Health and economic impact of non-adherence to preventative cardiovascular medicines
Suboptimal adherence to prescribed cardiovascular medicines is highly prevalent, associated with increased morbidity and mortality, and costly to manage. Adherence is defined by the three phases of initiation, implementation, and discontinuation. Up to one in six patients prescribed a statin do not initiate treatment and less than 60% of patients persist with therapy at 2 years. Even among patients who engage with the dosing regimen, about 10% of scheduled doses are missed on any given day. There is no evidence of significant differences in persistence across different classes of cardiovascular medicines, but persistence is worse in the context of primary prevention, compared with secondary prevention. The relative risk of development of cardiovascular disease in patients with good versus poor adherence is 0.85 and 0.81 for statins and antihypertensive medications, respectively. The consequences of variable dose implementation may be tempered by the use of drugs which are forgiving to variable dosing, that is, drugs whose pharmacological activity persists despite the occasional late or missed dose. The use of specific interventions that involve electronic reminders, pharmacist-led interventions, and healthcare professional education of patients may be an effective strategy to improve adherence to statins, and to achieve corresponding decreases in low-density lipoprotein cholesterol. Improving adherence to preventative cardiovascular medicines could result in savings of over £109 million (€126 million) per year in the United Kingdom alone, and could lead to a 35% reduction in the risk of all-cause mortality.
Suboptimal adherence to prescribed medicines is highly prevalent, associated with increased morbidity and mortality, and costly to manage.1,2,3,4 It is recognized as one of the main barriers to patients achieving the full benefits of prescribed medicines. Key to the understanding of reduced adherence and its consequences is an appreciation of the dynamics of how patients take (or miss) their doses and prescriptions. Adherence is defined by the three phases of initiation, implementation, and discontinuation.5 Initiation occurs when a patient takes the first dose of a prescribed medication. Implementation is the extent to which a patient’s actual dosing corresponds to the prescribed dosing regimen, from initiation until the last dose. Discontinuation occurs when a patient stops taking their prescribed medicine, with persistence representing the length of time between initiation and the last dose that immediately precedes discontinuation.
As initiation is dependent upon a medicine being prescribed and dispensed for the first time, and on the patient taking their first dose, it requires the cooperation of different stakeholders. It is influenced by many contextual factors, including the healthcare setting and healthcare provider, as well as patient-related factors such as their beliefs about the benefits of the treatment, and their understanding of the disease being managed. Studies of the prevalence of non-initiation of antihypertensive or antihyperlipidaemic medications indicate a higher non-initiation rate for statins compared to antihypertensive treatment, with absolute rates dependent on the period of observation.6,7,8 These range from 3.2% of patients not picking up their antihypertensive prescription within 60 days, to 15.4% of patients not picking up their statin prescriptions within 90 days of the order date.
A limitation of many studies of treatment non-initiation is their reliance on prescription, dispensing, or electronic claims records, which underestimate non-initiation resulting from patients having the medicine in their possession, but not having taken any doses. Data from such sources also lack sufficient validity to provide precise and unbiased estimates of dose implementation. The use of electronic monitoring devices,9 however, has revealed the high variability that exists in the timing and taking of doses. Even among patients recruited to clinical trials, who tend to be more motivated and better cared for than the wider population, implementation of dosing is far from optimal. An analysis of 21 phase IV clinical studies, in which adherence was monitored using an electronic device fitted to the lid of the tablet container and involving 43 different antihypertensive drugs, found that about half of all patients had stopped taking their medication within 1 year.10 On any given day, patients who were still engaged with the drug dosing regimen omitted about 10% of scheduled doses. Almost half of the patients had at least one drug holiday (three or more consecutive days of missed doses) a year. Similar data exist for other classes of cardiovascular medicines, as well as in other therapeutic areas. A review of 95 clinical studies reported that the number of patients taking prescribed oral medications decreased progressively over time.11 By day 100, about 20% of patients had discontinued treatment, and 12% of those still engaged with the dosing regimen were omitting a proportion of the prescribed doses. Thus, less than 70% of patients were fully adherent.
