Effect of candesartan on New York Heart Association functional class

Results of the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) programme

Eileen O'Mearaa, Scott Solomonb, John McMurraya,*, Marc Pfefferb, Salim Yusufc, Eric Michelsond, Chris Grangere, Bertil Olofssonf, James B. Youngg and Karl Swedbergh

a Department of Cardiology, Western Infirmary, Glasgow, Scotland, UK
b Brigham & Women's Hospital, Boston, MA, USA
c HGM-McMaster Clinic, Hamilton, Ontario, Canada
d AstraZeneca LP, Wilmington, DE, USA
e Duke University Medical Center, Durham, NC, USA
f AstraZeneca, R&D Mölndal, Sweden
g Medicine, Cleveland Clinic Foundation, Cleveland, USA
h Department of Medicine, Sahlgrenska University Hospital/Östra, Göteborg, Sweden

Received March 25, 2004; revised July 8, 2004; accepted July 15, 2004 * Corresponding author. Tel.: +44 141 211 1838; fax: +44 141 211 2252 (E-mail: j.mcmurray{at}bio.gla.ac.uk).


    Abstract
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
AIMS: To evaluate the effect of the angiotensin receptor blocker candesartan on New York Heart Association (NYHA) functional class in a broad spectrum of patients with chronic heart failure (CHF).

METHODS AND RESULTS: Patients in the CHARM Programme with symptomatic CHF were randomized to placebo (n=3796) or candesartan (n=3803) and followed for a median of 38 months. NYHA class was assessed at baseline, at two weekly intervals during dose titration and 4 monthly thereafter. Patients were classified as "better", "unchanged" or "worse" at the end of the study compared to baseline. Both a simple "last visit carried forward" (LVCF) analysis and "worst rank carried forward" (WRCF) analysis (where patients who died were allocated NYHA class V) were used. In the LVCF analysis, compared to placebo, more candesartan patients improved (35.4% versus 32.5%) and fewer worsened (9.0% versus 10.3%) in NYHA class (p=0.003). The WRCF analysis also showed a better overall change in NYHA class with candesartan compared to placebo. There was no heterogeneity in the response to candesartan between the CHARM component trials.

CONCLUSIONS: Candesartan improves NYHA functional class to a similar extent to other proven treatments for CHF when added to these other treatments.


    Introduction
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
An ideal treatment for chronic heart failure (CHF) should improve symptomatic well-being and functional capacity, as well as reduce mortality and morbidity. The New York Heart Association (NYHA) classification has been used for over three decades as a simple summary measure of a clinician's assessment of a patient's functional limitation due to the characteristic symptoms of CHF.1,2 Though a relatively simple tool, NYHA classification of functional status is very widely used and has been shown to correlate with symptom burden, signs of congestion, quality of life, exercise capacity and prognosis.2–7 Furthermore, treatments known to improve clinical outcomes in CHF, such as angiotensin converting enzyme (ACE) inhibitors, beta-blockers and spironolactone, also improve NYHA class.8–14 Here, we describe the effect of the angiotensin receptor blocker, candesartan, on NYHA class in the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) Programme.15–18


    Methods
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
The CHARM Programme
The design, baseline findings and primary results of the CHARM Programme have been reported in detail.15–20 Briefly, the CHARM Programme consisted of three independent but related trials in which patients with NYHA class II–IV CHF were randomized to placebo or candesartan (target dose 32 mg once daily). In CHARM-Added patients in NYHA Class II needed to have had a hospital admission for a cardiac reason in the previous 6 months (this had the effect of increasing the proportion of NYHA class III/IV patients in CHARM-Added). Patients were enrolled into the individual CHARM trials according to left ventricular ejection fraction (LVEF) and baseline treatment with an ACE-inhibitor. Patients with an LVEF ⩽0.40, intolerant of an ACE-inhibitor, were enrolled in CHARM-Alternative whereas patients with an LVEF ⩽0.40 and taking an ACE-inhibitor were enrolled in CHARM-Added. Patients with an LVEF >0.40 were randomized into CHARM-Preserved. The CHARM Programme was completed, as planned, two years after the last patient was randomized. Because the rate of recruitment varied between the CHARM trials, overall follow-up ranged from a median of 41 months in CHARM-Added, to 37 months in CHARM-Preserved and 34 months in CHARM-Alternative (38 months in the overall CHARM Programme).

Measurement of NYHA class
Investigators were asked to assess NYHA class at baseline, at two weekly intervals during dose titration (usually carried out over 3–4 visits) and 4 monthly thereafter.

Analysis of NYHA class
Patients were classified as "better", "unchanged" or "worse" at the end of the study compared to baseline. Because there is no consensus on how best to do this analysis, the two approaches most commonly used in prior studies were adopted.14,15 The first was a simple "last visit carried forward" approach; here the last available NYHA assessment was used when this assessment was missing for a subsequent visit (or visits) e.g., because of withdrawal from the study or death. The other approach was a "worst rank" approach, where patients who died were assigned "NYHA class V" and this was carried forward. The following example illustrates the difference between these approaches. In the simple "last visit carried forward" analysis, a patient in NYHA class IV at baseline, who improves to NYHA class III after 4 months of treatment, but dies before the eight month assessment, would have their class III assessment carried forward i.e., be classified "better" at the end of the study. Using the second, "worst rank," analysis, this patient would be assigned "NYHA class V" at the eight month visit (because of death) and this value would be carried forward, resulting in the patient being categorized as "worse" at the end of the study. Consequently, the "worst rank" analysis typically yields a larger proportion of patients showing deterioration in NYHA class than the simple last visit carried forward approach.

Because patients in NYHA class II have less scope to improve than those in NYHA class III/IV, these analyses were also carried out according to baseline NYHA class. This was also done to allow comparison with previous studies.

Four additional exploratory subgroups of interest were examined: gender, baseline beta-blocker use, age (<75 years/⩾75 years) and LVEF ⩽0.40>0.40.

The difference between treatments in change of NYHA class from baseline was compared using a two-sided Wilcoxon rank-sum test (stratified for study in the CHARM Overall analysis), with a significance level of 0.05. Interaction between treatment and trial was examined using a permutation test.


    Results
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Baseline NYHA class
The distribution of NYHA class and other characteristics at baseline in each of the three CHARM trials and the overall CHARM-Programme are shown in Table 1.


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Table 1. Baseline characteristics of the patients enrolled in each of the three component studies of the CHARM Programme
 
Change in NYHA class (last visit carried forward)
Change in NYHA class in each of the CHARM trials and in the overall Programme is shown in Table 2. The last visit carried forward analysis showed that, compared to placebo, more patients treated with candesartan showed an improvement (35.4% versus 32.5%) and fewer showed a deterioration (9.0% versus 10.3%) in NYHA class (Fig. 2, p=0.003). A test for heterogeneity showed no statistically significant interaction between treatment and trial (p=0.11).


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Table 2. Change in New York Heart Association functional class in exploratory subgroups in the CHARM component trials
 


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Fig. 2 Change in New York Heart Association (NYHA) class from baseline to end of study in the exploratory subgroups in the overall CHARM Programme. Horizontal bars show the proportion (%) of patients better and worse (unchanged not shown). This figure shows simple last visit carried forward analysis. ({square}) candesartan, ({blacksquare}) placebo.

 
Fig. 1 shows change in NYHA class in each of the CHARM trials and in the overall Programme, according to the baseline NYHA class. As expected, more patients in NYHA class III or IV at baseline showed an improvement compared to those who were in NYHA class II at baseline. Candesartan-treated patients, however, showed more improvement (and less deterioration) than placebo-treated patients in the Overall Programme, especially in patients with the worst baseline NYHA class.



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Fig. 1 Change in New York Heart Association (NYHA) class from baseline to end of study in each of the component CHARM trials and the overall CHARM Programme. Horizontal bars show the proportion (%) of patients better and worse (unchanged not shown). This figure shows the simple last visit carried forward analysis. Patients are divided according to whether they were in NYHA class II, or class III or IV at baseline. ({square}) candesartan, ({blacksquare}) placebo.

