We found that a single-item measure of self-reported medication nonadherence was associated with a greater than 2-fold increased risk of CHD death, MI, or stroke in 1007 outpatients with stable CHD. During 3.9 years of follow-up, self-reported medication nonadherence was at least as powerful a predictor of adverse cardiovascular events as diabetes and current smoking. This association between medication nonadherence and adverse events was independent of important potential confounding variables, including age, educational level, income, cardiovascular risk factors, cardiac disease severity, and depression. Our findings demonstrate that self-reported medication nonadherence identifies patients at increased risk for secondary cardiovascular events.
Prior studies of patients with cardiac disease have demonstrated medication nonadherence to be associated with adverse outcomes. The Coronary Drug Project studied the effect of clofibrate in the treatment of hyperlipidemia in patients with CHD.4
Although there was no benefit of clofibrate compared with placebo at 5 years' follow-up, those patients who were more than 80% adherent to the protocol prescription had a substantially lower mortality than those who were nonadherent. Similar findings were noted in the placebo group. In the Beta Blocker Heart Attack Trial, patients who were not adherent to propranolol hydrochloride had an increased risk of death 1 year after an MI.3
Again, nonadherence (<75%) was predictive of mortality even in the placebo group. This risk was independent of the severity of MI and sociodemo-graphic features such as educational level, life-stress, or social isolation. In the Canadian Amiodarone Myocardial Infarction Arrhythmia Trial of patients who have had an MI, poor adherence to treatment with amiodarone or placebo (<80%) was associated with an increased risk of sudden cardiac death and all-cause mortality.5
In the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity trial, poor adherence to the study drug (<80%) as measured by pill count was associated with increased mortality, and this association was independent of whether the study drug was candesartan or placebo.6
Recently, Ho et al8
showed in a prospective cohort of patients that medication discontinuation 1 month after MI hospitalization was associated with a lower 1-year survival. Rasmussen et al10
showed that poor adherence to statins and β-blockers after an MI was associated with an increase in mortality rate.
The consistent association between nonadherence to placebo and adverse outcomes in these trials may be the result of a “healthy adherer” effect. Patients who report adherence to their medications are probably less likely to engage in risky behaviors and more likely to be adherent to other treatment recommendations than those who report nonadherence to medications. Therefore, the association we observed between medication nonadherence and subsequent cardiovascular events may be the result of a less healthy overall lifestyle rather than medication nonadherence alone; however, this was recently called into question.10
Our study extends the observations of prior studies to patients with stable CHD. To our knowledge, only the Coronary Drug Project has studied the outcome of medication nonadherence in patients with stable CHD. Furthermore, few prior studies have adjusted for potential confounders and none have adjusted for depression. Because depression has been established as a risk factor for morbidity and mortality in patients with CHD11
and depression has been associated with medication nonadherence,12
this is an important confounder that must be measured.
Although a number of methods are available for measuring medication adherence, each has its advantages and disadvantages and no particular method (other than direct serum levels) is considered the gold standard.1
Self-reported medication adherence has been shown to correlate well with pill count19
and electronic monitoring of bottles.20
In addition, several prior studies have used self-report for the assessment of medication adherence.21,22
Although prior studies have shown self-reported adherence to be reliable, estimates of adherence rates are often inflated compared with pill counts and may be affected by comorbidities such as depression and cognitive function.19,21,23,24
Our study further demonstrates the predictive validity of self-reported medication adherence as a simple and effective method to identify patients with an increased risk of adverse cardiovascular events. A straightforward method to distinguish patients at risk for nonadherence helps to target the use of reminders or other more comprehensive interventions that can effectively improve adherence and clinical outcomes.25
It should be noted that the prevalence of nonadherence in our study population was remarkably low (only 8%) and likely underestimates the prevalence of nonadherence in outpatients with cardiovascular disease. Patients who volunteer for research studies tend to be more health-conscious than the general population. Moreover, our participants were enrolled in a clinical study with frequent contact with the medical system. It has been demonstrated that patients tend to adhere more closely to treatment recommendations in the few days before and after a clinic appointment, a phenomenon known as “white coat” adherence.26
Also, when assessing self-reports, adherence may be overestimated in an effort to “please the physician.” Despite its low prevalence in our study population, however, nonadherence was still an independent risk factor for cardiovascular events.
Several limitations must be considered in interpreting the results of this study. First, we measured overall adherence rather than adherence to specific medications. However, as described before, adherence to any medication recommendation, including placebo, has been associated with adverse events in prior studies. Second, as discussed before, the overall rate of nonadherence was low so that the absolute effect on outcomes may be underestimated. Finally, most of the participants in our study were men, so the results may not generalize to women.
In conclusion, we found that in a prospective study of 1007 outpatients with stable CHD, medication nonadherence was predictive of a greater than 2-fold increased rate of CHD death, MI, or stroke, independent of several potential confounders, including depression. The increased rate of cardiovascular events associated with nonadherence was similar in magnitude to the rate associated with diabetes or smoking. Our findings suggest that self-reported adherence may be a simple and straightforward method to identify patients at risk for adverse cardiovascular outcomes in patients with CHD.