Combined treatment with losartan and an ACE inhibitor in mild to moderate heart failure: Results of a double-blind, randomized, placebo-controlled trial☆

Article Outline

• Abstract
• Methods
  • Study protocol
    • Cardiac output
    • Regional hemodynamics
    • Neurohumoral and biochemical parameters
  • Dose titration and follow-up
  • Statistical analysis
• Results
  • Patients
  • Tolerability of study drugs
  • Exercise testing
  • Central and regional hemodynamics
  • Biochemical and neurohumoral parameters
  • Quality-of-life assessment
• Discussion
• References
• Copyright

Abstract 

Background Although the beneficial effects of angiotensin-converting enzyme (ACE) inhibitors in patients with heart failure are well recognized, there are theoretical advantages in combining ACE inhibition with angiotensin (AT)₁ receptor antagonism. Methods Twenty patients with mild to moderate heart failure and maximally treated with an ACE inhibitor were randomly assigned to losartan or placebo. Patients underwent repeated assessment of exercise tolerance, quality of life, central and regional hemodynamics, and neurohumoral and biochemical parameters over a period of 12 weeks. Results Losartan treatment was well tolerated in terms of adverse events, heart rate, and blood pressure response, and there were no significant changes in serum creatinine or potassium. After 12 weeks of treatment, no significant differences were observed between the losartan and placebo groups in exercise tolerance, quality of life, central and regional hemodynamics, or neurohumoral parameters. Conclusions In patients with mild to moderate heart failure already maximally treated with an ACE inhibitor, additional treatment with losartan is well tolerated, but we have not observed any significant improvement in exercise capacity, quality of life, central and regional hemodynamics, or neurohormones. Our data suggest that the combination of losartan with an ACE inhibitor does not offer any substantial advantages over treatment with an ACE inhibitor alone in these patients. (Am Heart J 2000;140:e25.)

Angiotensin-converting enzyme (ACE) inhibitors confer significant improvements in morbidity and mortality rates in patients with heart failure secondary to left ventricular systolic dysfunction.¹, ², ³, ⁴ However, despite their undeniable benefits, ACE inhibitors are not without their drawbacks. For instance, the production of angiotensin II can be catalyzed by enzymes other than ACE, such as chymase.⁵ These alternative pathways provide an “escape” mechanism that prevents ACE inhibitors from completely blocking the production of angiotensin II.⁶

In addition, ACE inhibitors have actions beyond those of inhibiting angiotensin II production. ACE is identical to kininase II, which is responsible for catalyzing the breakdown of bradykinin; ACE inhibitors therefore increase bradykinin levels.⁷ Because bradykinin has vasodilatory actions (by causing nitric oxide and prostacyclin release) it has been speculated that bradykinin may play a role in the beneficial hemodynamic effects of these drugs. Unfortunately, there is also evidence that the increased bradykinin levels are responsible for some of the adverse effects associated with ACE inhibitors, including cough and angioneurotic edema.⁸, ⁹ It is therefore possible that the effects on bradykinin breakdown are a necessary evil of ACE inhibition, responsible for some of the adverse effects as well as many of the beneficial ones.

Interest in this field has been stimulated by the recent introduction of orally active, nonpeptide angiotensin II type 1 (AT₁)-receptor antagonists such as losartan.¹⁰, ¹¹ Because these drugs act directly at the AT₁ receptor, the problem of angiotensin II formation by non-ACE pathways is overcome. A less clear-cut benefit is their lack of effect on bradykinin levels.¹² Although one might expect the AT₁-receptor antagonists to be better tolerated than the ACE inhibitors, their lack of potentiation of bradykinin could also reduce their hemodynamic benefits. The relative merits of the AT₁-receptor antagonists and ACE inhibitors remain unclear. Although an initial trial of losartan in elderly patients with heart failure suggested that it was associated with a lower mortality rate than captopril,¹³ a subsequent larger trial has failed to confirm this.¹⁴ Further evaluation of the AT₁-receptor antagonists is ongoing in a number of clinical trials in heart failure both in comparison with ACE inhibitors and, as in the case of the VALIANT (Valsartan in Acute Myocardial Infarction), Val-HeFT (Valsartan Heart Failure Trial), and CHARM (Candesartan Cilexitil in Heart Failure Reduction in Mortality and Morbidity) studies, in combination with ACE inhibitors.

