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European Journal of Heart Failure 1999 1(3):211-217; doi:10.1016/S1388-9842(99)00039-2
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© 1999 European Society of Cardiology

Perindopril for elderly people with chronic heart failure: the PEP-CHF study

John G.F. Cleland*, Michal Tendera, Jerzy Adamus, Nick Freemantle, Christopher S. Gray, Michael Lye, Denis O'Mahony, Lech Polonski, Jacqueline Taylor PEP investigators

University of Hull, Castle Hill Hospital Kingston-upon-Hull HU16 5JQ, UK

* Corresponding author. Tel.: +44-1482-624084; fax: +44-1482-624085.


   Abstract
Top
 Abstract
1. Introduction
 2. Aims
 3. Intervention
 4. Study design
 References
 
Background: The prevalence of chronic heart failure (CHF) rises with increasing age, from <1% in those below 65 years of age to > 5% in those over 65 years of age and is a major cause of morbidity and mortality in older people. Recent European guidelines point to a major deficiency in our knowledge of how to treat diastolic chronic heart failure, and a lack of information on treatment for heart failure in the elderly in general.

Aims: The aims of this trial are to assess the potential benefits of the ACE inhibitor perindopril to treat chronic heart failure in elderly people, in the absence of any major left ventricular systolic dysfunction.

Subjects: One thousand people over the age of 70 years will be recruited into this study. Evidence of chronic heart failure will be confirmed by clinical criteria and echocardiography.

Methods: Once a diagnosis of chronic heart failure has been confirmed, the patient will receive either perindopril or placebo in addition to their usual treatment. Death, and unplanned heart failure related hospitalisations, are the primary outcomes. Quality of life, as measured by the Guyatt questionnaire will be assessed at the beginning of the study and at 1 year. Sub-studies of this trial include a 6-min walking test and more detailed evaluation of ventricular function (as assessed by echocardiography). Both parameters will be measured at 8 weeks and 1 year, and analysed against baseline data. Cognitive function in this group of patients will also be evaluated at baseline and 1 year. This trial is due to report in the year 2001.

Key Words: ACE inhibitors • Perindopril • Chronic heart failure • Elderly • Quality of life

Received June 28, 1999; Revised July 1, 1999; Accepted July 1, 1999


   1. Introduction
Top
 Abstract
 1. Introduction
2. Aims
 3. Intervention
 4. Study design
 References
 
The prevalence of chronic heart failure (CHF) rises with increasing age from <1% in those below 65 years to >5% in those over 65 years of age and is a major cause of morbidity and mortality in older people [1–3]. The overall prevalence of CHF appears to be rising inexorably, largely though not exclusively, due to the ageing of the population [4–6]. CHF is one of the commonest reasons for admissions to hospital in older people, and one of the main determinants of the overall high cost of treating CHF [4,7].

The mean age of CHF in the community is 74 years [8]. Patients >75 years have a higher mortality and morbidity than younger patients with CHF [9] and are admitted to hospital more often and stay in for longer [10]. Thus patients >70 years require 10–50 times more bed days for the management of CHF than do younger patients [11]. Patients >70 years of age probably contribute to two thirds of the total health care spending on CHF. Obviously CHF is an important problem in the elderly but it is less clear if the morbidity and mortality in this age group can be modified.

1.1. Effect of angiotensin converting enzyme inhibitors (ACE-I) in elderly patients with CHF
Several treatments have been shown to be effective in reducing mortality and hospital admission rates in selected populations of younger patients with CHF due to major left ventricular systolic dysfunction (LVSD) [5,12]. Despite the obvious importance of CHF in the elderly only one major trial of CHF, the CONSENSUS study, has addressed the therapeutic impact of ACE inhibitors compared to placebo in patients with a mean age of >70 years [13]. Overall a very clear benefit occurred in CONSENSUS and older patients benefited as much as did younger patients. The SOLVD study of mild to moderate CHF suggested only a small mortality benefit among patients >70 years (18% of the SOLVD population) but the effect on re-hospitalisation for CHF was as great or greater than that in younger patients [9]. The ELITE study [14] (mean age 73 years), that compared the effects of captopril with losartan, is difficult to interpret as the patients studied had a relatively good prognosis and no placebo control was involved. More recently beta-blockers have been shown to improve the prognosis of CHF but the mean age of patients in these studies has been approximately 60 years [5,12].

