CHARM: Candesartan in Heart Failure-Assessment of Reduction in Mortality and Morbidity

Linda Brookes, MSc

Disclosures

September 02, 2003

Editorial Collaboration

Medscape &

The results of Candesartan in Heart failure - Assessment of moRtality and Morbidity (CHARM) program of trials were presented for the first time at the 2003 ESC meeting in Vienna, Austria, and show that the long-acting angiotensin II type-1 receptor blocker (ARB) candesartan (Cilexetil, AstraZeneca) reduces both cardiovascular (CV) mortality and hospital admissions for congestive heart failure (CHF) in a broad spectrum of patients. Most notably, these benefits were achieved on top of "best treatment" with other effective concomitant therapies, including beta-blockers and/or angiotensin-converting enzyme (ACE) inhibitors.

The results were presented by the CHARM program co-chairmen, Karl Swedberg, MD (Sahlgrenska University Hospital/Ostra, Goteborg, Sweden), and Marc A Pfeffer, MD (Brigham and Women's Hospital, Boston, Massachusetts, USA), with each component trial result presented by the relevant principal investigators.[1,2,3,4] All of the component trials of the CHARM program were reported in the September 7 issue of The Lancet. [5,6,7,8]

The CHARM Program

The CHARM program consisted of 3 component trials, each comparing candesartan with placebo in a distinct population of patients with symptomatic heart failure[9]:

  1. CHARM-Alternative: patients with left ventricular ejection fraction (LVEF) ≤ 40% and intolerant of ACE inhibitors;

  2. CHARM-Added: patients with LVEF ≤ 40% who tolerated and were treated with whichever ACE inhibitor the patient's physician chose;

  3. CHARM-Preserved: patients with LVEF > 40%, who may or may not have received an ACE inhibitor.

Patients were randomized in a double-blind manner to receive either candesartan or placebo. The initial dose of candesartan was 4 mg or 8 mg once daily, doubled up to a maximum dose of 32 mg daily, based on tolerability. Patients were seen at 2, 4, and 6 weeks and at 6 months after randomization, and every 4 months thereafter.

The primary outcome for each component trial was CV death or CHF hospitalization. The primary outcome for the overall program (CHARM-Overall) was all-cause death. Analysis was by intention to treat.

The entire CHARM program included 7601 patients recruited between March 1999 and March 2001 from 26 countries.[10] The design of the trial was to assess ARB therapy in relatively low-risk CHF patients, and eligibility was defined simply as patients aged ≥ 18 years with symptomatic heart failure NYHA class II-IV.

Exclusion criteria included serum creatinine ≥ 265 mcmol/L, serum potassium ≥ 5.5 mmol/L, bilateral renal artery stenosis, symptomatic hypertension, women of childbearing potential, myocardial infarction (MI), stroke, or open-heart surgery in the previous 4 weeks, and the use of an ARB during the previous 2 weeks.

Also fundamental to the trial design was that patients were being treated with current state-of-the art heart failure therapy, including beta-blockers, diuretics, digitalis, spironolactone, and/or ACE inhibitors, at dosages close to current recommended levels.

Mirroring the presentation order of the program at the 2003 ESC Congress, the results below are presented as

  • CHARM Alternative: best therapy, including the ARB not no ACE inhibitor;

  • CHARM Added: best therapy, including the ARB in addition to an ACE inhibitor;

  • CHARM Preserved: best therapy including the ARB in patients with EF ≥ 40%, with or without an ACE inhibitor;

  • CHARM Overall: the enrollment of all of the above trials, combined for an analysis of overall mortality.

CHARM-Alternative

CHARM-Alternative randomized 2028 participants with LVEF ≤ 40% who were ACE inhibitor intolerant to standard therapy, or standard therapy plus candesartan. The most common reason for ACE inhibitor intolerance was cough (72%), followed by hypotension (13%) and renal dysfunction (12%).

Candesartan was associated with a significant 23% relative risk reduction (RRR) in CV death or hospitalization for CHF (P = .0004) (Table 1). This RRR is similar to the RRR of 26% seen in the Studies of Left Ventricular Dysfunction (SOLVD) treatment trial[11]and other previous trials with ACE inhibitors.[12] During a median follow-up of 33.7 months, 33% of patients on candesartan had a primary outcome of CV death or hospitalization for CHF, compared with 40% of those on placebo. The absolute reduction of 7 major events per 100 patients corresponds to a need to treat 14 patients with candesartan to prevent 1 patient from having CV death or hospitalization for CHF.

Table 1. CHARM-Alternative: Primary Outcome and Individual Components
Candesartan
(n = 1013)
Placebo
(n = 1015)
Unadjusted HR (95% CI) P
CV death or hospital admission for CHF 33.0% 40.0% 0.77 (0.67-0.89) .0004
CV death 21.6% 24.8% 0.85 (0.71-1.02) .072
Hospital admission for CHF 20.4% 28.2% 0.68 (0.57-0.81) < .0001
CHF, congestive heart failure; CI, confidence interval; CV, cardiovascular; HR, hazard ratio.

Good tolerance for candesartan was exhibited by these ACE inhibitor-intolerant patients, with similar numbers of patients in the candesartan and placebo groups having to discontinue study drug (21.5% vs 19.3%, respectively; P = .23). However, significantly more patients discontinued candesartan than placebo due to hypotension (3.7% vs 0.9%, P < .0001), increased creatinine (6.1% vs 2.7%, P < .0001), and hyperkalemia (1.9% vs 0.3%, P = .0005), and the CHARM-Alternative principal investigator, Christopher B Granger, MD (Duke Clinical Research Institute, Durham, North Carolina, USA), was quick to emphasize that this highlights the need to monitor patients for side effects when using candesartan.

On the other hand, angioedema was rare in CHARM-Alternative, with only 1 of 39 patients on candesartan with a history of angioedema with ACE inhibitors having a recurrence leading to drug discontinuation. Thus, angioedema on an ACE inhibitor should not be a contraindication to use of an ARB, Dr. Granger emphasized.

CHARM-Added

CHARM-Added randomized 2548 patients with CHF and LVEF ≤ 40% who had been taking an ACE inhibitor as part of conventional therapy at least 30 days prior to study entry. Most patients were taking either enalapril, lisinopril, captopril, or ramipril (Table 2), and importantly, the trial investigators estimated that 96% of CHARM-Added patients were taking optimum doses of ACE inhibitor at randomization.

Table 2. CHARM-Added: Baseline ACE Inhibitor
ACE Inhibitor Proportion of Pts Taking Mean Daily Dose of ACE Inhibitor (mg)
Candesartan Placebo
Enalapril 27% 16.8 17.2
Lisinopril 19% 17.7 17.7
Captopril 17% 82.2 82.7
Ramipril 11% 6.8 7.3

In addition, 55% of patients were also being treated with beta-blockers and 17% with spironolactone.

In CHARM-Added, candesartan was associated with a significant 15% reduction in the relative risk of CV death or hospital admission (Table 3). Over the median follow-up of 41 months, the primary outcome occurred in 42.3% of patients in the placebo group and 37.9% of those in the candesartan group.

Table 3. CHARM-Added: Primary Outcomes and Individual Components
Candesartan
(n = 1278)
Placebo
(n = 1272)
Unadjusted HR (95% CI) P
CV death or hospital admission for CHF 37.9% 42.3% 0.85 (0.75-0.96) .011
CV death 23.7% 27.3% 0.84 (0.72-0.98) .029
Hospital admission for CHF 24.2% 28.0% 0.83 (0.71-0.96) .014

CHF, congestive heart failure; CI, confidence interval; CV, cardiovascular; HR, hazard ratio.

CHARM-Added principal investigator John J V McMurray, MD (Western Infirmary, University of Glasgow, Scotland, UK), noted that the clinically important benefit seen with candesartan added to an ACE inhibitor (and beta-blockers) was obtained with relatively few side effects, although higher rates of withdrawal because of increased creatinine (7.8% vs 4.1%, respectively, P = .0001) and hypokalemia (3.4% vs 0.7%, P < .0001) indicated the need for monitoring of renal function and serum potassium.

