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European Journal of Heart Failure 2008 10(9):899-906; doi:10.1016/j.ejheart.2008.07.004
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© 2008 European Society of Cardiology

Design of the Heart failure Endpoint evaluation of AII-Antagonist Losartan (HEAAL) study in patients intolerant to ACE-inhibitor

Marvin A. Konstama,*,1, Philip A. Poole-Wilsonb,1, Kenneth Dicksteinc,1, Helmut Drexlerd,1, Steven J. Justicee,1, Michel Komajdaf,1, William Malbecqg,1, Felipe A. Martinezh,1, James D. Neatoni,1, Gunter A.J. Rieggerj,1 and Soneil Gupthae,1

a Tufts Medical Center Boston, MA, USA
b National Heart & Lung Institute, Imperial College London UK
c University of Bergen, Stavanger University Hospital Stavanger, Norway
d Department of Cardiology, Medicine Highschool Hannover Hannover, Germany
e Merck & Co Whitehouse Station, NJ, USA
f Université Pierre et Marie Curie-Paris 6, Departement De Cardiologie, Hospital Pitie-Salpetriere Paris, France
g MSD (Europe) Inc Brussels, Belgium
h Córdoba National University, President of Rusculleda Foundation for Clinical Research Cordoba, Argentina
i University of Minnesota, School of Public Health, Division of Biostatistics Minneapolis, MN, USA
j Clinic and Policlinic for Internal Medicine II Cardiology, University Hospital Regensburg Regensburg, Germany

* Corresponding author. Tufts Medical Center, Box 108, Boston, MA 02111, USA. E-mail address: mkonstam{at}tuftsmedicalcenter.org (M.A. Konstam).


   Abstract
Top
 Notes
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 Conflict of interest
 References
 
Background: In patients with heart failure and reduced left ventricular ejection fraction, angiotensin receptor blockers have been found to reduce mortality and morbidity and to prevent or reverse left ventricular remodelling, compared to optimized background treatment. In light of these data, The Heart failure Endpoint evaluation of Angiotensin II Antagonist Losartan (HEAAL) study was developed to determine whether losartan 150 mg is superior to losartan 50 mg (antihypertensive dose) in reducing morbidity and mortality among patients with symptomatic heart failure who are intolerant of angiotensin-converting enzyme (ACE)-inhibitors.

Aims/methods: To compare the effect of high and moderate doses of losartan on the primary endpoint of all-cause mortality and hospitalisation due to heart failure in patients (n=3834) with symptomatic heart failure and an ejection fraction ≤40% who are intolerant of ACE-inhibitor treatment.

Results: This paper presents the rationale, trial design, and baseline characteristics of the study population. The study, which completed recruitment on 31 March 2005, is event-driven and is estimated to accrue the target of 1710 adjudicated primary events during the latter half of 2008.

Conclusions: The results of HEAAL should facilitate selection of an optimal dosing regimen for losartan in patients with symptomatic heart failure who are intolerant of ACE-inhibitors.

Key Words: Angiotensin receptor blocker • Losartan • Heart failure • Morbidity • Mortality

Received December 11, 2007; Revised June 17, 2008; Accepted July 3, 2008


   1. Introduction
Top
 Notes
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 Conflict of interest
 References
 
The treatment options for managing patients with heart failure are being continuously refined. A number of recent trials have reported incremental benefit of angiotensin receptor blockers (ARBs) over prior background therapy with angiotensin-converting enzyme (ACE)-inhibitors alone [1,2], and several guidelines have been developed for their long-term use [3-7]. Both ACE-inhibitors and ARBs counter the effects of renin-angiotensin-system (RAS) activation, reducing blood pressure, and systemic vascular resistance in patients with heart failure. However, ACE-inhibitors do not prevent the production of angiotensin II through non-ACE-dependent enzymatic pathways (cathepsin G, tonin, trypsin and chymase) [8], which may contribute to the progression of heart failure [2,6]. ACE-inhibitors also inhibit the degradation of bradykinin [9]. In contrast, ARBs block the effects of angiotensin II at the receptor level, inhibiting the effects of angiotensin II produced through both ACE-dependent and ACE-independent pathways. Recent evidence demonstrates that ARBs administered in relatively high dosage can reduce morbidity and mortality in patients with heart failure [10].