Discontinuation rates are higher in routine practice. A meta-analysis of data from 20 observational studies assessing adherence using prescription refill frequency for aspirin, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, calcium channel blockers, thiazides, and statins estimated persistence to be 57% (95% confidence interval (CI) 50–64%) after a median of 24 months.12 There were statistically significant differences in persistence between primary and secondary prevention: 50% (95% CI 45–56%) and 66% (95% CI56–75%), respectively, but not among drug classes.
The consequences of non-initiation are clear, given the overwhelming evidence that drug treatment to lower blood pressure13 and lipid levels reduce the incidence of and mortality from cardiovascular disease (CVD).14 However, the health and economic impact of variable day-to-day implementation of dosing is determined not only by the effectiveness of treatment and severity of the disease, but also by the level of forgiveness of the drug in question.15 A forgiving drug is one whose pharmacological activity persists despite the occasional late or missed dose. Drugs with long elimination half-lives in relation to their dosing interval, or which irreversibly inhibit an enzyme, for instance, have clinical utility in patients who do not adhere fully to their medications. Atorvastatin, as one example, results in a significant reduction in low-density lipoprotein cholesterol among patients who variably implement their dosing, despite many missed doses and frequent episodes of drug holidays.16 Other notable examples of forgiving cardiovascular drugs are aspirin, amlodipine, chlorthalidone, and trandolapril.17,18,19,20
Cardiovascular medicines which are less forgiving, and which may have a detrimental impact if missed, include hydrochlorothiazide which is less forgiving than chlorthalidone, and ticagrelor, which has a rapid offset of action as it binds reversibly to the P2Y12 receptor (compared with clopidogrel which binds irreversibly). It has been hypothesized that chlorthalidone’s superiority over amlodipine, lisinopril, and doxazosin in reducing cardiovascular events in the ALLHAT trial21 may be attributed to its superior forgiveness.15
The clinical implications of reduced forgiveness are difficult to dissect from efficacy trials, as it is standard to analyse such studies on an intention-to-treat basis, and adherence monitoring and measurement are typically based on less reliable methods, such as pill count or questionnaires. Studies reporting the association between cardiovascular morbidity and mortality and adherence are limited by quantifying adherence in terms of the medication possession ratio (which masks non-initiation and discontinuation), and applying an arbitrary threshold for defining adequate adherence (which fails to consider a particular treatment’s forgiveness).
Chowdhury and colleagues22 published a systematic review and meta-analysis of prospective studies (cohort, nested case–control, or clinical trials) to determine the extent to which adherence to cardiovascular medicines influenced the risk of CVD and all-cause mortality. They included 44 studies, comprising nearly 2 million patients, and found 60% of study participants had good adherence (defined by medication possession ratio or the proportion of days covered exceeding the arbitrary threshold of ≥80%). The relative risks of development of CVD in those with good versus poor adherence were 0.85 (95% CI 0.81–0.89) and 0.81 (95% CI 0.76–0.86) for statins and antihypertensive medications, respectively. Based on typical CVD rates across Europe, this corresponds to 9 additional cardiovascular events because of poor adherence to statins (per 100,000 individuals per year), and 13 for antihypertensive agents. Moreover, good adherence to cardiovascular medicines could be associated with a 35% reduced risk of all-cause mortality.
The economic implications are significant. An analysis from the United Kingdom estimated the additional annual cost per patient of being non-adherent to antihypertensive medication at £339 (€400).23 Extrapolated to the hypertensive population of the United Kingdom, the authors suggest that improving adherence might result in savings of over £100 million (€116 million) per year. For statins in the primary prevention of CVD, the authors estimate a cost differential of £47 (€55) per patient per year, which might realize savings of just under £9 million (€10.5 million) per year if adherence could be improved effectively. These were projected figures, and did not consider the likely benefit or cost of adherence-enhancing interventions.23
Interventions to improve medication adherence have had limited success.24 However, a recent Cochrane review which included seven studies of 11,204 patients with hyperlipidaemia randomized to an intervention (e.g. electronic reminders, pharmacist-led interventions, or healthcare professional education of patients) or usual care revealed important differences.25 In the short term (≤6 months), participants in the intervention group had better adherence to their statins than those receiving usual care (odds ratio (OR) 1.93; 95% CI 1.29–2.88). Improvements were sustained (>6 months) in thee evaluable studies (OR 2.87; 95% CI 1.91–4.29). These corresponded to decreases in low-density lipoprotein cholesterol of 19.51 mg/dL and 17.57 mg/dL, respectively, suggesting that meaningful health improvements can be achieved by interventions that intensify patient care.