Theoretically, combination treatment of heart failure with an ACE inhibitor and an AT₁-receptor antagonist may offer benefits beyond those provided by either drug on its own. Use of an ACE inhibitor would preserve the potentially important hemodynamic actions of bradykinin, whereas the AT₁-receptor antagonist would provide more complete blockade of the renin-angiotensin system than can be afforded by the ACE inhibitor alone. The need to examine this question further has been given added impetus by a case report of one patient who gained considerable symptomatic improvement on combination treatment.¹⁵ We therefore conducted this double-blind, randomized, placebo-controlled trial of losartan in patients with heart failure already treated with maximally recommended or tolerated does of an ACE inhibitor to assess its effects on exercise capacity, quality of life, central and regional hemodynamics, and biochemical and neurohumoral parameters.

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Methods 

This randomized, double-blind, parallel-group, placebo-controlled study was designed to assess the effects of losartan treatment in patients with heart failure who were already receiving diuretics and ACE inhibitors. The local ethics committee approved the study protocol, and all patients gave their informed consent to participation.

Criteria for enrollment were age ≥18 years, symptomatic (New York Heart Association [NYHA] functional class II or III) heart failure of at least 12 weeks’ duration, and echocardiographic evidence of left ventricular systolic dysfunction (ejection fraction <40%, fractional shortening <25%, or visual assessment by an experienced echocardiographer). In addition, eligible patients had to be taking a minimum of 40 mg furosemide (or equivalent) daily and be treated with maximally tolerated doses of either enalapril or captopril for at least 3 months before random assignment and be taking stable doses of these drugs for at least 4 weeks. The target doses of the ACE inhibitors used were 20 mg daily enalapril or 150 mg daily captopril. Patients taking lower doses were only enrolled if they were taking at least 10 mg daily enalapril or 75 mg daily captopril and had been proven unable to tolerate higher doses because of hypotension or renal dysfunction. Exclusion criteria were hemodynamically significant obstructive valvular disease or recent (within 12 weeks) myocardial infarction, stroke, or symptomatic arrhythmia.

Study protocol 

After an initial screening visit, at which a complete medical history and physical examination were undertaken, patients entered into a run-in phase. All the patients’ usual medications were continued during the run-in phase and throughout the remainder of the trial. During the run-in period, patients made weekly visits to a temperature-controlled laboratory (23°C to 24°C) in the morning after an overnight fast. Medication was also omitted on the morning of the visit. Patients rested supine for at least 30 minutes before undertaking a symptom-limited treadmill exercise test with a modified (low level) Bruce protocol. The slope of the treadmill was increased at 3-minute intervals in 0°, 1.3°, 2.6°, 4.3°, 5.4°, and 6.3° stages; the treadmill speed was 2.7 km/h for the first 4 stages, 4.0 km/h for the fifth stage, and 5.4 km/h for the sixth stage.

Patients also undertook a 100-m corridor walk test at self-selected slow, normal, and fast speeds. The time taken to complete each 100-m walk was recorded. This test has been used previously in studies of patients with heart failure.¹⁶, ¹⁷ Customary daily activity was assessed in the patients’ homes by using a pair of hip-borne pedometers issued for a period of 2 weeks. These pedometers have previously been validated and used in studies of patients with heart failure.¹⁷, ¹⁸, ¹⁹, ²⁰

Patients were only eligible for random assignment if their exercise tolerance was limited by dyspnea or fatigue and if their treadmill exercise duration was consistent (defined as a variation of <30 seconds or 5% from the previous visit). Patients who met these criteria within a maximum of 4 run-in visits were allocated treatment with either losartan at an initial dose of 12.5 mg once daily (the dose was up-titrated to 50 mg daily at subsequent visits) or placebo in a randomized, double-blind fashion. The random allocation codes were generated before the commencement of the study by the use of an in-house software package called A-RAND (University Hospital Pharmacy Department, Nottingham, UK). The codes were held in sealed envelopes under secure conditions in the pharmacy department and were not accessed by the trial investigators at any time during the study. Trial drugs, which were formulated by the pharmacy department in identical capsules, were issued by the pharmacy department on a visit-by-visit basis. All the allocation codes were finally released to the investigators only after the final participant had completed the final visit.