1.2. CHF with preserved left ventricular function
The above studies, with the exception of the CONSENSUS study, excluded patients if they had well-preserved left ventricular systolic function (LVSD). A series of studies has reported that 50% or more of patients with CHF aged >70 years do not have LVSD [15]. There are no studies to indicate which treatments might be beneficial in this large sub-group of patients. CHF in the absence of LVSD, otherwise termed ‘diastolic’ CHF, is associated with a somewhat lower mortality in the short-term than CHF due to systolic dysfunction but rates of re-hospitalisation are high [16,17]. In the medium term (>6 months) mortality in systolic and ‘diastolic’ CHF appear similar. The 1-year mortality of unselected elderly patients with CHF in the absence of LVSD may be as high as 28% [16,17].

There is limited and conflicting evidence for a benefit of ACE inhibitors in patients with CHF and well preserved systolic function [18,19]. The CONSENSUS study suggested no benefit although this sub-group probably comprised only 50 patients. The V-HeFT-II study suggested a mortality benefit in a subgroup of approximately 250 patients with EF >40%.

Recent European guidelines point to the major deficiency in our knowledge of how to treat diastolic CHF and the lack of information on treatment for heart failure in the elderly in general [21,20]. Because no drug has been shown to be effective in elderly patients with heart failure in the absence of major left ventricular systolic dysfunction a placebo-controlled trial is both feasible and necessary.

1.3. Under-use of ACE-I in elderly with CHF
Elderly patients have a higher prevalence of carotid and renal vascular disease and renal function is more precarious, some or all of which might be considered contra-indications to treatments such as ACE inhibitors [22], although they could also be considered as targets for therapy. Perhaps because of these concerns it is the elderly majority of patients with CHF who are least likely to receive an ACE inhibitor. This is a further reason for targeting elderly patients with heart failure for a placebo-controlled study of an ACE inhibitor.

A recent study reported by Rich et al. [23] is important in that it clearly indicates that improved treatment of elderly patients with CHF can reduce readmission rates and probably improve prognosis (Table 1). Thus the prognosis of a relatively unselected group of elderly patients with CHF many of whom would not have LVSD can be modified.


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  		Table 1 Ninety-day event rate

 
1.4. Rationale for the use of perindopril in the PEP-CHF trial
Perindopril is a long acting ACE inhibitor. Its anti-hypertensive efficacy has been demonstrated at doses of 4 mg and 8 mg once daily. These doses lead to significant blood pressure lowering over the whole 24 h-period with a trough-to-peak ratio between 75 and 100%, one of the highest among ACE inhibitors [24,25].

There is extensive experience with perindopril that confirms that it is well tolerated even in at-risk patients such as elderly. In a group of 2297 hypertensive patients above 80 years treated for 1 year with perindopril 2–8 mg o.d., the withdrawal rate due to side effects was 6.3% [26]. In hypertensive patients with recent ischaemic stroke, perindopril caused no adverse change in cerebral circulation [27]. In controlled studies in CHF [28,29] perindopril initiated at a dose of 2 mg has been associated with little risk of first dose hypotension. Perindopril has a simple one step titration scheme which ensures that most patients are maintained on an adequate dose of 4 mg o.d.

The effects of perindopril on cardiovascular remodelling are well documented: perindopril improves arterial compliance in large arteries [30] and restores the structure of small resistance arteries [31] and cause regression of left ventricular hypertrophy [32]. In addition; perindopril restores flow-mediated coronary vasodilatation in hypertensive patients [33] and reverses endothelial dysfunction in patients with heart failure [34,35]. The above effects, which, are not entirely explained by the drug’s ability to reduce blood pressure, could be clinically relevant and continue to be an important area of study.


