Elsevier

The Lancet

Volume 366, Issue 9502, 10–16 December 2005, Pages 2005-2011
The Lancet

Articles
Adherence to candesartan and placebo and outcomes in chronic heart failure in the CHARM programme: double-blind, randomised, controlled clinical trial

https://doi.org/10.1016/S0140-6736(05)67760-4Get rights and content

Summary

Background

Chronic heart failure (CHF) is an important cause of hospital admission and death. Poor adherence to medication is common in some chronic illnesses and might reduce the population effectiveness of proven treatments. Because little is known about adherence in patients with CHF and about the consequences of non-adherence, we assessed the association between adherence and clinical outcome in the CHARM (Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity) programme.

Methods

CHARM was a double-blind, randomised, controlled clinical trial, comparing the effects of the angiotensin receptor blocker candesartan with placebo in 7599 patients with CHF. Median follow-up was 38 months. The proportion of time patients took more than 80% of their study medication was defined as good adherence and 80% or less as poor adherence. We used a Cox proportional hazards regression model, with adherence as a time-dependent covariate in the model, to examine the association between adherence and mortality in the candesartan and placebo groups.

Findings

We excluded 187 patients because of missing information on adherence. In the time-dependent Cox regression model, after adjustment for predictive factors (demographics, physiological and severity-of-illness variables, smoking history, and number of concomitant medications), good adherence was associated with lower all-cause mortality in all patients (hazard ratio [HR] 0·65, 95% CI 0·57–0·75, p<0·0001). The adjusted HR for good adherence was similar in the candesartan (0·66, 0·55–0·81, p<0·0001) and placebo (0·64, 0·53–0·78, p<0·0001) groups.

Interpretation

Good adherence to medication is associated with a lower risk of death than poor adherence in patients with CHF, irrespective of assigned treatment. This finding suggests that adherence is a marker for adherence to effective treatments other than study medications, or to other adherence behaviours that affect outcome. Understanding these factors could provide an opportunity for new interventions, including those aimed at improving adherence.

Introduction

In Europe an estimated 10 million patients are affected by heart failure, and in the USA chronic heart failure (CHF) accounts for more than 1 million hospital admissions and more than a quarter of a million deaths every year.1, 2, 3, 4 Although the findings of numerous studies have shown that medications and lifestyle modifications reduce mortality in CHF, adherence to these interventions is often below optimum. Poor adherence limits the effectiveness of proven therapies, resulting in lost opportunities to reduce mortality and readmission rates. Indeed, poor adherence accounts for up to two-thirds of preventable admissions in heart failure and coronary artery disease,5, 6, 7 and is associated with mortality in patients with other chronic illnesses, including breast cancer, asthma, rheumatoid arthritis, and coronary artery disease.8, 9, 10, 11, 12

Improved adherence, even to placebo, is associated with improved survival; in both the Coronary Drug Project (CDP)13 and the Beta Blocker in Heart Attack Trial (BHAT),11 patients on placebo who were highly adherent had lower mortality and fewer cardiovascular events than those who were not. However, in CHF, the nature of the association between adherence and clinical outcomes remains unclear, and efforts to identify patients at risk for poor adherence have been inconclusive.

For this study, therefore, we used patients enrolled to the CHARM (Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity) programme to address two questions: first, does the association between better adherence and lower mortality hold in patients with heart failure; and, second, can factors associated with better adherence be identified in this contemporary cohort of patients followed-up for a long period?

Section snippets

Participants

The CHARM programme and its results have been previously described.14 In summary, patients with symptomatic CHF from 618 sites in 26 countries were enrolled into three concomitant, independent studies with uniform definitions, endpoints, and procedures for randomisation and follow-up. Patients aged 18 years or older who had symptomatic CHF (New York Heart Association [NYHA] class II–IV) for 4 weeks or more before randomisation were eligible for inclusion: CHARM-Alternative15 included patients

Results

7599 patients were enrolled to the CHARM programme: 2028 to CHARM-Alternative,15 2548 to CHARM-Added,16 and 3023 (of which two patients left out of analysis) to CHARM-Preserved.17 Of these, we excluded 187 patients from the adherence analysis because of missing information on adherence. The mean baseline age of patients enrolled was 66 years, and females comprised 32% (n=2400) of the sample. Patients had moderate-to-severe CHF; at baseline they were predominantly in NYHA functional class II or

Discussion

The CHARM dataset provided an opportunity to examine the association between adherence and mortality in a large, contemporary cohort of patients with symptomatic CHF and a wide range of ejection fractions. Moreover, the placebo group provided an opportunity to assess how much of the advantage associated with better adherence is unrelated to the effect of active treatment. Our findings extend the findings of two randomised clinical trials of patients with myocardial infarction—namely, CDP13 and

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