On the first day of treatment, patients attended the laboratory for a series of hemodynamic and neurohumoral assessments. The assessments made were as follows.

Cardiac output 

Cardiac output was measured by the indirect Fick principle, monitoring respiratory gases with a mass spectrometer (Marquette, Jupiter, Fla), with carbon dioxide used as the indicator. The method has been demonstrated to correlate closely with cardiac output measurement by thermodilution.²¹

Regional hemodynamics 

Blood flow was measured in the forearm and calf by venous occlusion plethysmography with mercury-in-silastic strain gauges.²² Blood flow in the right renal artery and superior mesenteric artery was measured by transcutaneous Doppler ultrasound with a 3.5-kHz curvilinear ultrasound probe (Sonotron, Santa Clara, Calif).²³, ²⁴, ²⁵

Neurohumoral and biochemical parameters 

Blood was obtained with an 18-gauge intravenous cannula and analyzed for serum potassium and creatinine, norepinephrine, epinephrine, atrial natriuretic peptide and plasma renin activity.

Quality of life was assessed by means of a self-administered, disease-specific questionnaire that has been validated within our department and used in a number of studies in patients with heart failure.²⁶, ²⁷, ²⁸ Before receiving their first dose of study drug, patients were given a quality-of-life questionnaire to complete. An identical questionnaire was administered after 12 weeks of treatment.

Dose titration and follow-up 

Patients taking losartan were titrated up to a dose of 25 mg once daily after 1 week and then to a maximum dose of 50 mg once daily 1 week later. Patients were reviewed after 4 weeks and 12 weeks of treatment and on each occasion underwent full physical assessment, exercise testing, and hemodynamic and neurohumoral assessment as described above. Patients completed the treatment phase after 12 weeks, at which point the study drug was discontinued.

Statistical analysis 

The primary outcome measure was the change in exercise duration on the treadmill exercise test. We calculated that a sample size of 10 patients in each treatment group would give the study a power of 75% to detect the primary outcome measure, a 25% difference in treadmill exercise time between losartan and placebo at a 0.05 level of significance. This was considered to represent a clinically significant difference, and the number of participants required could be recruited at a single center within a reasonable time period. Secondary outcome measures were changes in corridor walk times, pedometer score, central and regional hemodynamic parameters, and quality of life.

The data were analyzed on an intention-to-treat basis and, where data were unavailable, by the last-observation-carried-forward principle. Nonparametric analytic methods were used throughout. Comparability of baseline patient characteristics and incidence of adverse events were analyzed by the Mann-Whitney U test or Fisher’s exact test as appropriate. Overall treatment differences between the losartan and placebo groups were assessed by the Mann-Whitney U test. Within-group comparisons were made with the Wilcoxon signed rank sum test. Data are expressed as mean (standard error of the mean).

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Results 

Patients 

Table I shows the baseline characteristics of the randomly assigned patients.

Table I. Baseline characteristics of patients

Both groups were well-matched except that the placebo-treated group were, on average, 8 years younger than the losartan-treated group. There was, however, no significant difference between the groups in the duration of their heart failure. All of the patients had been taking stable doses of diuretics and ACE inhibitors for at least 4 weeks before commencing the study and continued to take the same dose throughout the duration of the study. The patients who entered the study established on captopril therapy were taking a mean total dose of 107 mg daily (range 75 to 150 mg); those established on enalapril were taking a mean total dose of 15 mg daily (range 10 to 20 mg). There were no significant differences in the mean total daily ACE inhibitor dose being taken by the losartan and placebo groups.

Tolerability of study drugs 

Of the 20 patients randomly assigned into the double-blind treatment phase, 18 completed the study. One placebo-treated patient was withdrawn because of worsening heart failure requiring additional treatment; one losartan-treated patient with diabetes mellitus was withdrawn after an admission to another hospital (with hypoglycemia), during which his existing medication was substantially altered, precluding further participation in the study.