   2. Aims
Top
 Abstract
 1. Introduction
 2. Aims
3. Intervention
 4. Study design
 References
 
The aim of this trial is to assess the benefits of the ACE inhibitor perindopril vs. placebo, in elderly patients with chronic heart failure but without major left ventricular systolic dysfunction (i.e. with moderate systolic LV dysfunction and/or diastolic dysfunction).


   3. Intervention
Top
 Abstract
 1. Introduction
 2. Aims
 3. Intervention
4. Study design
 References
 
This will consist of the following treatment periods:

  • A 24-h open label run in phase, during which patients will receive a single 2-mg dose of perindopril.
  • A double-blind period during which patients will initially be randomly allocated to perindopril 2 mg/day or matching placebo. Patients who tolerate this initial dose level will undergo forced titration to 4 mg of perindopril or matching placebo. Patients who do not tolerate the initial dose level of medication will have treatment withdrawn but will continue to be followed on an intention to treat basis.


   4. Study design
Top
 Abstract
 1. Introduction
 2. Aims
 3. Intervention
 4. Study design
References
 
This study is a multicenter, double-blind, randomised, parallel-group, placebo-controlled trial. Participating centres are a mixture of cardiology and care of the elderly centres.

Patients aged ≥70 years who are currently or have recently (within 3 months) been in hospital (including day hospital care) for a cardiovascular problem and who have heart failure (suspected or confirmed) will be screened for participation in this study. A complete prospective log of patients will be attempted recording whether they died, had evidence of systolic CHF or had other reasons for inclusion/exclusion from the study. Recruitment of consecutive patients who are suitable for the study will be attempted. Screening procedures include a history, symptom scores, quality of life (Guyatt questionnaire), current medication, physical examination, routine laboratory tests, measurement of natriuretic peptides, chest X-ray, 12 lead ECG and echocardiogram.

If the patient meets the selection criteria, he/she will receive a test dose of 2 mg perindopril after which they will be monitored for 6 h to detect serious first dose hypotension. First dose hypotension (fall in systolic blood pressure >20 mmHg) will be categorised into: (a) asymptomatic; (b) symptomatic; and (c) alarming. Asymptomatic patients includes all patients who have a fall in systolic blood pressure >20 mmHg without symptoms. Symptomatic patients include those with a >20 mmHg fall in systolic blood pressure who complain of side effects. Alarming events include patients who require intravenous fluids, develop focal neurological signs, impaired consciousness, prolonged (>15 min) pain suggestive of myocardial ischaemia, myocardial infarction, cardiac arrest or death. Patients who have a non-fatal alarming reaction will be withdrawn from the study.

Twenty-four hours after the open-label test dose of perindopril key baseline tests are repeated and suitable patients are randomised to 2 mg/day of perindopril or matching placebo, double-blind. Patients are then reviewed after 1 week to determine how well the drug (or placebo) is being tolerated. Blinded therapy is discontinued if serum creatinine has risen to >250 µmol/l or by >50 µmol/l from baseline or potassium has risen to >5.5 mmol/l. If treatment is well tolerated and sitting systolic blood pressure >100 mmHg patients will be titrated to 4 mg of perindopril or matching placebo. Patients will be reviewed after a further week and maintained at this dose for the rest of the study unless uptitration is not tolerated symptomatically or by the above biochemical criteria, in which case medication will be down-titrated to 2 mg/day. At least two attempts should be made to attain the target maintenance dose. Thereafter patients are reviewed at 8 weeks and thereafter at approximately 12 week intervals for assessment of symptoms and general progress. At the 1 year follow-up baseline investigations will be repeated.

If the investigator is convinced that the patient requires an ACE inhibitor, then the double-blind treatment period should be stopped and the patient should be followed as required for an intention to treat analysis.

At any time during the course of the study, if the investigator is aware of any clinical signs/symptoms that may be attributable to the study medication, then the dose of the drug can be reduced or stopped as required. If the patient is withdrawn from therapy they will continue to be followed according to the intention to treat principle.