 
As shown in Table 2 and Fig. 2, candesartan had a similar benefit in each of the other exploratory subgroups. Of note, elderly patients in both treatment groups and all trials were less likely to show improvement. In patients with a reduced LVEF, use of a beta-blocker at baseline was associated with greater improvement, irrespective of randomized treatment assignment; this effect was not as marked in patients with a preserved LVEF.

Change in NYHA class (worst rank carried forward)
This analysis confirmed that candesartan improved the overall NYHA class distribution compared to placebo in the Overall Programme (p=0.003) [Table 2 and Fig. 3]. However, as anticipated, a smaller proportion of patients improved and a greater proportion deteriorated, when worst rank substitution was used instead of simple last visit carried forward (Table 2; Fig. 1 compared to 3). The difference between the two methods of analysis was least marked in CHARM-Preserved (in which fewer patients died). As was also expected with this analysis, patients in NYHA class III or IV at baseline were more likely to show deterioration because of their greater risk of death i.e., death is counted as "worse" in this analysis (Fig. 3).



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Fig. 3 Change in New York Heart Association (NYHA) class from baseline to end of study in each of the component CHARM trials and the overall CHARM Programme. Horizontal bars show the proportion (%) of patients better and worse (unchanged not shown). This figure shows the worst rank carried forward analysis. Patients are divided according to whether they were in NYHA class II, or class III or IV at baseline. ({square}) candesartan, ({blacksquare}) placebo.

 
As shown in Table 2 (and by comparison of Figs. 2 and 4), the findings in relation to age and baseline beta-blocker treatment were similar to those noted in the simple last visit carried forward analysis.


    Discussion
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 Abstract
 Introduction
 Methods
 Results
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 References
 
This analysis shows that, in addition to reducing the risk of death and admission to hospital with worsening heart failure, candesartan also improves NYHA class in patients with CHF and a reduced LVEF.15–18

Our finding that candesartan had a favourable effect on NYHA class in low LVEF CHF was robust and consistent. It was apparent whether a simple last visit carried forward or a worst rank analysis was used. Similarly, candesartan improved functional status regardless of whether patients had mild symptoms at baseline (i.e., were in NYHA class II) or were more severely symptomatic at baseline (i.e., in NYHA class III/IV).

It is noteworthy that the favourable effect of candesartan on NYHA class was as apparent in the patients in CHARM-Added as in those in CHARM-Alternative, even though the patients in CHARM-Added were already well treated by contemporary standards.16 That is, in CHARM-Added, all patients were taking an ACE-inhibitor, 56% were also receiving a beta-blocker, 58% digoxin and 17% were also treated with spironolactone. In part this was probably due to the higher proportion of NYHA class III/IV patients in CHARM-Added (see below). However, candesartan was even able to improve functional status in these patients who were in NYHA class II at baseline.

Comparison with the effect of other treatments in CHF is difficult for a number of reasons. Often, the method of analysis of NYHA class has not been described. The NYHA classification used (e.g., splitting a class into "a" and "b" subclasses) and the duration of follow-up have also frequently differed between studies.9 Other studies have excluded patients unable to improve (those in NYHA class I) or deteriorate (those in NYHA class IV when no worst rank is used) from their analysis of change.11,12

Some comparisons are possible however. In the Valsartan Heart Failure Trial (Val-HeFT), most patients were in NYHA class II at baseline and 93% were taking an ACE-inhibitor, 35% a beta-blocker and 5% spironolactone at baseline. The proportions better/worse were 20.7/12.8% in the placebo group and 23.1/10.1% in the valsartan group (p<0.001), over an average follow-up period of 23 months (using a simple last visit carried forward approach).21 In CHARM-Added, these proportions in patients in NYHA class II at baseline, using the same type of analysis, were 18.7/20.3% and 23.8/13.8%, over a median of 41 months of follow-up.

In the Randomized Aldactone Evaluation Study (RALES), where almost all patients were in NYHA class III or IV at baseline, the proportions better/worse were 33/48% in the placebo group and 41/38% in the spironolactone group (p<0.001), over a mean follow-up of 24 months, using a worst rank analysis.14 In CHARM-Added, the equivalent proportions in patients in NYHA class III/IV at baseline, using the same type of analysis, were 34.8/37.3% in the placebo group and 40.2/33.3% in the candesartan group.

It is more difficult to find comparable data for beta-blockers. The major outcome trials with these agents were much shorter in duration (1.0–1.3 years) than for the other treatments described above. Only the Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF) describes the effect of treatment on NYHA class.13 In a last visit carried forward analysis, the proportions improved/deteriorated in the placebo group were 25.8/7.5% compared to 28.6/6.0% in the metoprolol group (p=0.003), after an average follow-up of one year. As 41% patients were in NYHA class II at baseline and 55% in class III, these patients were probably best compared with CHARM-Alternative and CHARM-Added pooled i.e., the patients with an LVEF ⩽0.40 in Fig. 2. In this pooled analysis, the proportions improved/deteriorated in the placebo-treated patients were 35.1/9.7% compared to 40.1/8.1% in the candesartan group (for CHARM-Added alone, with a majority of patients in NYHA class III at baseline, these proportions were 39.5/8.8% and 43.4/6.5%, respectively).

Collectively, these findings suggest that candesartan improves NYHA functional class to a similar extent as other effective treatments in CHF. Moreover, can also do so when used in conjunction with these other effective treatments i.e., candesartan has an incremental benefit over and above that of ACE-inhibitors and beta-blockers.

In CHARM-Preserved we examined the effect of candesartan in patients with an LVEF >0.40. While at first sight the effect of candesartan on NYHA class does not appear as favourable in this trial, this probably reflects the low proportion of patients in NYHA class III/IV (39%) compared to the two low LVEF trials (53% in Alternative and 76% in Added). The generally more favourable effect of candesartan in CHARM-Added and less favourable effect in CHARM-Preserved, is almost certainly explained by the very different proportions of these more severely symptomatic patients with greater scope to improve in the NYHA classification (e.g., from IV/III to II or to I versus from II to I, that is up to 3 classes versus 1 class at most). Comparison of patients in NYHA class III/IV at baseline across all 3 component trials of the CHARM Programme (Figs. 1 and 3) shows a comparable effect of candesartan.

As with any study of NYHA class, our analysis has limitations. There is no agreed or entirely satisfactory analytical approach. The main problem is dealing with missing data, especially death. The limitation of the simple last visit carried forward approach is obvious in this context. The worst rank approach, however, treats all deaths in the same way and it is arguable whether a sudden death in an otherwise relatively symptom-free patient should be dealt with in a similar fashion to a death from progressive heart failure following a period of symptomatic deterioration. Nevertheless, both analytical approaches gave the same result (i.e., that candesartan improves functional class) and this is in keeping with evidence from another smaller study which showed that candesartan improved symptoms and exercise tolerance in patients with CHF.22 That candesartan leads to a better overall NYHA functional class is also consistent with the marked reduction in hospital admissions for worsening heart failure obtained with this treatment in the CHARM Programme.15–18 Another limitation (which may have made it harder to detect a treatment effect) was that there was no requirement for the same investigator to assess NYHA class in an individual patient over the whole duration of the study (this was impractical given that average follow-up was 38 months).

In summary, the angiotensin receptor blocker candesartan improved overall NYHA functional class in patients with CHF and a low LVEF in the CHARM Programme. This benefit was seen even in patients treated with full conventional therapy and was similar in magnitude to that observed with other effective treatments for CHF. Candesartan improves symptoms, reduces hospital admissions and increases survival in patients with CHF and a low LVEF.



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Fig. 4 Change in New York Heart Association (NYHA) class from baseline to end of study in the exploratory subgroups in the overall CHARM Programme. Horizontal bars show the proportion (%) of patients better and worse (unchanged not shown). This figure shows the worst rank carried forward analysis. ({square}) candesartan, ({blacksquare}) placebo.

 

    References
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
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