Table II shows the heart rate and blood pressure data for both treatment groups at baseline and after 1 to 12 weeks of treatment.

Table II. Heart rate and blood pressure response

HR, Heart rate; SBP, systolic blood pressure; DBP, diastolic blood pressure.

Although the mean systolic blood pressure fell by 6 mm Hg during 12 weeks of losartan therapy, this change was not significant. Six patients in the losartan group reported a total of 9 adverse events during treatment, compared with 8 patients in the placebo group reporting 13 adverse events (Table III).

Table III. Incidence of adverse events during study treatment phase

A deterioration in heart failure symptoms was reported by 4 placebo-treated patients and none of the losartan-treated patients (P = .09).

Exercise testing 

Table IV shows the exercise times for the symptom-limited modified Bruce protocol for both treatment groups.

Table IV. Exercise test results

There were no significant differences in total exercise time between the groups at baseline (P = .79), after 4 weeks of treatment (P = .47), or after 12 weeks of treatment (P = .52). Although mean exercise time fell in the losartan group from 479 to 470 seconds (compared with an increase in the placebo group from 494 to 554 seconds), this was not significant.

There were also no significant differences between the two treatment groups for the corridor walk times. There were no significant differences in pedometer scores between the groups at baseline (P = .47), after 4 weeks of treatment (P = .19), or after 12 weeks of treatment (P = .91). Pedometer scores remained stable in the placebo group, falling by 4.9% during the 12-week study. In the losartan group, pedometer scores increased by +29.8% during the 12-week study, although this within-group change failed to reach statistical significance (P = .07).

Central and regional hemodynamics 

Table V shows central and regional hemodynamic parameters throughout the study.

Table V. Central and regional hemodynamic parameters

After 12 weeks of treatment, resting cardiac output, forearm blood flow, and calf blood flow did not differ significantly between the two treatment groups. Satisfactory imaging of the right renal artery and superior mesenteric artery was possible in 7 of the losartan group and 8 of the placebo group; no significant differences were seen between the two groups in either parameter at 4 or 12 weeks.

Biochemical and neurohumoral parameters 

No significant changes in serum potassium or creatinine were observed in either treatment group during the treatment period (Table VI), nor were there any significant changes in levels of norepinephrine, epinephrine, renin, or atrial natriuretic peptide.

Table VI. Biochemical and neurohumoral parameters

One losartan-treated patient had transient hyperkalemia (6.2 mmol/L at week 2), but this had fallen to 4.9 mmol/L by week 4 without the need for any change in study medication.

Quality-of-life assessment 

No significant differences were observed between the two treatment groups in overall quality-of-life scores assessed by questionnaires administered at baseline (losartan group, mean score of 149 [8]; placebo group, mean score of 129 [10], P = .42) and week 12 (losartan group, mean score of 151 [8]; placebo group, mean score of 128 [9], P = .09).

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Discussion 

We have demonstrated that the AT₁-receptor antagonist losartan is well tolerated when combined with an ACE inhibitor in patients with stable chronic heart failure. There were no significant differences between the two groups in terms of patients withdrawn and the number of adverse events, and cases of worsening heart failure were actually slightly lower (albeit not statistically significant) in the losartan-treated group. There were also no detrimental effects on heart rate, blood pressure, serum potassium levels, or renal function over the 12-week treatment period. Previous studies of losartan used without a concomitant ACE inhibitor have also demonstrated a good tolerability profile in patients with heart failure or hypertension.²⁹, ³⁰, ³¹, ³²

However, although combination treatment with losartan and an ACE inhibitor is well tolerated, it also has disappointingly few beneficial effects on exercise tolerance, quality of life, central or regional hemodynamics, or neurohumoral parameters. 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.¹⁹, ²⁰ Nonetheless, we did not observe any difference between the treatment groups in either maximal treadmill exercise times or self-paced corridor walk times and, although we did observe a 29.8% increase in pedometer scores with losartan, there was no significant difference when compared with the placebo-treated group.