A number of sub-studies are planned including an echocardiographic sub-study to investigate the effects of perindopril on short-term (8 week) and long-term (1 year) ventricular structure and function and another at similar time periods to investigate the effects on 6-min corridor walk distance. A large sub-study on cognitive dysfunction is also planned with assessment at baseline and 52 weeks.

4.1. Inclusion criteria

  • Able to give written informed consent.
  • Greater than or equal to 70 years of age.
  • Clinical diagnosis of chronic heart failure (see below).
  • Treated with diuretics (at least 3 days/week) for at least 1 week.
  • No major left ventricular systolic dysfunction (e.g. WMI<1.4 or ejection fraction <40% are excluded).
  • Patients must have been hospitalised as an in-patient or received day hospital care for a cardiac problem (e.g. myocardial infarction, arrhythmia, CHF) within the last 3 months.
  • Able to walk without the aid of another person.

4.2. Definition of heart failure without major left ventricular systolic dysfunction
To satisfy this study definition patients must have CHF in the investigators opinion and this opinion must be supported by at least three of nine clinical criteria (Table 2) and at least two out of four echocardiographic criteria (Table 3). Major left ventricular systolic dysfunction will be excluded at this time. Atrial fibrillation as a cause of heart failure with preserved left ventricular systolic dysfunction is not excluded.


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  		Table 2
 


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  		Table 3
 
The centres will determine the WMI, the atrial dimensions and the ventricular wall thickness. A copy of the echocardiogram will be sent to a core laboratory for confirmation. Feedback will be given to centres during the course of the study to ensure the entry criteria are being applied.

4.3. Exclusion criteria

  • Inadequate echocardiographic window by which to assess valves and ventricular function.
  • Haemodynamically significant (in the investigators opinion) left ventricular outflow tract obstruction (due either to aortic stenosis or ventricular hypertrophy) or mitral valve stenosis.
  • Patients with important aortic or mitral regurgitation in the investigators opinion.
  • Previous history of ACE-inhibitor intolerance (e.g. angio-neurotic oedema or severe ACE inhibitor induced cough).
  • Patients treated with an ACE inhibitor or angiotensin II receptor antagonist within the last week.
  • Serum creatinine >200 µmol/l (or urea >20 mmol/l) or K+>5.4 mmol/l.
  • Sitting systolic arterial pressure <100 mmHg.
  • Hypertension that has not been controlled to the satisfaction of the investigator by agents other than ACE inhibitors or angiotensin II receptor antagonists.
  • Stroke in the previous month.
  • Patients who are haemodynamically unstable following myocardial infarction or who have ongoing unstable angina.
  • Other disease likely to cause death or serious disability within the following year (e.g. lung cancer: However, low grade malignancies, e.g. some lymphomas are allowed. Predicted life expectancy due to CHF should be shorter than for the malignancy).
  • Serious liver disease. If the ASAT or ALAT is greater than three times normal values, then further investigation of liver disease must be performed before inclusion.
  • Contraindicated concomitant therapy (e.g. ACE inhibitors, angiotensin II antagonists, monoamine oxidase inhibitors, potassium-sparing diuretics (other than low dose spironolactone), potassium supplements, calcium channel blockers that slow atrio-ventricular conduction).
  • Patients who do not tolerate the test dose of perindopril of 2 mg.
  • Participation in a clinical study of another agent in the previous 30 days.

4.4. Endpoints
4.4.1. Primary
The primary end-point of this study will be the time to first occurrence of the combined end-point of total mortality and unplanned heart failure related hospitalisation. A broad definition of heart failure related hospitalisation that includes hospitalisation due to an increase in severity of the signs and/or symptoms of CHF, hospitalisation for declining renal function or acute myocardial ischaemic events or arrhythmias that are inevitably associated with some worsening of heart failure is intended. Patients admitted with other problems, such as infection, that lead to an exacerbation of CHF are also included in this definition. Admissions to a new course of daycare therapy or routine admissions for investigations do not constitute an unplanned admission and are excluded from the primary end-point.

