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European Journal of Heart Failure 1999 1(4):385-393; doi:10.1016/S1388-9842(99)00038-0
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© 1999 European Society of Cardiology

Haemodynamic, neurohumoral and exercise effects of losartan vs. captopril in chronic heart failure: results of an ELITE trial substudy

Andrew R. Houghton*, Maxine Harrison and Alan J. Cowley

Department of Cardiovascular Medicine D Floor, South Block University Hospital, Queen's Medical Centre Nottingham NG7 2UH, UK

* Corresponding author. Present address: Department of Cardiology, Leicester General Hospital, Gwendolen Road, Leicester, LE5 4PW, UK. Tel.: +44-116-249-0490; fax: +44-116-258 4666. E-mail address: houghtons{at}talk21.com


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: The AT1 receptor antagonists differ from the angiotensin converting enzyme inhibitors by achieving a more complete blockade of angiotensin II's actions and by not affecting bradykinin metabolism. There is little information on whether this causes clinically significant differences in haemodynamics, neurohormones and exercise tolerance in heart failure.

Aims: To compare the effects of losartan and captopril upon central and regional haemodynamics, neurohormones and exercise capacity in heart failure.

Methods: In a double-blind, randomised trial 18 patients aged ≥ 65 years with symptomatic heart failure were allocated to treatment with losartan (10 patients) or captopril (eight patients). Patients underwent assessment at baseline, after the first dose, at 12 weeks and at 24 weeks.

Results: Systolic blood pressure fell by –10.7% 1 h after captopril 6.25 mg (P = 0.007) and by –4.8% 3 h after losartan 12.5 mg (P = 0.02). The blood pressure reduction was sustained with losartan at 12 and 24 weeks. Systemic vascular resistance fell acutely after captopril (–16.4%, P = 0.01). Captopril caused an acute and sustained rise in superior mesenteric artery blood flow (+22.9%, P = 0.04), and a slower rise in renal artery blood flow (+31.7%, P = 0.01). Losartan had no acute effects on regional haemodynamics but had increased superior mesenteric artery blood flow by 38.1% at 12 weeks (P = 0.02). There were no substantial differences between losartan and captopril, and no changes occurred in neurohormones or exercise capacity.

Conclusion: No substantial differences were observed between losartan and captopril on central or regional haemodynamics, neurohormones or exercise capacity in elderly patients with stable symptomatic heart failure.

Key Words: Losartan • Captopril • AT1 receptor antagonist • Heart failure • Haemodynamics • Neurohormones

Received March 16, 1999; Revised June 30, 1999; Accepted July 1, 1999


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
A number of large, randomised controlled trials have clearly demonstrated that angiotensin converting enzyme (ACE) inhibitors confer significant improvements in morbidity and mortality in patients with heart failure [1–4]. However, ACE inhibitors are not without their drawbacks. Alternative pathways for the conversion of angiotensin I to angiotensin II, means that angiotensin II production still occurs even in the presence of complete ACE inhibition [5,6]. In addition, ACE is identical to kininase II, which is responsible for catalysing the breakdown of bradykinin; ACE inhibitors, therefore, increase bradykinin levels [7]. It remains unclear whether this action of ACE inhibitors is beneficial or deleterious.

The development of orally active angiotensin II type 1 (AT1) receptor antagonists such as losartan [8,9] has rekindled interest in the various effects of ACE inhibitors. Because the AT1 receptor antagonists act directly at the AT1 receptor, the problem of angiotensin II formation by non-ACE pathways is overcome. In addition, the AT1 receptor antagonists do not interfere with bradykinin metabolism [10]. Because of these differences, it was unclear how drugs such as losartan would compare with ACE inhibitors in the treatment of heart failure.

In addition to the effects on morbidity and mortality, treatment with ACE inhibitors is associated with significant changes in central and regional haemodynamic parameters [11,12], neurohumoral activity [13] and exercise capacity [14,15]. Little is currently known about whether long-term treatment with losartan has comparable effects. In the study presented in this paper we compared the effects of losartan and captopril on a number of central and regional haemodynamic, neurohumoral and exercise parameters in elderly patients with chronic heart failure.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Design
This double-blind, randomised comparison of losartan and captopril in elderly patients with chronic heart failure formed a substudy of the Evaluation of Losartan in the Elderly (ELITE) study [16]. The investigation conforms with the principles outlined in the Declaration of Helsinki. The protocols for both the ELITE study and this substudy were approved by the local Ethics Committee and all patients gave their written informed consent to participation.

