1. The following slides highlight a report on presentations at a Hotline Session and a Satellite Symposium of the European Society of Cardiology 2003 Congress held in Vienna, Austria from August 30 to September 3, The original presenters were: C.B. Granger, MD; J.J.V. McMurray, MD; S. Yusuf, MD; and M.A. Pfeffer, MD. The presentations were reported and discussed by Gordon Moe, M.D, in a Cardiology Scientific Update.
The prognosis of patients with congestive heart failure (CHF) has improved over the last decade due, in part, to the application of results from several landmark clinical trials. However, almost all of these clinical trials have focused on patients with reduced left ventricular ejection fraction (LVEF). In clinical practice, a substantial number of patients with CHF have preserved LVEF, for which there is no known effective evidence-based therapy.
The Candesartan in Heart failure – Assessment of Reduction in Mortality and morbidity (CHARM) program is the largest study ever designed to assess the use of an angiotensin II receptor blocker (ARB), candesartan, in a broad spectrum of patients with CHF, including those with reduced and preserved LVEF and those intolerant to angiotensin-converting enzyme (ACE) inhibitors. The Cardiology Scientific Update issue discussed the late-breaking results of CHARM, as well as their clinical implications.

2. The CHARM study was conceived as a program to provide definite and quantitative clinical information regarding the role of the ARB, candesartan cilexitil, in the management of a broad spectrum of patients with CHF. Candesartan is a long-acting ARB with sustained receptor binding. The rationale and design of CHARM was based on finding answers to 3 important questions concerning CHF:
Does the addition of an ARB to ACE inhibitor therapy confer more effective protection than an ACE inhibitor alone, in patients with CHF and systolic dysfunction?
Do ARBs have a greater protective effect than placebo in patients with systolic CHF who are intolerant to ACE inhibitors?
Does an ARB protect CHF patients with preserved LV systolic function?
The CHARM program prospectively identified 3 distinct patient populations: CHARM Alternative, CHARM Added, and CHARM Preserved, as seen in the above slide. Importantly, each of the 3 studies had adequate power to detect an impact of candesartan on the primary outcome of CV death and CHF hospitalization. In all 3 studies, the initial dose was 4 or 8 mg of candesartan once daily or matching placebo. Study drug dose was doubled every 2 weeks to the target dose of 32 mg once daily. Randomization to each of the studies was dependent on LVEF and tolerance to ACE inhibitors.

3. The results of each of the component studies, as well as the overall CHARM program, have been published. Between March 1999 and March 2001, 7601 patients were randomized. Diuretics were the most commonly prescribed agents in all 3 trials. -blockers were used in over 50% of the patients, whereas aldosterone receptor antagonists were used in about 20% of the patients with systolic dysfunction. Lipid-lowering therapy and aspirin were also used in a substantial number of patients.
In the ALTERNATIVE study, 2028 patients with CHF and reduced LVEF who were intolerant to ACE inhibitors were randomly assigned to candesartan (n=1013) or placebo (n=1015). Two patients in the candesartan group and 1 patient in the placebo group were lost to follow-up. The stated reasons for ACE inhibitor intolerance were cough in 70% and 74%, renal dysfunction in 13% and 10%, and angioedema/ anaphylaxis in 4% and 4% of the candesartan and placebo groups, respectively. The median follow-up was 33.7 months.
Data for the primary outcome, CV death and CHF hospitalization, are shown in the above slide. Candesartan reduced this combined endpoint by 23%. This reduction was more significant after a pre-planned covariate adjustment for prespecified baseline variables known to affect prognosis. The survival curves of the 2 groups separated early after randomization and remained virtually parallel during the entire follow-up.

4. Data for the secondary endpoints in the ALTERNATIVE arm are shown in the above slide. Candesartan significantly reduced all composite endpoints, as well as CHF hospitalization. There were 265 deaths from any cause in the candesartan group, and 296 in the placebo group (unadjusted hazard ratio 0.87 [0.74–1·03], p=0.11; covariate adjusted 0.83 [0.70–0.99], p=0.033). The investigator-reported number of patients admitted to hospital for CHF and the total number of hospital admissions for CHF were significantly lower in the candesartan group. The effect of candesartan on CV death or CHF hospitalization was generally consistent across prespecified subgroups.
Angioedema occurred in 3 candesartan patients and in none of the placebo patients. None of the 3 cases was deemed life-threatening and 2 cases continued on candesartan without recurrence. All 3 cases occurred in patients who had a history of ACE inhibitor intolerance because of angio-edema. Thus, angioedema that required the discontinuation of candesartan occurred in only 1/39 patients with a history of angioedema on ACE inhibitors.