4.4.2. Secondary

  1. Death (all causes).
  2. Death or worsening symptoms and/or signs of CHF requiring hospitalisation or an increase in diuretic treatment for CHF of >40 mg/day of frusemide compared to baseline (or equivalent, e.g. 1 mg bumetanide) or the new initiation of combination of loop and thiazide diuretics. This will be a time to first event analysis.
  3. Cardiovascular mortality.
  4. Number of days alive and out of hospital.
  5. Number of days alive and not in hospital for cardiovascular reasons (including CHF).
  6. QoL questionnaire (change from baseline to 1 year.)
  7. CHF symptom score (change from baseline to 1 year).
  8. NYHA heart failure score (change from baseline to 1 year).

4.5. Sample size and power calculations
The intention is to randomise 1000 patients (500 per treatment arm) with the last patient followed for a minimum of 1 year. A review of recent literature suggests that the annual incidence of primary events, as defined in this protocol and in this patient population, will be in the region of 50%. The power of a randomised trial using a log rank test of survival data may be estimated using the approach described by Collett [36]. Approximately 451 primary end points will be required to identify a 10% absolute difference in event rates for double-sided {alpha} of 0.05 and a power (1–β) of 0.9. This will be achieved by randomising 502 patients to each group with a predicted hazard ratio of 0.74 and following them for 1 year. However, it is expected that the average follow-up in this study will be in excess of 18 months and therefore the study is powered to detect differences at lower event rates or smaller differences at the predicted event rate.

4.6. Planned subgroups
Age, gender and WMI will be applied in multi-variate analyses. If these variables are important determinants of outcome or treatment effect then sub-group data will be shown.

4.7. Analysis plan and stopping rules
Time to event variables will be analysed using the log-rank test and the survival distribution will be summarised according to the Kaplan Meyer method. Treatment centres will be defined as strata in the log-rank test and Cox regimen model. There are no formal stopping rules, the trial is expected to run to completion. If event rates are significantly lower than expected the trial duration may be extended to achieve 451 primary end-points. An independent data safety and monitoring committee will advise the Steering Group on the appropriateness of continuation of the trial on the basis of slower than expected accrual of endpoints.

For multivariate analysis, the Cox proportional hazards model will be performed on:

  • Age (in bands of 5 years).
  • Gender.
  • Dose.
  • WMI (≥1.6 vs. ≤ 1.6).

Outcomes such as days alive out of hospital will be analysed using parametric or non-parametric statistics as appropriate.

4.8. Centres
This study will involve 26 centres in the UK, Ireland and Poland.

4.9. Data monitoring
Source data verification will be performed in all centres by a professional clinical research organisation. Baseline echocardiograms and ECGs will be gathered in core laboratories. Samples for natriuretic peptides gathered at baseline and 1 year will be measured in a core laboratory. Clinical events are subject to rigid definitions and an end-points committee is thought unnecessary. The steering committee will monitor the situation and may appoint and end-points committee if required.

4.10. Ethical and indemnity issues
The study will be conducted in accordance with the principles stated in the Declaration of Helsinki, 1964, as revised in South Africa in 1996. The study has been submitted for approval to a UK national multi-centre ethics committee and will be submitted to a local hospital ethics committee at each centre. Written informed consent is required from each patient. The conduct and compensation arrangements for the study are in accordance with the Association of the British Pharmaceutical Industry (ABPI) guidelines.

4.11. Current status of the study
The study is due to start enrolling patients in the fourth quarter of 1999.

4.12. Conclusions
The PEP-CHF study is unique in several respects. This is the first study of an ACE inhibitor in patients with CHF but without major left ventricular systolic dysfunction that has sufficient power to determine with confidence whether ACE inhibitors are indicated in this setting. It is also the first outcome study comparing an ACE inhibitor with placebo to concentrate solely on older patients. However, ‘biological’ rather than chronological age may be the greater determinant of the risk of events in patients with CHF and may also be the greater determinant of the risk of side effects with ACE inhibitors, such as hypotension and renal dysfunction. The PEP-CHF study is the first substantial multi-centre study to recruit from care of the elderly units rather than just from cardiologists. This should ensure that a ‘biologically’ aged population truly representative of clinical practice in the elderly is obtained. The population recruited into the PEP-CHF study may reflect the general elderly heart failure population better than any other study of CHF so far.