2.2. Study population
All the patients participating in this substudy were required to meet the enrolment criteria of the ELITE study [16]. In brief, all participants were aged 65 years or over (two-thirds were 70 years or over) with symptomatic heart failure, left ventricular ejection fraction 40% or less, and had received no prior treatment with ACE inhibitors. No additional inclusion or exclusion criteria were applied.

2.3. Substudy protocol
Following a 2-week placebo run-in period patients were randomised to receive active therapy, either to losartan 12.5 mg (titrated to 25 and then 50 mg once daily) plus placebo for captopril, or to captopril 6.25 mg (titrated to 12.5, 25 and then 50 mg three times daily) plus placebo for losartan. Dose titration was generally performed at 7-day intervals as tolerated. Concomitant treatment with the patients’ usual additional cardiovascular therapies was permitted.

On assessment visits, patients attended a temperature-controlled laboratory (23–24°C) in the morning following an overnight fast. Medication was also omitted on the morning of the visit. Patients rested supine for at least 30 min before measurements were undertaken. On their placebo run-in visit, prior to randomisation, patients undertook a baseline assessment of their exercise capacity. At the following randomisation visit, patients underwent a baseline assessment of central and regional haemodynamics, and neurohumoral assays were undertaken. They then received their first dose of active study drug and underwent repeated measurements for the following 4 h and monitoring of their heart rate and blood pressure for 5 h.

Following a period of dose titration, patients were reviewed in the laboratory after 12 and 24 weeks for a further assessment of their haemodynamic and neurohumoral status and their exercise capacity. The assessments made at each visit were as follows.

2.3.1. Cardiac output
Cardiac output was measured using the indirect Fick principle, monitoring respiratory gases with a mass spectrometer (Marquette, Jupiter, FL, USA) and using carbon dioxide as the indicator. The method has been demonstrated to correlate closely with cardiac output measurement by thermodilution [17]. Carbon dioxide production was calculated from minute ventilation and mixed expired carbon dioxide concentration, the partial pressure of carbon dioxide in pulmonary venous (systemic arterial) blood was derived from endtidal carbon dioxide concentration and the partial pressure in mixed venous blood was measured following a rebreathing manoeuvre. These three variables can then be used to solve the Fick equation.

2.3.2. Regional haemodynamics
Overall systemic vascular resistance was calculated from the equation — 80x(mean arterial pressure/cardiac output). A variety of non-invasive methods were employed to assess blood flow within specific vascular territories. Blood flow in the right forearm and left calf was measured by venous occlusion plethysmography [18] with mercury in silastic strain gauges. Blood flows in the superior mesenteric artery [19,20] and the right renal artery [21] were measured by transcutaneous Doppler ultrasound using a 3.5-kHz curvilinear ultrasound probe (Sonotron, Santa Clara, CA, USA). The vessels were identified by ultrasound and the sample volume of the pulsed Doppler system was adjusted to the size of the vessel being interrogated. Doppler spectral analysis was recorded with the subjects’ breath held in mid-inspiration. Vessel diameter was calculated from the mean of three values, with measurements and Doppler signals taken from the proximal portion of each vessel.

2.3.3. CV% for non-invasive measurements
With non-invasive haemodynamic measurements close attention must be paid to potential errors resulting from measurement variability. The non-invasive methods used for this study have all been well-validated and the coefficient of variation (CV%) has previously been reported for patients studied in our laboratory as follows: cardiac output 7.8%, superior mesenteric artery blood flow 10.1%, right renal artery blood flow 10.8% and calf blood flow 7.5% [22]. The CV% for forearm blood flow was 10.5% [23].

2.3.4. Neurohumoral assays
Blood was obtained via an 18 gauge intravenous cannula and analysed for noradrenaline, atrial natriuretic peptide (ANP) and plasma renin activity. All blood samples were centrifuged and the plasma stored at –20°C until assayed by Corning Hazleton (Harrogate, UK). Plasma noradrenaline was determined by radioimmunoassay (IBL Amicyl Katcombi). Atrial natriuretic peptide was measured by direct radioimmunoassay (Nichols Institute). Plasma renin activity was measured by a two-step radioimmunassay (angiotensin I generation followed by solid phase radioimmunoassay).

2.3.5. Exercise capacity
Patients were issued with a pair of hip-borne pedometers for periods of 2 weeks to assess their customary activity at home [24]. Patients also undertook a 100-m corridor walk test at self-selected slow, normal and fast speeds.

2.4. End of study
The duration of this substudy was 24 weeks following randomisation; following completion of the substudy, patients continued in the ELITE study for a further 24-week period. Randomisation codes were not released until after the completion of the main ELITE study.

2.5. Statistical analysis
The sample size of 18 patients gives the study a power of 75% to detect a 35% difference in cardiac output or systemic vascular resistance, a 40% difference in plasma noradrenaline levels, and a 15% difference in corridor walk times, between losartan and captopril at a P=0.05 level of significance. These were considered to represent clinically significant differences and the number of patients required could realistically be enrolled at a single centre within the time period of recruitment for the ELITE study.

The data were analysed on an intention to treat basis and, where data were unavailable, using the last-observation-carried-forward principle. Non-parametric analytical methods were used throughout. Comparability of baseline patient characteristics were analysed by the Mann–Whitney U-test or Fisher’s exact test as appropriate. Overall treatment differences between the losartan and captopril groups were assessed using the Mann–Whitney U-test. Within-group comparisons were made using the Wilcoxon signed rank sum test. Data are expressed as mean±S.E. of the mean (S.E.M.).


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1. Subjects
Eighteen patients participated in this substudy, of whom 10 were allocated to the losartan group and eight to the captopril group. Of the 10 patients allocated to the losartan group, all 10 completed the study. Of the eight patients allocated to the captopril group, four completed the study. Three patients withdrew following adverse clinical events and one patient died.

Baseline characteristics of the losartan and captopril groups, listed in Table 1, indicate that they were well-matched, with no significant differences in gender or New York Heart Association (NYHA) functional class. Both groups were of comparable age (P=0.89), duration of heart failure (P=1.0), weight (P=0.96), body mass index (P=0.63), body surface area (P=0.82) and left ventricular ejection fraction (P=0.72). Ischaemic heart disease was the underlying aetiology of the heart failure in five of the losartan group and six of the captopril group.


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  		Table 1 Patient characteristics at randomisation. Table shows numbers, or, where appropriate, mean±S.E.M.

 
3.2. Heart rate and blood pressure
Fig. 1 shows the mean systolic blood pressure responses to captopril or losartan after the first dose of either losartan 12.5 mg or captopril 6.25 mg, and at the 12- and 24-week follow-up visits. There was a modest (–4.8%) fall in systolic blood pressure 3 h after losartan (P=0.02) and a more rapid fall of –10.7% 1 h after captopril (P=0.007). The between-group difference recorded 1 h post-dose just attained statistical significance (P=0.048).


Figure 1
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  		Fig. 1 Mean (S.E.M.) systolic blood pressure from 0 to 5 h after the first dose of active drug, and at 12 and 24 weeks, for captopril ({circ}) and losartan ({blacksquare}). *Captopril vs. baseline (P<0.05); **losartan vs. baseline (P<0.05); $=captopril vs. losartan (P<0.05).

 
At the 12- and 24-week visits no significant reductions in systolic blood pressure were observed in the captopril group. In the losartan group, however, systolic blood pressure remained significantly lower than baseline both at 12 (P=0.008) and 24 weeks (P=0.046). No significant between-group differences in heart rate were observed during the study.

3.3. Cardiac index
Fig. 2 shows the mean cardiac index data from both treatment groups. Measurements were made from 0–4 h following the first dose of study drug and repeated at 12 and 24 weeks. No significant changes were observed within or between groups.


Figure 2
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  		Fig. 2 Mean (S.E.M.) cardiac index from 0 to 4 h after the first dose of active drug, and at 12 and 24 weeks, for captopril ({circ}) and losartan ({blacksquare}).

 
3.4. Systemic vascular resistance
Fig. 3 shows the mean systemic vascular resistance in both treatment groups. A significant fall in systemic vascular resistance was observed in the captopril group at 1 h (–14.3%, P=0.01) and 2 h (–16.4%, P=0.01) after the first dose. The largest fall in the losartan group was seen at week 12, but this did not reach statistical significance (–11.7%, P=0.11). There were no significant between-group differences.


Figure 3
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  		Fig. 3 Mean (S.E.M.) systemic vascular resistance from 0 to 4 h after the first dose of active drug, and at 12 and 24 weeks, for captopril ({circ}) and losartan ({blacksquare}). *captopril vs. baseline (P<0.01).

 
3.5. Blood flow in the renal artery
Satisfactory imaging of the right renal artery was possible in eight (80%) of the losartan group and eight (100%) of the captopril group. No significant acute changes were seen in either group. With chronic treatment, renal artery blood flow had increased in the captopril group by +23.4% at week 12 (P=0.03), and by +31.7% at week 24 (P=0.01). The corresponding increases in the losartan group were +7.9% and +15.9%, neither of which achieved statistical significance.

3.6. Blood flow in the superior mesenteric artery
Satisfactory imaging of the superior mesenteric artery (SMA) was possible in eight (80%) of the losartan group and six (75%) of the captopril group. In the captopril group SMA blood flow increased by +22.9% after 2 h (P=0.04) and by +19.4% 3 h after the first dose (P=0.046). Blood flow had increased by +29.2% from baseline values at 12 weeks (P=0.04), and by 24.5% at 24 weeks (P=0.04). In the losartan group there were no acute changes in SMA blood flow. However, at 12 weeks blood flow had increased by +38.1% (P=0.02), and at 24 weeks by +35.3% (P=0.04).

3.7. Limb blood flow
Limb blood flow data for the forearm and calf are shown in Fig. 4. There were no significant between-group differences during the course of the study.


Figure 4
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  		Fig. 4 Mean (S.E.M.) forearm blood flow (upper figure) and calf blood flow (lower figure) from 0 to 4 h after the first dose of active drug, and at 12 and 24 weeks, for captopril ({circ}) and losartan ({blacksquare}).

 
3.8. Neurohormones
Table 2 shows the levels of noradrenaline, renin and atrial natriuretic peptide at baseline, 12 weeks and 24 weeks for the losartan and captopril groups. There were no significant changes in any of the neurohormonal parameters during the course of the study.


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  		Table 2 Neurohumoral parameters at baseline and week 12 for the placebo and losartan treatment groups (values are mean±S.E.M.)

 
3.9. Exercise capacity
Table 3 shows the corridor walk times and pedometer scores at baseline, week 12 and week 24. No significant differences were seen within or between groups.


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  		Table 3 Exercise test results for the losartan and captopril treatment groups (values are mean±S.E.M.)

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
Previous work has found little correlation between cardiac output and exercise tolerance, and has suggested that skeletal muscle and renal blood flow may be more important in determining patients’ symptoms [22]. In our study we saw a fall in overall systemic vascular resistance with both losartan and captopril, with captopril having an acute effect within 1 h of administration. The effects of losartan did not become apparent until patients were reassessed at week 12. We also observed significant long-term increases in both renal artery blood flow and superior mesenteric artery blood flow with both captopril and losartan. However, although captopril tended to have a more acute time-course of action than losartan, we found no significant differences in regional blood flow between the captopril and losartan groups. We have, therefore, found no evidence to suggest that the drugs differ significantly in their redistribution of regional blood flow in patients with heart failure.

We chose to assess exercise tolerance in this study using the self-paced corridor walk test and by assessing customary activity using pedometers. There are strong arguments that treadmill testing is a poor measure of overall symptomatology, and that self-paced tests or measurements of customary activity are more representative of a patient’s actual capabilities [25,26]. Pedometer scores and corridor walk times remained virtually static throughout the 24-week study period.

Favourable haemodynamic and neurohumoral responses have been reported in previous studies of losartan in patients with heart failure [27,28]. Exercise capacity and neurohumoral activity have also previously been assessed with losartan. In a previous comparative trial of losartan and enalapril in patients with moderate to severe chronic heart failure, no significant differences were seen in exercise capacity either within or between treatment groups [29].

We acknowledge the inevitable limitations of a study of this nature, not least because of the small patient numbers recruited. Although we cannot exclude the possibility that more subtle differences between losartan and captopril may be uncovered with larger trials, one must remember that statistical significance does not necessarily imply clinical significance. The absence of a placebo control group makes it difficult to comment with certainty about the improvements seen in certain parameters during treatment, although we can assume a degree of improvement by comparison with earlier placebo-controlled studies.

The ELITE study unexpectedly demonstrated a reduction in total mortality in patients treated with losartan compared to captopril, and this seemed primarily due to a reduction in sudden cardiac death [16]. In this substudy we have not observed any haemodynamic or neurohumoral differences between losartan and captopril that might account for this difference in mortality, and this apparent property of losartan remains a subject for future studies. We did not, however, make any unexpected observations with either drug in this substudy and both losartan and captopril acted as one might predict from their recognised pharmacological characteristics. Moreover, our observations are largely in accordance with those of previous investigators. We believe, therefore, that the apparent similarity between losartan and captopril is real and justifies the current interest in losartan as a potential alternative agent for the treatment of heart failure.


   Acknowledgements
 
This substudy was supported by Merck Sharp and Dohme Ltd and we thank the company. We would also like to thank Debbie Blakey for her invaluable help during patient follow-up visits, and Jackie Richardson and her staff for their help in undertaking the echocardiograms and performing the ejection fraction analysis. Finally, we are of course indebted to all the patients who participated in the study.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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