Intensive interventions are likely to be costly, and careful consideration of their cost-effectiveness is necessary before wider implementation. A recent position paper by the European Society of Cardiology proposed a pathway for the management of patients who are either unwilling to initiate statin treatment, or who discontinue early.26 This involves counselling about the potential risks and consequences of no treatment, identification of potential causative factors, such as muscle pain, and where appropriate, the prescribing of alternative treatments. Indeed, a strategy to enhance statin adherence may result in a significantly larger reduction in the aggregate risk of CVD death than a strategy to lower treatment thresholds.27
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22. Chowdhury R, Khan H, Heydon E, Shroufi A, Fahimi S, Moore C, Stricker B, Mendis S, Hofman A, Mant J, Franco OH. Adherence to cardiovascular therapy: a meta-analysis of prevalence and clinical consequences. Eur Heart J 2013;34:2940–8.Find this resource:
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24. Nieuwlaat R, Wilczynski N, Navarro T, Hobson N, Jeffery R, Keepanasseril A, Agoritsas T, Mistry N, Iorio A, Jack S, Sivaramalingam B, Iserman E, Mustafa RA, Jedraszewski D, Cotoi C, Haynes RB. Interventions for enhancing medication adherence. Cochrane Database Syst Rev 2014;11:CD000011.Find this resource:
25. van Driel ML, Morledge MD, Ulep R, Shaffer JP, Davies P, Deichmann R. Interventions to improve adherence to lipid-lowering medication. Cochrane Database Syst Rev 2016;12:CD004371.Find this resource:
26. Vonbank A, Agewall S, Kjeldsen KP, Lewis BS, Torp-Pedersen C, Ceconi C, Funck-Brentano C, Kaski JC, Niessner A, Tamargo J, Walther T, Wassmann S, Rosano G, Schmidt H, Saely CH, Drexel H. Vonbank. Comprehensive efforts to increase adherence to statin therapy. Eur Heart J 2017. 10 January [Epub ahead of print]. DOI:10.1093/eurheartj/ehw628Find this resource:
27. Shroufi A, Powles JW. Adherence and chemoprevention in major cardiovascular disease: a simulation study of the benefits of additional use of statins. J Epidemiol Community Health 2010;64:109–13.Find this resource:
Blaschke TF, Osterberg L, Vrijens B, Urquhart J. Adherence to medications: insights arising from studies on the unreliable link between prescribed and actual drug dosing histories. Annu Rev Pharmacol Toxicol 2012;52:275–301.Find this resource:
Osterberg L, Blaschke T. Adherence to medication. N Engl J Med 2005;353:487–97.Find this resource:
van Driel ML, Morledge MD, Ulep R, Shaffer JP, Davies P, Deichmann R. Interventions to improve adherence to lipid-lowering medication. Cochrane Database Syst Rev 2016;12:CD004371.Find this resource:
Vonbank A, Agewall S, Kjeldsen KP, Lewis BS, Torp-Pedersen C, Ceconi C, Funck-Brentano C, Kaski JC, Niessner A, Tamargo J, Walther T, Wassmann S, Rosano G, Schmidt H, Saely CH, Drexel H. Vonbank. Comprehensive efforts to increase adherence to statin therapy. Eur Heart J 2017. 10 January [Epub ahead of print]. DOI:10.1093/eurheartj/ehw628Find this resource:
Vrijens B, De Geest S, Hughes DA, Przemyslaw K, Demonceau J, Ruppar T, Dobbels F, Fargher E, Morrison V, Lewek P, Matyjaszczyk M, Mshelia C, Clyne W, Aronson JK, Urquhart J; ABC Project Team. A new taxonomy for describing and defining adherence to medications. Br J Clin Pharmacol 2012;73(5):691–705.Find this resource:
Vrijens B, Vincze G, Kristanto P, Urquhart J, Burnier M. Adherence to prescribed antihypertensive drug treatments: longitudinal study of electronically compiled dosing histories. BMJ 2008;336(7653):1114–7.Find this resource: