European Heart Journal Advance Access originally published online on November 5, 2008
European Heart Journal 2008 29(24):3022-3028; doi:10.1093/eurheartj/ehn476
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Benefits and safety of candesartan treatment in heart failure are independent of age: insights from the Candesartan in Heart failure—Assessment of Reduction in Mortality and morbidity programme
1 Lariboisiere Hospital and INSERM U 942 Paris, France
2 Western Infirmary, Glasgow, UK
3 Sahlgrenska University Hospital/Östra, Göteborg, Sweden
4 Brigham and Women’s Hospital, Boston, MA, USA
5 AstraZeneca, Molndal, Sweden
6 AstraZeneca, LP Wilmington, DE, USA
7 McMaster University, Hamilton, ON, Canada
8 Duke University Medical Center, Durham, NC, USA
Received 17 September 2007; revised 10 April 2008; accepted 10 September 2008; online publish-ahead-of-print 5 November 2008.
* Corresponding author. Tel: +33 1 49956608, Fax: +33 1 49958439. Email: alain.cohen-solal{at}lrb.aphp.fr
Aims: Ageing may affect drug efficacy and safety in patients with heart failure (HF). The Candesartan in Heart failure-Assessment of Reduction in Mortality and morbidity (CHARM) programme offered an opportunity to study the relationship between increasing age and the efficacy and safety of treatment in an uniquely broad spectrum of patients with symptomatic HF and either reduced or preserved left ventricular ejection fraction.
Methods and results: A total of 7599 patients in NYHA Class II–IV HF were randomized to candesartan (target dose 32 mg once daily, mean dose 24 mg) or placebo, including 3169 patients age >70 years. Mean follow-up was 37.7 months. The proportional hazards model was used to estimate the treatment effect on efficacy and safety within five age groups: <50 years (n = 605) (8% of all study patients), 50–59 years (n = 1474) (19%), 60–69 years (n = 2351) (31%), 70–79 years (n = 2474) (33%), and 
80 years (n = 695) (9%). The risk of cardiovascular (CV) death or HF hospitalization (primary outcome) increased from 24% in the lowest age group to 46% in the highest age group (and mortality from 13 to 42%). The relative reduction in risk of the primary outcome with candesartan (15% in the overall study population) was similar irrespective of age. Consequently, the absolute benefit was greater with advancing age (3.8 patients avoided a primary outcome per 100 patients treated in the lowest age group compared with 6.8 in the highest). Adverse events leading to drug discontinuation were more frequent in the candesartan group: placebo/candesartan risk (%), lowest compared with highest age category: hyperkalemia (0.0/1.6 vs. 0.6/2.7), increased serum creatinine (1.0/3.9 vs. 6.1/5.4) and hypotension (1.7/2.0 vs. 2.8/5.7).
Conclusion: Older patients were at a greater absolute risk of adverse CV mortality and morbidity outcomes but derived a similar relative risk reduction and, therefore, a greater absolute benefit from treatment with candesartan, despite receiving a somewhat lower mean daily dose of candesartan. Adverse effects were more common with candesartan than with placebo, although the relative risk of adverse effects was similar across age groups. The benefit to risk ratio for candesartan was thus favourable across all age groups.
Key Words: Heart failure • Candesartan • Age • Mortality • Hospitalization • Adverse events • Dose