistically significant reductions seen in the 2.5-mg group. The SD ranged from 5.0 to 8.4 mm Hg.
During short-term administration, little discernible effect was seen on CI except at 3 hours in the 10-mg group and at 10 hours in the 10- and 25-mg groups when CI was lower than in the placebo group (P<.05) (Fig 3⇓). However, after 12 weeks of therapy, although there was little difference in CI over the 24 hours in the placebo or 2.5- and 10-mg group, a clear effect was seen in the higher-dosage groups. In the 50-mg group, CI tended to be greater at baseline and was significantly greater than placebo from 0.5 (+0.3 L · min−1 · m−2, P<.05) through 24 hours (+0.4 L · min−1 · m−2, P<.01). In the 25-mg group, losartan resulted in a less marked and somewhat delayed beneficial effect on CI (+0.3 L · min−1 · m−2, P<.05 at 10 through 24 hours). The SD ranged from 0.3 to 0.6 L · min−1 · m−2.
Mean Arterial Pressure
During short-term administration, blood pressure decreased significantly from 1 through 12 hours in the 25-mg group, with slightly greater decreases in blood pressure in the 50-mg group (Fig 4⇓). After 12 weeks of therapy, there was no discernible decrease in blood pressure at baseline in any active treatment group. After drug administration, blood pressure fell to an extent similar to the decreases seen after the first dose in the 25- and 50-mg groups. The SD ranged from 5 to 14 mm Hg.
During short-term administration, the heart rate tended to decrease in the 25- and 50-mg groups, but only at 3 hours in the 25-mg group did this achieve significance (−3.0 beats per minute, P<.05) (Fig 5⇓).
However, after 12 weeks of therapy, the heart rate was lower at baseline in all active treatment groups (−4.6 beats per minute, P=NS, 2.5 mg; −5.8 beats per minute, P<.05, 10 mg; −7.5 beats per minute, P<.01, 25 mg; −5.7 beats per minute, P<.05, 50 mg; compared with placebo values) and remained lower over the 24-hour period, with the greatest effect being seen with 25 mg losartan. The SD ranged from 8 to 12 beats per minute.
There were no differences in baseline neurohormones between treatment groups (Table 2⇓). Aldosterone did not change significantly during short-term administration but fell significantly after 12 weeks of therapy. Levels were significantly lower than for placebo at 5 hours in the 10, 25, and 50 mg losartan groups and at 24 hours in the 10 and 25 losartan groups.
Plasma renin activity increased during short-term administration, with a significant increase above placebo values occurring at 5 hours in the 25 and 50 mg losartan groups and at 24 hours in the 10-, 25-, and 50-mg groups. Plasma renin activity also tended to be greater than placebo in the 25- and 50-mg groups after 12 weeks of therapy before the dose and at 5 and 24 hours, but these increases failed to achieve statistical significance.
Angiotensin II levels increased significantly above placebo levels at 5 hours in the 25- and 50-mg groups and at 24 hours in the 50-mg group during short-term administration. After 12 weeks of therapy, angiotensin II levels tended to be higher in the 50-mg group, but this increase was not statistically significant.
There was little effect on plasma norepinephrine both during short-term administration and after 12 weeks of therapy. Norepinephrine was reduced at 24 hours after 12 weeks of therapy in the 25-mg group only (P<.05).
Heart failure is a major cause of mortality and morbidity. Heart failure is characterized by activation of the renin-angiotensin-aldosterone system,15 which results in inappropriate fluid retention and vasoconstriction and may contribute to the progressive decline in left ventricular function and progression of symptoms.9 ACE inhibitors act to block the formation of angiotensin II and have been clearly shown to improve symptomatic status in patients with heart failure. In contrast to direct vasodilators, ACE inhibitors do not exhibit tachyphylaxis and tend to have increasing benefit with time.1 4 5 6 Furthermore, they reduce progressive LV dysfunction after myocardial infarction9 and improve survival in heart failure.7
Losartan is a novel, orally active, nonpeptide specific angiotensin receptor blocker that may have a beneficial action similar to ACE inhibitors without effects on other humoral systems. This specificity of action may improve tolerability and possibly efficacy. ACE inhibitors cannot be tolerated in many patients with heart failure because of cough that is probably due to nonangiotensin effects of ACE inhibition such as the effect on bradykinin and prostaglandins.
In the present study, losartan at 25 and 50 mg/d acutely increased plasma renin activity and angiotensin II levels, and after long-term therapy, aldosterone was suppressed by losartan (10 to 50 mg/d), consistent with significant angiotensin II receptor blockade. In association with these neurohormonal effects, we found clear short-term hemodynamic effects on SVR and blood pressure, with the greatest effect seen with 50 mg, a lesser effect seen with 25 mg, but no discernible effect seen with 2.5 or 10 mg daily. These short-term effects on SVR and blood pressure are comparable to the short-term effects of the ACE inhibitor enalapril in heart failure.16
After 12 weeks of therapy, there was no evidence of attenuation of these effects on SVR and blood pressure. In addition, beneficial effects on PCWP, CI, and heart rate were seen, which had not been observed with short-term administration. Furthermore, the lower doses of 2.5 and 10 mg appeared to have beneficial effects on heart rate and possibly PCWP despite the absence of discernible hemodynamic effects after short-term administration. The evidence of sustained beneficial effects and the tendency toward increased hemodynamic benefit with long-term therapy is in clear distinction to the tachyphylaxis often seen with direct vasodilators.17 This is similar to the durable and progressive beneficial effects seen with ACE inhibitors.1 4 16 Furthermore, heart rate did not increase with short-term administration and fell with long-term therapy, similar to the effects seen with ACE inhibitors16 and in contrast to the tachycardia that is often seen with direct vasodilators.18 The absence of tachycardia with losartan reflects the absence of reflex sympathetic activation and may be of particular benefit in patients with heart failure due to coronary disease.
In this 12-week study, losartan was generally very well tolerated by these patients with heart failure. In the 25- and 50-mg groups, hypotension did occasionally occur, but usually after the first dose, or the first dose after completion of the hemodynamic procedures, which required the patient to be supine for 36 hours. Blood pressure usually returned to normal ranges, and symptoms, if present, resolved. Hypotension was not observed with lower doses. This suggests that dose titration may help prevent symptomatic hypotension. Overall, adverse experiences were similar in all treatment groups. Of importance is that excess cough was not reported in the active treatment groups, consistent with the hypothesis that cough is induced by ACE inhibition via nonangiotensin mechanisms. A higher incidence of progression of heart failure was observed in the placebo and low-dose groups than the high-dose groups, confirming the beneficial clinical effects of losartan in heart failure.
The present study assessed only the short-term and 12-week neurohumoral and hemodynamic effects of losartan in patients with heart failure. Despite the apparently beneficial effects observed, it is not possible to conclude that losartan will improve functional capacity or mortality in heart failure. A number of patients in this study were excluded from subsequent analysis, either because they did not fulfill the previously defined entry criterion or, in one case, because an exaggerated hemodynamic result was observed that was considered likely to be due to factors other than trial therapy. There were significant differences in baseline PCWP; however, these were likely to bias against observing a beneficial effect with losartan. The majority of the patients in this study had milder grades of heart failure (NYHA II and III), and it is not possible to extrapolate the results to patients with severe heart failure.
Losartan appears to be a promising new drug for the treatment of chronic heart failure. It has demonstrated clearly beneficial hemodynamic effects that are not diminished with long-term therapy and was very well tolerated with infrequent hypotension and no cough.
The following investigators and centers participated in this study: Najam A. Awan, MD, Scott West, MD, Minerva Consertal, Sacramento, Calif; Martial G. Bourassa, MD, Montreal Heart Institute, Canada; George Broderick, MD, Gary Collins, MD, Wright-Patterson Air Force Base Medical Center, Ohio; John Cleland, MD, Nigel Stephens, MD, Royal Postgraduate Medical School, London, UK; Robert J. Cody, MD, Garrie Haas, MD, Philip Binkley, MD, Ohio State University Hospitals, Columbus, Ohio; Morten Dahle, MD, Rikshospitalat, Oslo, Norway; Martine DeKock, MD, Universite Catholique de Louvain, Belgium; Kenneth Dickstein, MD, Central Hospital in Rogaland, Norway; Eckehard Fleck, MD, V. Regitz, MD, Deutsches Herzzentrum Berlin, Germany; Martin J. Frey, MS, MD, Heart Center of Sarasota, Fla; Stephen G. Gottlieb, MD, University of Maryland School of Medicine (Baltimore); Hamid Ikram, MD, Ian Crozier, MD, Christchurch Hospital, Christchurch, New Zealand; John B. Kostis, MD, Daniel Shindler, MD, UMDNJ-Robert Wood, Johnson Medical School, New Brunswick, NJ; David Lantz, MD, 60th Medical Group (AMC), Travis AFB, Calif; Gary Ledley, MD, Maria Babicki, MD, Albert Einstein Medical Center, Philadelphia, Pa; Chang-seng Liang, MD, Joseph Delehanty, MD, University of Rochester Medical School, Rochester, NY; Peter Liu, MD, Toronto General Hospital, Canada; Eulo Lupi, MD, Instituto Nacional de Cardiolgia IC, Mexico; Eduardo Meaney, MD, Hospital Regional 1° De Octubre, Mexico; Alan Niederman, MD, Ft Lauderdale, Fla; Kenneth E. Shafer, MD, West Plains, Mo; Finn Waagstein, MD, C.-H. Bergh, MD, Wallenberg Laboratory, Sweden; James Young, MD, Baylor College of Medicine, Houston, Tex.
This work was funded by a project grant from Merck Research
↵1 A complete list of participating investigators and centers is provided in the Appendix.
- Received April 19, 1994.
- Accepted August 19, 1994.
- Copyright © 1995 by American Heart Association
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