5. In the ADDED arm, 2548 patients were randomized to candesartan (n=1276) or placebo (n=1272). Three patients in the candesartan group and 1 patient in the placebo group were lost to follow-up. The median duration of follow-up was 41 months. Investigators stated that 96% of patients were receiving an optimum dose of ACE inhibitors, eg, the mean daily dose for enalapril was 16.8 mg in the candesartan group and 17.2 mg in the placebo group. Importantly, 55% of patients were treated with ß-blockers at baseline and 17% with spironolactone. By the end of the study, 64% and 68% of patients in the candesartan and placebo group, respectively, were taking ß-blockers.
Data for the primary outcome – CV death and CHF hospitalization – are shown in the above slide. Candesartan reduced this combined endpoint by 15%.

6. Selected secondary outcomes for the CHARM-ADDED arm are shown in the above slide. Both CV mortality and CHF hospitalization were significantly reduced. Investigator-reported number of patients hospitalized for CHF and the number of CHF hospitalizations were significantly reduced. All-cause mortality was 30% in the candesartan group and 32% in the placebo group, with a trend for reduction by candesartan (unadjusted hazard ratio 0.89, [ ], p=0.086; adjusted p=0.105). Candesartan reduced the risk of CV death or CHF admission in all prespecified subgroups. In particular, candesartan reduced the risk of primary endpoint in patients, regardless of whether or not they were taking ß-blockers or the recommended dose of ACE inhibitor (defined as captopril 150 mg, enalapril 20 mg, lisinopril 20 mg, or perindopril 4 mg, all daily). The study drugs were well-tolerated. Over 75% of patients were still taking the study medication at the study end. Although adverse effects such as hyperkalemia and increased creatinine were more frequent in the candesartan group, the overall incidence for these adverse effects was still exceedingly low.

7. In the PRESERVED arm of the study, 3023 patients with NYHA class II-IV CHF and EF >40% were randomized to candesartan (n=1514) or placebo (n=1509, 2 patients had no data post-randomization). Two patients in the candesartan group and 1 patient in the placebo group were lost to follow-up. Median follow-up duration was 36.6 months. At baseline, 20% and 19% of patients in the candesartan and placebo group, respectively, were taking ACE inhibitors.
Data on the primary outcome of CV death and CHF hospitalization are shown in the above slide. The annualized event rate was 8.1% and 9.1% in the candesartan and placebo groups, respectively. The relative risk reduction of 11% was not significant. After adjustment for baseline variables, the relative risk reduction was 14% with borderline statistical significance.

8. Data for the secondary outcomes of the PRESERVED arm are shown in the above slide and generally yielded results similar to those for the primary outcome. The number of patients admitted to hospital for CHF once, more than once, and the total number of CHF hospitalizations was significantly lower in the candesartan group. One additional prespecified analysis was the development of diabetes. Forty per cent fewer patients were diagnosed with new diabetes in the candesartan group (47 cases) than in the placebo group (77 cases, hazard ratio 0.60, [0.41, 0.86], p=0.005).

9. The predefined primary outcome of the overall program was all-cause mortality from a pooled analysis of the 3 concurrent component trials. Results are shown in the above slide; 886 (23%) in the candesartan group and 945 (25%) in placebo group died, (hazard ratio 0.91 [0.83-1], p=0.055, adjusted hazard ratio 0.90 [ ], p=0.032). The annual mortality rates were 8.1% and 8.8% in the candesartan and placebo groups, respectively. The reduction in mortality was driven almost exclusively by a reduction in CV deaths (hazard ratio 0.88 [ ], p=0.012, adjusted 0.87 [ ], p=0.006).
In terms of absolute reduction, the CHARM program demonstrated that in patients with systolic CHF, treating 23 patients with candesartan for 3 years would prevent one CV death or admission for CHF. In patients with systolic CHF and intolerance to ACE inhibitor, this number to treat for 3 years is 14. In a broad spectrum of patients with CHF, treating 63 patients in 3 years will prevent 1 death and treating 71 patients will prevent 1 case of new diabetes.

10. Combined CV death and CHF hospitalization in the entire program was reduced by 16%, p<0.0001, as shown in the above slide. There were also significantly less investigator-reported hospital admissions for CHF. For the entire program, the cases for newly diagnosed diabetes were also significantly reduced (163 versus 202 cases, hazard ratio 0.78 [ ], p=0.02).
For the ALTERNATIVE arm, data firmly support the practice of substituting an ARB for an ACE inhibitor in patients with CHF and systolic dysfunction, intolerant to ACE inhibitors. An ARB like candesartan appears to be very well-tolerated in these patients.
In the ADDED arm, data suggest that adding an ARB such as candesartan to optimal background therapy of ACE inhibitors and -blockers confers additional benefit on CV hospitalization and CHF hospitalization in patients with CHF and reduced EF. There is no adverse interaction with -blockade therapy. Adverse effects such as hyperkalemia and renal dysfunction, although infrequent, will still happen more frequently in patients on combination therapy, mandating caution in monitoring these parameters.
The data of the PRESERVED arm, while not statistically significant provides some supportive evidence decreasing CHF hospitalizations and the development of diabetes for patients with preserved systolic function. The 1-PRESERVE study should provide additional data.
In summary, given all these data, there is now relatively strong evidence to support the use of an ARB such as candesartan in optimally-treated patients with CHF and reduced LV systolic function.