ELITE II failed to demonstrate superiority of losartan, 50 mg/day, over captopril, 150 mg/day, in reducing morbidity and mortality in elderly patients with heart failure and reduced left ventricular ejection fraction (LVEF) [11,12]. One possible reason for this outcome is that the dose of losartan (50 mg) was too low. The Heart failure Endpoint evaluation of Angiotensin II Antagonist Losartan (HEAAL) study was therefore designed to compare the effect of two doses of losartan (50 mg daily versus 150 mg daily) on the combined endpoint of all-cause mortality and hospitalisation due to heart failure; the study population consisted of patients with heart failure and reduced LVEF who had documented intolerance to ACE-inhibitor treatment. HEAAL is an international, multi-centre, event-driven, double-blind, randomised trial, initiated in November 2001 and expected to terminate in late 2008. The aim of this paper is to present the rationale for the study, the trial design, and baseline characteristics of the patients who have been enrolled.


   2. Methods
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 Conflict of interest
 References
 
The study conforms to the principles outlined in the Declaration of Helsinki and all subjects provided their written informed consent prior to participation.

2.1. Study population
To be eligible for study entry, patients must satisfy the inclusion and exclusion criteria listed in Table 1. Patients enrolled had symptomatic heart failure [New York Heart Association (NYHA) Class II-IV] with LVEF ≤40%, had been on stable cardiovascular medical therapy for at least 2 weeks, and had known intolerance to ACE-inhibitors. Intolerance was defined as discontinuation of ACE-inhibitor treatment due to one or more of the following adverse effects: cough, symptomatic hypotension, azotaemia, hyperkalaemia, taste disturbance, gastrointestinal disturbance, or rash. Re-challenge with ACE-inhibitor was not required for entry into the trial.


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  		Table 1 Inclusion/exclusion criteria

 
2.2. Study design
HEAAL is an international, multi-centre, double-blind, randomised, event-driven parallel group study comparing two doses of losartan: 50 mg daily and 150 mg daily, administered in the morning.

Patients who were not receiving a beta-blocker at screening were evaluated for this therapy, in order to conform to current treatment recommendations [3-7]. It was left to the clinical judgement of individual investigators to decide whether or not these patients should be initiated on beta-blocker therapy. Investigators were encouraged to make every effort to ensure maximal beta-blocker dose titration and stabilization (for a minimum of 2 weeks) prior to enrolment. An open-label period of 1 to 2 weeks was used to gradually titrate patients onto losartan (Fig. 1). Patients who were not already receiving an ARB were titrated with losartan 12.5 mg for 1 week, followed by 25 mg for 1 week, prior to randomisation. Patients who were already receiving treatment with an ARB discontinued their prescription. Depending on the patient's prior ARB dose, investigators had the option of either initiating a 1-week open-label titration period with losartan 25 mg daily or directly randomising the patient, who would then receive losartan 50 mg daily during the following week (see below). During the open-label period, baseline and eligibility measures were recorded, including physical examinations, vital signs, resting electrocardiogram (ECG), and laboratory tests.


Figure 01
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  		Fig. 1 Study design.

 
Patients were randomly assigned to group 1 (50 mg losartan daily) or group 2 (150 mg losartan daily, uptitrated from 50 mg daily over a 3-week period). Every effort was made to achieve the target dose, and patients were maintained on the highest dose received during the titration period for the remainder of the study (see Fig. 1). Patients are assessed during titration (weeks 0, 1, 2 and 3 after randomisation) and after dose stabilisation (months 1, 2, 4, 6, 9 and 12), with subsequent 6-monthly monitoring until study completion. Each visit includes a physical examination and assessment of vital signs and compliance, with selected laboratory tests performed every 3 months and a resting ECG taken annually.