CHARM-Preserved

A total of 3023 patients with CHF and preserved LVEF > 40% were randomized in CHARM-Preserved. The principal investigator of this component, Salim Yusuf, MB MS, DPhil (McMaster University, Hamilton, Ontario, Canada), pointed out that although around half of all CHF patients seen in the "real world" clinical practice have preserved LV systolic function, there have been very few trials specifically assessing treatments of these patients.

After a median follow-up of 36.6 months, candesartan was associated with a strong trend toward a reduction in CV deaths or hospital admissions for CHF, consistent with the other component trials of the CHARM program (Table 4), but failing to reach significance in CHARM-Preserved.

Table 4. CHARM-Preserved: Primary Outcome and Individual Components
Candesartan
(n = 1514)
Placebo
(n = 1509)
Unadjusted HR (95% CI) P
CV death or hospital admission for CHF 22.0% 24.3% 0.89 (0.77-1.03) .118
CV death 11.2% 11.3% 0.99 (0.80-1.22) .918
Hospital admission for CHF 15.9% 18.3% 0.85 (0.72-1.01) .072

CHF, congestive heart failure; CI, confidence interval; CV, cardiovascular; HR, hazard ratio

Although there was no difference in the incidence of cardiovascular deaths, fewer candesartan-treated patients were hospitalized for CHF compared with the placebo group (402 vs 566, P = .014). Prof. Yusuf suggested that, taken in the context of the robust results in the other CHARM trials, this result is still important and it may be that a longer follow-up will be needed for the full effects of candesartan to emerge in this population.

Importantly, a significant 40% reduction was seen in the development of new diabetes mellitus in the candesartan group compared with the placebo group in this study (4% vs 7%, P = .005). This finding is similar to that with ramipril in the Heart Outcomes Prevention Evaluation (HOPE) trial[13] and with losartan in the Losartan Intervention For Endpoint (LIFE) reduction in hypertension study,[14] and suggests that blocking the renin-angiotensin system with ACE inhibitors or ARBs prevents the progression to diabetes.

When taken in the context of the results of the two parallel CHARM studies in patients with low LVEF, Prof. Yusuf believes that physicians may want to consider candesartan in patients with CHF, irrespective of EF.

CHARM-Overall

Summarizing the cumulative experience from CHARM-Overall, Marc A Pfeffer, MD (Brigham and Women's Hospital, Boston, Massachusetts, USA), reported that pooled analysis of the 3 studies showed, after a median follow-up of 37.7 months, a 9% reduction in the primary outcome of all-cause mortality that approached statistical significance (23% vs 25% in the candesartan and placebo groups, respectively; HR 0.91 [95% CI 0.83-1.00], P = .055).

Although failing to achieve significance in this very broad endpoint, significant reductions were seen in CV death (12%), hospital admission for CHF (21%), and CV death or hospital admission for CHF (16%) (Table 5).

Table 5. CHARM-Overall: Secondary Outcomes
Candesartan
(n = 3803)
Placebo
(n = 3796)
Unadjusted HR (95% CI) P
CV death or hospital admission for CHF 30.2% 34.5% 0.84 (0.77-0.91) < .0001
CV death 18.2% 20.3% 0.88 (0.79-0.97) .012
Hospital admission for CHF 19.9% 24.2% 0.84 (0.72-0.87) < .0001

CHF, congestive heart failure; CI, confidence interval; CV, cardiovascular; HR, hazard ratio

These results were similar in men and women and in patients older and younger than 75 years of age. Most importantly, the beneficial effects of candesartan were seen as incremental and additional to concomitant use of other effective therapies such as beta-blockers and/or ACE inhibitors.

According to the investigators, these results suggest that only 23 patients need to be treated with candesartan for 3 years in order to prevent 1 CV death or CHF hospitalization -- an extremely important result.

When the results of the CHARM program are assessed in CHARM-Overall, candesartan did not significantly reduce the risk of MI, stroke, or use of coronary revascularization procedures, but, as in CHARM-Preserved, a significant reduction in cases of new-onset diabetes was seen with candesartan (163 cases vs 202, 6.0% vs 7.4%, candesartan vs placebo, respectively; hazard ratio 0.78 [95% CI 0.64-0.96]; P = .02).