Previous studies have shown that losartan has beneficial hemodynamic effects in patients with heart failure when used in the absence of an ACE inhibitor.²⁹, ³³ Losartan used alone also has been shown to have effects comparable to enalapril in terms of exercise capacity, clinical status, and neurohumoral activation.³⁰ The lack of any significant changes when losartan is used in combination with an ACE inhibitor suggests that treatment with an ACE inhibitor alone maximizes patients’ exercise potential and optimizes their hemodynamic and neurohumoral parameters. Although the formation of angiotensin II through non-ACE pathways suggests room for further improvement by achieving more complete inhibition of the renin-angiotensin system, our results indicate that there is little to gain from this approach. In particular, we believe that the role of bradykinin in the action of ACE inhibitors needs further clarification. There is good evidence that bradykinin makes a significant contribution to the vasodilatory effects of ACE inhibitors but not to those of losartan.³⁴, ³⁵ If increased levels of bradykinin make an important contribution to the action of ACE inhibitors, this may explain why the greater blockade of the renin-angiotensin system provided by the addition of losartan appears relatively unimportant.

At present, there are few published data on combination therapy with ACE inhibitors and AT₁-receptor antagonists in clinical heart failure trials. In human subjects, Hamroff et al³⁶ have studied the safety of 2 weeks of combination treatment in 43 patients with symptomatic congestive heart failure and found a small but statistically significant fall in blood pressure and no change in serum electrolytes or renal function. In an extension of this study,³⁷ 33 patients with NYHA class III to IV heart failure went on to receive 50 mg daily losartan or placebo for 6 months. The investigators found improvements in the losartan-treated group in NYHA functional class and in peak aerobic capacity during maximal treadmill testing, although they do not present data on total exercise times or quality of life. In our study, heart failure symptoms did worsen in 4 of the placebo-treated patients and none of the losartan-treated patients, but this did not reach statistical significance. However, the patients studied by Hamroff et al had more severe heart failure than ours (NYHA functional class III-IV versus class II-III). In a study of the ACE inhibitor cilazapril, it was shown that the beneficial effects of ACE inhibition are greater in those patients with the most impaired exercise tolerance at baseline.³⁸ If the same is true of combination treatment with an ACE inhibitor and losartan, this would help to account for the different findings of the study by Hamroff et al and our own.

The only large randomized trial of combination treatment to have been published so far was the RESOLVD (Randomized Evaluation of Strategies for Left Ventricular Dysfunction) pilot study that compared candesartan alone, enalapril alone, and their combination in 768 patients with NYHA functional class II-IV heart failure.³⁹ Combination treatment led to no significant changes in 6-minute walk distance, NYHA functional class, quality of life, or ejection fraction. Unlike our own study, the RESOLVD study did not include treadmill exercise times, pedometer scores, or regional hemodynamic measurements. Although the RESOLVD study did find significant and favorable improvements with combination treatment in neurohumoral levels and ventricular volumes, as in our own study, there were no associated clinical (or mortality) benefits.

Although ours was a small study, the two treatment groups in our study were well matched. Although the losartan-treated group was, on average, 8 years older than the placebo-treated group, there was no significant difference in terms of the duration of heart failure. We therefore do not believe that the age difference has any bearing on our observations. Because small trials carry the possibility of type II error, we cannot rule out the possibility that more subtle differences between losartan and placebo may be uncovered with a larger trial, although one must, of course, remember that statistical significance does not necessarily imply clinical significance.

In summary, in patients with mild to moderate heart failure already maximally treated with an ACE inhibitor, additional treatment with losartan is well tolerated, but we have not observed any clinically significant improvement in exercise capacity, quality of life, central and regional hemodynamics, or neurohormones. Our data suggest that the combination of losartan with an ACE inhibitor does not offer any substantial advantages over treatment with an ACE inhibitor alone in these patients. Comparing our findings with the existing literature indicates that if there is any substantial clinical benefit to be gained from combination treatment with an ACE inhibitor and an AT₁-receptor antagonist, then it may be more likely to be found in patients with moderate to severe heart failure than in those with milder symptoms. This observation should be taken into account when planning future studies in this field.

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