A significant proportion of patients for whom statins are prescribed discontinue their therapy or take it incorrectly. Large cohort studies in a variety of settings have confirmed high rates of discontinuation of lipid lowering therapies and poor adherence to drug regimens.1-5 Not suprisingly, there is a failure to reach targets for lipid lowering in current practice.6 Further, nonadherence has significant impact on subsequent outcomes. Patients who do not take their medication as prescribed are more likely to be hospitalized than are patients who follow prescription instructions.7,8
Patients with low adherence are also responsible for substantially greater health care costs than are patients with good adherence. Even accounting for savings in drug costs, patients who take less than 20% of their lipid-lowering medications have more than US$3000 greater yearly health care costs than do patients with at least 80% adherence.9 Given the significant burden of cardiovascular disease, the known benefits of lipid lowering, and the poor health consequences of nonadherence, strategies to improve adherence are essential to improving health globally.
Definitions—Adherence, Persistence and Compliance
'Adherence' is defined as behavior that follows the recommendations of a healthcare provider. Some publications use the term 'compliance'. However, the World Health Organization (WHO) favors the term 'adherence' because it better reflects the patient's involvement in his or her own healthcare. 'Compliance' is defined as the extent to which a person follows doctor's orders. 'Persistence,' on the other hand, is defined as the length of time a patient fills his/her prescriptions. This is another useful term in the field of adherence study, especially in the treatment of chronic conditions.10,11
Magnitude of the Problem
Lipid lowering with statins has been demonstrated to significantly reduce morbidity and mortality in a broad range of patients. Despite these findings, these drugs are underutilized in clinical practice and, when prescribed, are often discontinued. Discontinuation rates at five years in clinical trials range from 6% to 30%, but in clinical practice the rates are much higher. Studies show that the number of patients continuing therapy falls sharply in the first few months of treatment, followed by a more gradual decline. In the US, it is estimated that only about 50% of patients continue at six months, and 30–40% at one year.2
Similar rates have been found internationally.4,5 More recently, several large-scale studies have assessed rates of adherence and persistence in older persons. In a cohort study using linked population-based administrative data from Ontario3 patients aged 66 years or older who received at least one statin prescription were followed up for two years from their first statin prescription. Two-year adherence rates in the cohorts were only 40.1% for patients with acute coronary syndromes, 36.1% for chronic coronary artery disease (CAD), and 25.4% for primary prevention. These data suggest that many patients initiating statin therapy may receive no or limited benefit from statins because of premature discontinuation.
Not surprisingly, many patients fail to meet lipid-lowering targets.While this may in part be due to the prescribing of insufficient doses of the statin, heterogeneity in individule responses to HMGCo reductase inhibitors, poor response to treatment seems primarily to be due to patients not taking the drug as prescribed (e.g. poor adherence or poor persistence). In an analysis to describe the patterns and predictors of long-term persistence with statin therapy in an elderly US population, Benner et al.2 utilized data from a retrospective cohort of 34,501 enrollees in the New Jersey Medicaid and Pharmaceutical Assistance to the Aged and Disabled programs who were 65 years of age and older and had initiated statin treatment. In this study, persistence with statin therapy in older patients declined rapidly over time, with the greatest drop occurring in the first six months of treatment. Only one in four patients persisted at five years.
In a large population study of 6,000 diabetics, adherence to low-density lipoprotein (LDL)-C-lowering statin therapy was associated with lower LDL-C levels. Similarly, the probability of achieving the LDL-C goal (<100mg/dL) rose progressively with mulitplanar reformation (MPR). While 19% of subjects with the lowest adherence rates were at goal, nearly 80% of those with the highest adherence achieved the cholesterol goal.12
While it is unclear just how adherent a patient needs to be to garner the benefits of lipid lowering, we can gain insights from clinical trials. In the West of Scotland Coronary Prevention Study (WOSCOPS), for example, patients taking at least 75% of their prescribed dose of pravastatin had significantly lower rates of non-fatal mycardial infarction (MI), revascularisation procedures, death from any cause, and cardiovascular death, compared with taking less than 75% of their prescribed dose.15 A study of patients' adherence to statin treatment after an initial MI showed that patients with greater adherence to statin therapy were significantly less likely to experience a second MI.
In this study, which included 5,590 patients, 7.7% used statins after the incident MI. Among all patients, 12.8% experienced at least one further MI. Compared with those not taking statins, those who had 80% or better adherence to statin treatment had an adjusted relative risk of recurrent MI of 0.19. There was no significant reduction in risk among those patients who were less than 80% adherent to statins.16 These data suggest that nonadherence to medication can impact the occurrence or reoccurrence of CV events, such as MI.
Other studies have shown that withdrawal of statins17 or sudden reduction of dose18 can increase the rate of thrombotic events. These findings may also factor into incremental risk with nonadherence and poor persistence.
Determinants of Nonadherence
A variety of patient characteristics have been associated with the risk for nonadherence. Some characteristics include age, sex, race, and presence of depression. In one study, older subjects were 1.03 times as likely to be adherent compared with younger subjects, while males were 1.42 times more likely to be adherent compared with women. In another study, patients with depression were 1.19 times more likely to have suboptimal persistence than were those untreated. Patients treated for depression were also less likely to persist in statin use, consistent with the study's observation that depressive symptoms correlate with poor persistence with antihyperintensive medications.19-21
Other studies have provided additional insights, although not specific for lipid-lowering. A retrospective study of 8,643 elderly beneficiaries of the New Jersey Medicaid and Medicare programs showed that patients with more visits to a physician were more likely to be adherent to antihypertensive therapy than were patients with fewer visits. This study defined adherence as having antihypertension medication available to cover at least 80% of the days during the study period.22
In a prospective study of patients filling antihypertensive medication at community pharmacies (n=821), patients reported that the single most common reason they did not take their medication as prescribed was forgetfulness. Other commonly cited reasons involved not being convinced of the need and value for therapy. Four major themes are reflected in patients' responses:
- perception of treatment benefits;
- perception of treatment risks;
- costs; and
It appears that patients weigh the perceived benefits, perceived risks, and costs (in terms of money and convenience). Education from the healthcare provider can make a large impact in convincing patients that drug therapy is necessary.23
Cost pressures are a substantial influence on the prescription-taking habits of Medicare beneficiaries. They may simply not fill the prescription, skip doses or take smaller doses to make the prescription last longer. And more than one in 10 Medicare beneficiaries report spending less on basic needs in order to afford their prescription medications.
Finally, patients with more out-patient visits for cholesterol during the baseline period also were more adherent than their counterparts with fewer visits. Patients who had undergone a cardiovascular procedure or who had been hospitalized were more adherent, but patients who had at least one emergency department visit were less likely to be adherent than those who had not had an emergency visit. Patients who filled their statin prescriptions via mail order were more likely to have statin medication on hand than those who used retail pharmacy stores.24 However, retail pharmacies, with their patient contact, may be a point of action to positively influence patient adherence.25
Interventions to Improve Adherence
There have been a number of reviews of interventions to improve patient adherence. One of the simplest ways to improve adherence is to simplify drug regimens. A study within a large managed care population (n=8406) showed that patients who initiated therapy with both antihypertensive and lipid-lowering drugs within 30 days of each other were more likely to be adherent to both drugs over time.26 At four months, 15-24% more patients were adherent among those who were prescribed AHT and LLT together versus those who were prescribed AHT and LLT separately.27 Finally, improvements in adherence have been seen in a single pill combination of atorvastatin and amlodipine versus a two-pill combination. In a retrospective analysis of pharmacy claims data, this single pill strategy was associated with a two- to three-fold improvement in likelihood of adherence.28 In brief, most interventions have a positive effect in the short term, but to be successful in the long term, a sustained multi-factorial approach is required. A combination of patient-focused, physician-focused, and system-focused interventions works best.
Lipid lowering with statins has the potential to dramatically reduce cardiovascular events by a third; however, in view of high rates of nonadherence and poor persistence these benefits are not being achieved. Given the significant burden of nonadherence in society, urgent strategies are required to improve medication adherence so that all patients may benefit from evidence-based therapies.