As in the individual studies, in CHARM-Overall, candesartan was associated with significant increases in hypotension (3.5% vs 1.7%, P < .0001,), serum creatinine (6.2% vs 3.0%, P < .0001), and hyperkalemia (2.2% vs 0.6%, P < .0001), which led to more discontinuations of study medication among the patients on candesartan and underscored yet again the need to monitor patients, Dr. Pfeffer stressed.

According to Dr. Pfeffer, the consistent effect of candesartan across the 3 CHARM studies suggests that the addition of the ARB candesartan can be considered in all patients with CHF irrespective of EF, age, and sex.

Official Critique: CHARM Results "Do Not Disappoint"

Invited by the ESC to give his personal interpretation of the CHARM results, Philip Poole-Wilson, MD (National Heart and Lung Institute, Imperial College London, London, UK), commented that they "do not disappoint and have important implications ... in parts decisive, in parts helpful, in parts tantalizing." He predicted that CHARM will be the last study to compare an ARB with placebo or with drugs of a different class.

Prof. Poole-Wilson recalled that before CHARM, the Losartan Heart Failure Survival Study (ELITE II) showed no significant differences between an ARB (losartan) and an ACE inhibitor (captopril), except that significantly fewer patients on the ARB discontinued study treatment because of adverse effects.[15] In the Valsartan Heart Failure Trial (Val-HeFT), the ARB valsartan added to standard prescribed therapy significantly reduced combined all-cause mortality and morbidity, largely driven by a highly significant reduction in heart failure hospitalizations.[16] A large reduction in mortality and morbidity was seen in a subset of Val-HeFT patients not on background ACE inhibitor therapy. Based on these 2 trials regulatory bodies around the world licensed ARBs for use as an alternative to ACE inhibitors. In CHARM, candesartan was used at a dose of about 24 mg, at which the drug acts as a powerful angiotensin II receptor inhibitor, which might explain why the CHARM studies showed some differences from ELITE and Val-HeFT, Prof. Poole-Wilson suggested.

Table 6. CHARM Program Results Summarized by Prof. Poole-Wilson
CHARM- Alternative CHARM- Added CHARM- Preserved CHARM- Overall
All-cause mortality Trend Trend No effect P = .055*
Cardiovascular death/heart failure P < .0004 P = .0.011 P = .118
Cardiovascular death P = 0.072 P = .029 No effect
Heart failure hospitalization P < .001 P = .014 P < .072
Drug discontinuation No difference P = .0003 P = .001

*< minus CHARM-Preserved, P =.018.

The results of the CHARM-Alternative and CHARM-Added studies (Table 6) would have been expected, Prof. Poole-Wilson said, adding that the results of CHARM-Added were "reasonably convincing" and that the benefit associated with candesartan was "quite considerable." As a result, adding candesartan "to the other drugs for heart failure is beneficial," he declared. "The only problem," he said, "is that this is going to be the eighth drug that heart failure patients are going to be taking. It is becoming a difficult question as to what dose and what combination of tablets these patients should receive."

Regarding the CHF patients with preserved left ventricular function (LVEF ≥ 40%) in CHARM-Preserved, Prof. Poole-Wilson acknowledged that this group of patients is very difficult to treat, noting that there was no therapeutic effect of candesartan on CV mortality, although there was some effect on hospitalization. Nevertheless, this was a landmark study, in a large number of seldom-studied patients, he said, even though in the end the evidence was less than convincing that these patients with preserved LVEF should all be treated in this way.

Prof. Poole-Wilson criticized the choice of endpoints of cause-specific mortality and cause-specific hospitalization, as they are controversial. It has been suggested that they are more likely to get a positive result and they do not necessarily reflect general practice. However, he praised the investigators' intention to look at all-cause mortality and all-cause hospitalization, which will allow comparisons to be made of the results with those of other studies and also calculation of costs.

Prof. Poole-Wilson cited 4 clinical points from the CHARM data that he considered important:

  1. CHARM-Overall showed an increase in fatal cancer (P = .038), but this was probably due to chance.

  2. CHARM-Added showed benefit in patients already on a beta-blocker and an ACE inhibitor. This finding contradicts Val-HeFT, which raised concern about the potential safety of this combination. The CHARM result is therefore reassuring.

  3. CHARM-Added showed benefit in patients on recommended doses of an ACE inhibitor, so this benefit cannot be explained by the fact that these patients were not using a high enough dose of ACE inhibitor.

  4. CHARM-Alternative found only 1 case of angioedema associated with candesartan in the 39 patients who were intolerant of ACE inhibitors because of angioedema.

"Cardiologists will have to make up their minds about how [the CHARM results] alter their clinical practice," Prof. Poole-Wilson advised.

Candesartan to be Submitted for Heart Failure Worldwide Approval

The CHARM program will form the basis of a regulatory submission for worldwide approval of candesartan cilexetil for the treatment of heart failure. Candesartan cilexetil is currently marketed for use in the management of hypertension by AstraZeneca and Takeda.

References
  1. Granger CB. Effect on cardiovascular mortality and hospitalization for heart failure in patients with left ventricular systolic dysfunction and intolerant of angiotensin-converting enzyme inhibitors. Presented at the ESC Congress 2003; August 30-September 3, 2003; Vienna, Austria. Hot Line I: Medical Treatment/Heart Failure, Presentation #79.

  2. McMurray JJV. Effects on cardiovascular mortality and hospitalization for heart failure in patients with left-ventricular systolic function when added to angiotensin-converting enzyme inhibitor therapy. Presented at the ESC Congress 2003; August 30-September 3, 2003; Vienna, Austria. Hot Line I: Medical Treatment/Heart Failure, Presentation #80.

  3. Yusuf S. Effects on cardiovascular mortality and hospitalization for heart failure in patients with preserved left-ventricular systolic function. Presented at the ESC Congress 2003; August 30-September 3, 2003; Vienna, Austria. Hot Line I: Medical Treatment/Heart Failure, Presentation #81.

  4. Pfeffer MA, Swedberg K. Candesartan in heart failure: effects on mortality and morbidity. Presented at the ESC Congress 2003; August 30-September 3, 2003; Vienna, Austria. Hot Line I: Medical Treatment/Heart Failure, Presentation #82.

  5. Granger CB, McMurray JJV, Yusuf S, et al, for the CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial. Lancet. Published online September 1, 2003.

  6. McMurray JJV, Ostergren J, Swedberg K, et al, for the CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet. Published online September 1, 2003.

  7. Yusuf S, Pfeffer MA, Swedberg K, et al, for the CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved trial. Lancet. Published online September 1, 2003.

  8. Pfeffer MA, Swedberg K, Granger CB, et al, for the CHARM Investigators and Committees. Effects of candesartan on mortality and morbidity in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Overall programme. Lancet. Published online September 1, 2003.

  9. Swedberg K, Pfeffer M, Granger C, for the Charm-Programme Investigators. Candesartan in heart failure-assessment of reduction in mortality and morbidity (CHARM): rationale and design. J Card Fail. 1999;5:276-282.

  10. McMurray J, Ostergren J, Pfeffer M, on behalf of the CHARM committees and investigators. Clinical features and contemporary management of patients with low and preserved ejection fraction heart failure: baseline characteristics of patients in the Candesartan in Heart failure -- Assessment of Reduction in Mortality and morbidity (CHARM) programme. Eur J Heart Fail. 2003;5:261-270.

  11. The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fraction and congestive heart failure. N Engl J Med. 1991;325:293-302.

  12. Flather MD, Yusuf S, Kober L, et al. Long-term ACE-inhibitor therapy in patients with heart failure or left-ventricular dysfunction: a systematic overview of data from individual patients. Lancet. 2000;355:1575-1581.

  13. Yusuf S, Gerstein H, Hoogwerf B, et al. Ramipril and the development of diabetes. JAMA. 2001;286:1882-1885.

  14. Dahlof B, Devereux RB, Kjeldsen SE, et al, for the LIFE Study Group. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet. 2002;359:995-1003.

  15. Pitt B, Poole-Wilson PA, Segal R, et al. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomised trial -- the Losartan Heart Failure Survival Study ELITE II. Lancet. 2000;355:1582-1587.

  16. Cohn JN, Tognoni G, for the Valsartan Heart Failure Trial Investigators. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med. 2001;345:1667-1675.

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