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Renin angiotensin blockade in heart failure with preserved ejection fraction: the signal gets stronger

John McMurray
DOI: http://dx.doi.org/10.1093/eurheartj/ehl249 2257-2259 First published online: 8 September 2006
This editorial refers to ‘The perindopril in elderly people with chronic heart failure (PEP-CHF) study’ by J.G.F. Cleland et al., on page 2338

Although up to half of all individuals with heart failure (HF) are said to have a preserved ejection fraction (HF-PEF), until recently only two sizeable, randomized placebo-controlled trials have been conducted in these patients (Tables 1 and 2).13 This small number compares with more than 20 trials in patients with a low EF. It is easy, therefore, to understand why the results of the Perindopril for Elderly People with Chronic Heart Failure (PEP-CHF) have been eagerly awaited.4,5

View this table:
Table 1

Large trials in HF-PEF

DIG-PEF2CHARM-Preserved3PEP-CHF4,5I-PRESERVE9,11
≥21 years≥18 years≥70 years≥60 years
LVEF>45%LVEF>40%No major LV systolic dysfunction (e.g. LVEF<40%)LVEF≥45%
Prior cardiac hospitalizationCardiac hospitalization in prior 3 monthsNYHA class II–IV and CHF hospitalization in prior 6 months or NYHA class III/IV and abnormal CXR (pulmonary congestion), ECG (LVH, LBBB), or echocardiogram (LVH, enlarged LA)
Clinical/radiological diagnosis of CHF
 NYHA class I–IVNYHA class II–IV ≥4 weeks (NYHA III/IV in prior 6 months if taking ACE-I)Diuretic ≥1 week
 Sinus rhythmThree of nine clinical criteria (e.g. exertional or paroxysmal nocturnal dyspnoea, oedema, raised JVP, etc) and two of four echo criteria (preserved wall motion, LA enlargement, LVH, or Doppler evidence of DD)
  • JVP, jugular venous pressure; LA, left atrium; ECG, electrocardiogram; DD, diastolic dysfunction; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; CXR, chest X-ray; LVH, left ventricular hypertrophy; LBBB, left bundle branch block.

View this table:
Table 2

Baseline characteristics in trials of HF-PEF

DIG-PEF (n=988)CHARM-Preserved (n=3023)PEP-CHF (n=850)I-PRESERVE (n=4128)
Mean age (year)67677572
Women (%)41405660
Mean LVEF (%)55546459
Co-morbidity (%)
 Hypertension60647963
 Myocardial infarction50442723
 Atrial FibrillationExcluded292129
 Diabetes29282127
Treatment (%)
 ACE-inhibitor8619aExcluded25a
 DigoxinExcluded281214
 CCB313340
 Beta-blocker565559
 Nitrate393351
 Diuretic767510083
  Loop46
  Thiazide1455
Spironolactone8b121015
  • aUse restricted.

  • bPotassium sparing diuretic.

  • CCB, calcium channel blocker.

The PEP-CHF investigators are to be congratulated for randomizing patients similar to those in epidemiological studies, a feat rarely achieved in prior trials in HF (Table 2). Indeed, patients with HF-PEF have proved to be harder to enrol in trials than patients with low EF, either because they are not as common as the epidemiological evidence suggests or because extreme age, frailty, and co-morbidity led to their exclusion (or both). Patients with HF-PEP in trials have also exhibited lower mortality and morbidity rates than anticipated from epidemiological studies and compared to patients with a low EF. The former may be due to the exclusion of high-risk patients (as stated previously), but concern remains that some patients without HF have been enrolled in trials of HF-PEF. In this context, Cleland et al. note that plasma natriuretic peptide concentrations (the measurement of which was prescient at the time of the design of PEP-CHF) were not elevated in all patients.5 Selection of patients for future trials on the basis of an elevated natriuretic peptide concentration is, therefore, attractive not only as a means of confirming an underlying cardiac problem but also as a way of identifying patients at higher risk of clinical events (thereby reducing sample size and improving the power of studies to show an effect of treatment).

In PEP-CHF, low recruitment and low event rates, despite a sterling effort by the investigators and sponsor, resulted in a considerable loss of statistical power to show an effect of perindopril on the primary composite outcome of death or HF-related hospitalization, even after follow-up was extended beyond the originally planned 1 year.4,5 This extension led to another problem, i.e. a high rate of study drug discontinuation and open-label ACE-inhibitor use, further reducing study power.

The PEP-CHF authors reported a trend to a reduction in the primary outcome (and some other benefits of treatment) at 1 year, but no effect on any outcome over the full study duration.5 We need to interpret the 1 year findings cautiously. Although it might have seemed reasonable to focus on 1 year outcomes, in the light of the original study design and the problems outlined previously, trials commonly show a large early benefit which may not represent the true effect of the treatment in the longer term.68 This phenomenon was recently illustrated in the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) programme, where there was a 30% reduction in the risk of death at 1 year (P<0.001) but only a 9% reduction (P=0.055) over the full duration of follow-up (median follow-up 38 months).68

What then does PEP-CHF tell us about the treatment of HF-PEF, taking account of all these considerations? The low rate of death (and, especially, cardiovascular death) means that the trial was unable to tell us about the effect of perindopril on survival. The same caveats apply to the PEF ancillary study of the Digitalis Investigator Group trial (DIG-PEF) and the CHARM–Preserved trial.2,3 I think perindopril probably did have an effect on heart failure hospitalization, as a similar effect was shown with another inhibitor of the renin–angiotensin system (RAS) in CHARM preserved trial, i.e. there was a 15% reduction in patients admitted with HF (P=0.017) and a 29% reduction in total hospital admissions (P=0.014), as reported by the investigators during the whole trial.3 The effects of perindopril on NYHA class and 6 min walk distance also support the interpretation that RAS blockade is of benefit in HF-PEF.5 Of course, none of this is definitive or sufficient for regulatory approval. Indeed, the task of proving the benefit of any treatment, using conventional trial outcomes, in HF-PEF is daunting, given the difficulties alluded to above. The relatively low death rate in the cohorts enrolled in trials to date and the high proportion of non-cardiovascular deaths (especially compared with low LVEF HF) means that demonstration of a modest reduction in mortality would require randomization of many thousands of patients. All three completed trials in HF-PEF suggest that the outcome most sensitive to a therapeutic intervention is hospitalization for HF and that, as part of a composite with cardiovascular death, may be the best outcome to evaluate in future studies (and this composite was reduced more than the primary outcome by perindopril in PEP-CHF). We will soon have the opportunity to examine these questions further, as one further, very large trial with the RAS blocker irbesartan (I-PRESERVE, Tables 1 and 2) is in its final phase of follow-up and a new trial with spironolactone is just beginning.911 CHARM-Preserved and PEP-CHF may have pointed us in the right direction but only time will tell.

Acknowledgement

J.M. served on the Executive Committee of the CHARM programme and he is currently a member of the Executive Committee of the I-PRESERVE trial.

Conflict of interest: none declared.

Footnotes

  • The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.

  • doi:10.1093/eurheartj/ehl250

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