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Aims: The Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM) programme consisted of three parallel, randomized, double-blind clinical trials comparing candesartan with placebo in patients with heart failure (HF) categorized according to left ventricular ejection fraction and tolerability to an angiotensin-converting enzyme inhibitor. We conducted a pharmacogenomic study of the CHARM trials with the objective of identifying genetic predictors of HF progression and of the efficacy and safety of treatment with candesartan., Methods: We performed genome-wide association studies in 2727 patients of European ancestry from CHARM-Overall and stratified by CHARM study according to preserved and reduced ejection fraction and according to assignment to the interventional treatment with candesartan. We tested genetic association with the composite endpoint of cardiovascular death or hospitalization for heart failure for drug efficacy in candesartan-treated patients and for HF progression using patients from both candesartan and placebo arms. The safety endpoints for response to candesartan were hyperkalaemia, renal dysfunction, hypotension, and change in systolic blood pressure between baseline and 6 weeks of treatment. To support our observations, we conducted a genome-wide gene-level collapsing analysis from whole-exome sequencing data with the composite cardiovascular endpoint., Results: We found that the A allele (14% allele frequency) of the genetic variant rs66886237 at 8p21.3 near the gene GFRA2 was associated with the composite cardiovascular endpoint in 1029 HF patients with preserved ejection fraction from the CHARM-Preserved study (hazard ratio: 1.91, 95% confidence interval: 1.55-2.35; P = 1.7 × 10 -9 ). The association was independent of candesartan treatment, and the genetic variant was not associated with the cardiovascular endpoint in patients with reduced ejection fraction. None of the genome-wide association studies for candesartan safety or efficacy conducted in patients treated with candesartan passed the significance threshold. We found no significant association from the gene-level collapsing analysis., Conclusions: We have identified a candidate genetic variant potentially predictive of the progression of heart failure in patients with preserved ejection fraction. The findings require further replication, and we cannot exclude the possibility that the results may be chance findings., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: To evaluate the effect of the angiotensin receptor blocker candesartan on patients' perception of symptoms, using the McMaster Overall treatment evaluation (OTE), in a broad spectrum of patients with chronic heart failure (CHF)., Methods and Results: Patients with symptomatic CHF, randomised in the CHARM Programme in North America (n=2498), were studied. OTE was assessed at baseline, at 6, 14 and 26 months and the patient's final or closing visit. Patient's status was classified as "improved (score +1 to +7)", "unchanged (score 0)" or "deteriorated (score -1 to -7)" 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 the worst OTE score) were used. In the LVCF analysis, compared to placebo, more candesartan patients improved (37.7% versus 33.5%) and fewer worsened (10.8% versus 12.0%) in OTE (p=0.017). The WRCF analysis also showed better overall OTE scores with candesartan compared to placebo (p=0.029). There was no heterogeneity in the response to candesartan between the CHARM component trials or across four exploratory sub-groups (age, sex, NYHA class and beta-blocker)., Conclusions: Candesartan was shown to be better than placebo, when using the McMaster OTE to measure patient perception of treatment. More patients treated with candesartan reported improvement and fewer reported deterioration. This benefit was obtained when candesartan was added to extensive background therapy and is consistent with the benefits of candesartan on NYHA class, hospital admission for worsening heart failure and mortality.

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.