The core echocardiography laboratory will provide invaluable data on ‘diastolic’ heart failure and be able to relate this in a large representative population to plasma concentrations of natriuretic peptides, an alternative diagnostic marker in heart failure. The PEP-CHF study will also be the largest study to investigate cognitive dysfunction in an elderly population with heart failure and the first to determine whether treatment with ACE inhibitors has a beneficial effect. Other key sub-studies will determine whether there are acute and/or chronic effects of perindopril on ventricular function or structure (as assessed by echocardiography) and exercise capacity (assessed by 6-min walk test) in patients without major left ventricular systolic dysfunction. These sub-studies should provide an integrated picture to explain any observed clinical effects.


   Acknowledgements
 
We wish to acknowledge the support of Servier Laboratories for this study.


   References
Top
 Abstract
 1. Introduction
 2. Aims
 3. Intervention
 4. Study design
 References
 

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Short to long term mortality of patients hospitalised with heart failure in the Czech Republic--a report from the EuroHeart Failure Survey
Eur J Heart Fail, August 1, 2005; 7(5): 780 - 783.
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F. Ceia, C. Fonseca, T. Mota, H. Morais, F. Matias, C. Costa, and A. G. Oliveira
Aetiology, comorbidity and drug therapy of chronic heart failure in the real world: the EPICA substudy
Eur J Heart Fail, October 1, 2004; 6(6): 801 - 806.
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M. D. Thomas, K. F. Fox, A. J.S. Coats, and G. C. Sutton
The epidemiological enigma of heart failure with preserved systolic function
Eur J Heart Fail, March 1, 2004; 6(2): 125 - 136.
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A. P. Coletta, J. G.F. Cleland, N. Freemantle, H. Loh, A. Memon, and A. L. Clark
Clinical trials update from the European Society of Cardiology: CHARM, BASEL, EUROPA and ESTEEM
Eur J Heart Fail, October 1, 2003; 5(5): 697 - 704.
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D.J.W. van Kraaij, P.E.J. van Pol, A.W. Ruiters, J.B.R.M. de Swart, D.J. Lips, N. Lencer, and P.A.F.M. Doevendans
Diagnosing diastolic heart failure
Eur J Heart Fail, August 1, 2002; 4(4): 419 - 430.
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J. Taylor and D. J. Stott
Chronic heart failure and cognitive impairment: co-existence of conditions or true association?
Eur J Heart Fail, January 1, 2002; 4(1): 7 - 9.
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J. G.F. Cleland
ACE Inhibitors for 'Diastolic' Heart Failure? Reasons not to jump to premature conclusions about the efficacy of ACE inhibitors among older patients with heart failure
Eur J Heart Fail, December 1, 2001; 3(6): 637 - 639.
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K. McDonald, M. Ledwidge, J. Cahill, J. Kelly, P. Quigley, B. Maurer, F. Begley, M. Ryder, B. Travers, L. Timmons, et al.
Elimination of early rehospitalization in a randomized, controlled trial of multidisciplinary care in a high-risk, elderly heart failure population: the potential contributions of specialist care, clinical stability and optimal angiotensin-converting enzyme inhibitor dose at discharge
Eur J Heart Fail, March 1, 2001; 3(2): 209 - 215.
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J. E. Sanderson
Letter to the editor
Eur J Heart Fail, March 1, 2000; 2(1): 115 - 115.
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C. G. Jones and J. G.F. Cleland
The LIDO, HOPE, MOXCON and WASH studies
Eur J Heart Fail, December 17, 1999; 1(4): 425 - 431.
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