2.3. Randomisation and blinding procedures
Randomisation was stratified by clinical centre and whether patients were receiving beta-blocker therapy. Within each stratum, patients were allocated to losartan 50 mg (group 1) or150 mg (group 2) in a 1:1 allocation using block randomisation.

Following randomisation, patients were titrated to the appropriate dose over a 3-week period. Patients randomised to group 1 received one tablet of losartan 50 mg plus one tablet of placebo 100 mg daily and underwent a mock titration period of 3 weeks (to match group 2). This regimen was continued for the duration of the study (Fig. 1). Patients randomised to group 2 were titrated towards the 150 mg dose as follows: during week 1 they received one tablet of losartan 50 mg plus one tablet of placebo 100 mg daily; during week 2 patients were given one tablet of losartan 100 mg and one tablet of placebo 50 mg daily; during week 3 patients received one tablet of losartan 50 mg and one tablet of losartan 100 mg daily. The week 3 regimen was continued for the duration of the study (Fig. 1).

This trial is being overseen by the sponsor and the Steering Committee, both blinded throughout. The safety and conduct of the study are being monitored by an independent Data and Safety Monitoring Board (DSMB). A statistician (employed by the sponsor, but responsible only to the DSMB) and the DSMB are unblinded prior to trial completion. A separate, blinded, Endpoint Classification Committee is responsible for adjudicating outcomes, based upon protocol-defined criteria.

2.4. Outcome measures
The primary efficacy outcome measure is a composite of all-cause death or hospitalisation for heart failure. Classification of death is based upon the cause: sudden cardiac death, progressive heart failure, myocardial infarction, other cardiac causes, vascular (stroke, pulmonary embolism, aortic aneurysm rupture), non-cardiovascular, or undetermined. Patients fulfilling the ‘hospitalisation for heart failure’ criteria are those with heart failure that is deemed the primary cause for hospitalisation as classified by the Endpoint Classification Committee in accordance with their Standard Operating Procedures.

The secondary efficacy outcome measure is a composite endpoint of all-cause death or cardiovascular hospitalisation. Other major outcomes include: all-cause mortality; all-cause mortality or all-cause hospitalisation; cardiovascular mortality; all-cause hospitalisations; cardiovascular hospitalisations; hospitalisations for heart failure; changes in the severity of heart disease (change in NYHA functional class); new-onset diabetes; and new-onset atrial fibrillation. All major outcomes will be assessed until a common closing date for the study irrespective of whether blinded study medication is discontinued.

Safety outcomes include: the discontinuation of study medication, non-cardiovascular disease-related hospitalisation, adverse experiences, and laboratory abnormalities detected during follow-up.

2.5. Statistical considerations
The primary hypothesis is that treatment with losartan 150 mg daily will be superior to losartan 50 mg daily, as assessed by the effect on the composite event rate of all-cause death and/or hospitalisation for heart failure. It was recognised that neither superiority nor inferiority of losartan 50 mg daily, compared with ACE-inhibitors or other ARBs, had been established in this patient population. In the ELITE II study, there were no significant differences between losartan 50 mg daily and captopril 50 mg three times daily in patients with symptomatic heart failure for a number of endpoints: 1) all-cause mortality (for which the study had a 90% power to detect a 25% difference in total mortality) — 11.7% losartan versus 10.4% captopril; hazard ratio [HR] 1.13, 95.7% CI 0.95-1.35, P=0.16; 2) composite endpoint of all-cause mortality and/or hospitalisation for heart failure (the primary endpoint for HEAAL) — HR 1.04 (95% CI: 0.91-1.19, P=0.59; 3) total number of hospital admissions and hospital admissions for heart failure [11,12].

The initial sample size calculation was based on the assumption that the annual rate of all-cause mortality or hospitalisation for heart failure in the HEAAL losartan 50 mg group would be similar to that observed in the ELITE II study (18%), and that this rate would be reduced by 15% (absolute reduction of 2.7%) in the losartan 150 mg group (hazard reduction of 16.3%, or HR 0.837). In order to provide approximately 95% power at the 4.3% significance level (two-sided, adjusted for interim analysis) a target of 1710 patients with primary events was set. However, with an observed overall annual event rate of 12% (lower than expected) and the observed recruitment rate, additional patients were required (total n=3834). The study will terminate on a common closing date when 1710 adjudicated primary events have been accumulated, expected to be approximately 3.5 years after the recruitment of the last patient (latter half of 2008).

Two interim analyses for efficacy are planned after 50% (n=855) and 75% (n=1283) of the 1710 adjudicated primary endpoints have been observed. Any recommendation for early termination due to superior efficacy of the 150 mg dose will be made by the DSMB using an O'Brien-Fleming boundary as a guideline; the critical P values at the two interim analyses are 0.0035 and 0.019, respectively, and, in order to maintain the overall significance level at 5%, the critical P value at the final analysis is 0.043.

The primary endpoint will be summarised with time-to-event methods. The primary analysis will be intention to treat and based on a Cox regression model with indicator variables for treatment group, beta-blocker stratum, and region. Any regional effect will be determined according to regions defined as follows: 1) Europe, Middle East, and Africa (including Belgium, Croatia, Egypt, France, Germany, Greece, Holland, Italy, Lebanon, Morocco, Norway, Poland, Russia, Slovenia, Southern-Africa, Spain, UK, and Turkey); 2) Asia and the Pacific (including China [and Hong Kong], Malaysia, the Philippines, and Taiwan, but excluding the Middle East); and 3) Latin America (including Brazil, Chile, Colombia, Mexico, and Peru).


   3. Results
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 Conflict of interest
 References
 
A total of 3834 patients from 255 sites in 30 countries (Table 2) were enrolled between November 2001 and March 2005. If the adjudicated primary events occur as anticipated by August 2008, the median follow-up will be 56 (range 40-82) months.


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  		Table 2 Number of patients enrolled by country

 
With the exception of ethnic background, the baseline characteristics of the patients were broadly similar across the three regions (Table 3). Fewer patients recruited from region 3 (Latin America) were receiving beta-blockers compared with those in regions 1 and 2, but the clinical history and presentation, and medication use, were similar across the regions (Table 2). The NYHA severity of heart disease was also similar across the regions and, overall, 69% of patients were classified as functional class II, 30% as class III, and 1% as class IV (Table 3).


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  		Table 3 Baseline characteristics of patients

 
The reasons for ACE-inhibitor intolerance in the total cohort (n=3834) reported by the investigators included: cough (n=3292, 85.9%), orthostatic hypotension (n=268, 7%), rash (n=96, 2.5%), taste disturbance (n=86, 2.2%), hyperkalaemia (n=55, 1.4%), azotaemia (n=36, 0.9%) and gastrointestinal upset (n=15, 0.4%), with some patients experiencing more than one of these symptoms.


   4. Discussion
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
Conflict of interest
 References
 
Several studies have documented the value of ARBs in improving clinical outcomes in patients with heart failure and reduced LVEF, either as a substitute for ACE-inhibitors among ACE-inhibitor intolerant patients [CHARM-Alternative; Val-HeFT] or as add-on therapy [CHARM-Added] [1,2,13]. However, these studies used considerably higher ARB doses than those generally employed to treat hypertension. ELITE II, the only large-scale direct comparison of clinical outcomes in patients with heart failure randomised to an ACE-inhibitor (captopril) or an ARB (losartan), failed to demonstrate superiority of losartan in reducing mortality [12]. In contrast to other more recent losartan trials (LIFE, RENAAL) [14,15], ELITE II used only a moderate dose of losartan: 50 mg daily. Consequently, HEAAL was designed to test the superiority of high-dose losartan (150 mg/day) versus moderate dose losartan (50 mg/day) in reducing the combined endpoint of death or heart failure hospitalisation in patients with heart failure, low LVEF, and ACE-inhibitor intolerance.

Previous investigation of the effects of losartan on morbidity and mortality in patients with heart failure has principally been performed in comparison with ACE-inhibition. ELITE-I [16] was designed to compare the impact of long-term losartan (50 mg/day) versus captopril (50 mg three times daily) on renal function in 722 elderly patients with heart failure and reduced LVEF. Although the impact on renal function was similar in both groups, a post-hoc analysis showed a nominally significant reduction in mortality in the losartan group vs. the captopril group [16]. ELITE-II [11] included 3152 patients with heart failure and was designed to test the superiority of losartan over captopril, using the same dosing regimen and similar entry criteria as ELITE-I. ELITE-II failed to demonstrate superiority of either drug, and statistical power was inadequate to test a non-inferiority hypothesis [11]. A subsequent analysis showed no differences between the two treatment arms for the secondary endpoints which were linked to heart failure events and symptom severity, suggesting comparable efficacy of the two treatments when used at these dosages [12]. For the primary endpoint used in HEAAL (all-cause mortality and/or hospitalisation for heart failure), the HR for losartan versus captopril in ELITE II was 1.04 (95% CI:0.91-1.19) [11].

The CHARM-Alternative trial examined the effect of candesartan 32 mg daily in ACE-inhibitor-intolerant patients with heart failure and reduced LVEF. The primary endpoint was time to first occurrence of cardiovascular death or heart failure hospitalisation. It was the first study to clearly demonstrate that an ARB had a beneficial effect versus placebo on clinical outcomes in these patients [13]. In two other studies in patients with clinical heart failure and reduced LVEF who were already being treated with standard therapy, including ACE-inhibitors and beta-blockers, addition of an ARB demonstrated a significant reduction in adverse clinical outcomes versus placebo [1,2]. In Val-HeFT [1], the principal observed benefit of reduced heart failure hospitalisations seen with valsartan 160 mg twice daily, was largely driven by findings in the 7% of patients not receiving ACE-inhibitors. A post-hoc analysis performed on this subgroup demonstrated a 33% reduction in mortality (not seen in the overall trial) and a 50% reduction in the risk of hospitalisation for heart failure [17]. In CHARM-Added [2], which included patients who were well-treated with ACE-inhibitors in doses shown to achieve significant clinical benefit, there was only a trend towards a reduction in all-cause mortality with candesartan (P=0.086). However, a pre-specified analysis combining results from CHARM-Alternative and CHARM-Added (the two CHARM trials enrolling patients with reduced LVEF), compared candesartan with placebo across the two trials; and showed that there was a 12% relative risk ratio (RRR) for all-cause death (P=0.018), and a 16% RRR for cardiovascular death (P=0.005) [18].

The optimal dose of ARBs and the relative clinical impact of various dose regimens in heart failure are unknown. This issue is clinically important, given the acceptable but significant rate of adverse effects observed with the high ARB doses used in CHARM and Val-HeFT[1,13]. In ELITE II, losartan 50 mg had a similar effect to an ACE-inhibitor on heart failure related outcomes and NYHA class [14]; however, the question remains as to whether a higher dose (analogous to the high doses used in CHARM and Val-HeFT [1,13]) would be more efficacious.

The potential impact of higher doses of losartan on cardiovascular outcomes is suggested by data from the LIFE and RENAAL trials [15,19,20], which included patients with hypertension and diabetic nephropathy, respectively. A post-hoc analysis of patients with diabetes included in both of these studies demonstrated that doses of losartan of up to 100 mg daily were associated with a significant reduction in heart failure hospitalisation compared with atenolol (LIFE) or placebo (RENAAL) [21].

In contrast, a large trial comparing the effect of losartan 50 mg to captopril 150 mg on clinical outcomes in patients following myocardial infarction with clinical evidence of heart failure or LV dysfunction (OPTIMAAL) failed to demonstrate non-inferiority for the ARB versus the ACE-inhibitor [22]. However, a similar trial (VALIANT [23]) in an essentially identical population compared valsartan 320 mg (high-dose) with the same comparator (captopril 150 mg), convincingly demonstrated non-inferiority for the ARB versus the ACE-inhibitor. Taken together, these results suggest that high-dose ARB would be more efficacious than low-dose treatment.

There is evidence to show that increasing the dose of losartan to the range being explored in the HEAAL trial results in more effective inhibition of the AT1 receptor [24]. Although studies in hypertensive patients have suggested that the haemodynamic effect reaches a plateau with doses above 50 mg daily [25], the relationship between effectiveness of receptor blockade and blood pressure response is likely to be non-linear. The clinical benefits of AT1 receptor blockade are probably mediated by preventing the direct deleterious effects of A-II stimulation in the heart and vasculature, in addition to reducing cardiac load [10,26].

Losartan administered in doses of up to 150 mg in patients with heart failure has been shown to result in progressive increases in plasma renin activity and in circulating A-II levels, indicating more inhibition at the receptor level with activated negative feedback [27]. These findings not only substantiate dose-related inhibition of the AT1 receptor, but also imply increased AT2 receptor stimulation through increased A-II production, an effect which may counter many of the effects of AT1 stimulation and which may also mediate at least some of the clinical benefits of AT1 receptor blockade [28].

The favourable safety and tolerability profile of losartan has been documented, and doses up to 150 mg also appear to be well-tolerated [29]. If HEAAL demonstrates improved efficacy with losartan at 150 mg compared to 50 mg daily, with either no increase in adverse event rates, or an increase within an acceptable range, then this study will substantiate the benefits of the aggressive dosing approach employed in previous trials.

HEAAL should provide important information, which will assist the clinician in targeting appropriate patients for treatment with ARBs and, importantly, in choosing the most appropriate dose. It should be noted that the population demographics and baseline characteristics for patients enrolled in HEAAL differ somewhat from those of the other major ARB trials (ELITE II [11,12], VAL-HeFT [1], and CHARM [13], Table 4), for example, ELITE II was not based on selection of patients intolerant of ACE-inhibitors. In addition, while the baseline age, sex profile, blood pressure and LVEF are similar in all four studies, the HEAAL population comprises a lower proportion of white subjects, fewer patients with severe heart disease, and a higher proportion of patients taking concomitant beta-blockers than other studies (Table 4). This increase in beta-blocker use reflects changes in standard therapy for heart failure, based on clinical trial evidence. Nevertheless, the HEAAL population is comparable to prior trials in its representation of the spectrum of patients presenting with heart failure, and results should be relevant to the clinician managing patients with heart failure.


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  		Table 4 Population demographics and baseline characteristics of the HEAAL study compared with the ELITE II (14,15), VAL-HeFT (1), and CHARM (13) studies

 
In conclusion, HEAAL is designed to evaluate the impact of high- versus low-dose losartan treatment on clinical endpoints in patients with heart failure and reduced LVEF, who are intolerant of ACE-inhibitors. Findings should provide important insights into the effects of ARBs on clinical outcomes and, particularly, in determining the relative risk-benefit ratio achieved with the two dosing regimens in patients with heart failure.


   Conflict of interest
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 Conflict of interest
References
 
Steven J Justice, William Malbecq and Soneil Guptha are employed by Merck & Co Inc, the manufacturer of the investigational medicine (losartan) in this study. All other authors have been consultants to Merck.


   Acknowledgements
 
Writing assistance for this paper was provided by Jane Stirling, PhD of Bioscript Stirling Ltd., UK, and funding was provided by Merck & Co. Inc., Whitehouse Station, NJ 08889, USA.


   Notes
Top
 Notes
Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 Conflict of interest
 References
 
1 On behalf of the Executive Committee of HEAAL investigators. Back


   References
Top
 Notes
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 Conflict of interest
 References
 

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