Curr Treat Options Cardio Med (2014) 16:349 DOI 10.1007/s11936-014-0349-7
Prevention (L Sperling and D Gaita, Section Editors)
Medication Adherence in Secondary Prevention Post-Myocardial Infarction Javier A. Valle, MD1,2,* P. Michael Ho, MD, PhD1,2 Address *,1 University of Colorado, 12631 East 17th Avenue, B130, Aurora, CO 80045, USA Email: [email protected] 2 Veterans Affairs Eastern Colorado Health Care System, Denver, CO, USA
Published online: 25 October 2014 * Springer Science+Business Media New York 2014
This article is part of the Topical Collection on Prevention Keywords Adherence
I
ACS
I
Nonadherence
I
Secondary prevention
Opinion statement Nonadherence to cardiovascular medications is common and has been associated with adverse outcomes. Patient adherence to medications is complex, with multiple factors contributing to the development of nonadherence, and these factors likely evolve over time. Significant efforts have gone into identifying factors that impact patient adherence, including patient, physician, and social/environmental factors. To date, various efforts to improve medication adherence have demonstrated modest results. The most successful interventions have addressed multiple potential reasons for nonadherence, suggesting that an adaptive approach with interventions that are flexible and can address patient-specific needs is important. Future research should be aimed at the development of an adaptive set of tools to identify and address evolving patient barriers to adherence.
Introduction Medical care following acute coronary syndromes (ACS) hospitalization has become more involved for both physicians and patients. Advances in medical therapy have led to declines in mortality and recurrent hospitalizations, while increasing the complexity of the prescribed medication regimen. With beta blockade, angiotensin-converting enzyme (ACE) inhibition, and mineralocorticoid receptor antagonism in addi-
tion to statin and antiplatelet therapy, patients are asked to take up to six new medications following a hospitalization for acute coronary syndrome, in addition to their medications for other chronic conditions. Facing the possibility of a new diagnosis of coronary artery disease and major changes to their medication regimens, patients may be at risk of nonadherence to recommended medications. An analysis by Melloni
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and colleagues found that nearly 30 % of post-ACS patients discontinued one or more of medications within 3 months of their coronary event [1••]. Even though prior studies have demonstrated a consistent association between cardiovascular medication adherence and improved cardiovascular outcomes [2–4], adherence rates remain low, ranging between 50 % and 79 % [5, 6•]. Observational studies have identified a number of factors that can impact the frequency with which a patient is able to comply with a prescribed medication regimen. These factors have been organized into three major groupings: patients (as individuals or groups, eg, ethnic or socioeconomic groupings), physicians or providers, and societal or environmental factors. Prior studies have shown that
medication nonadherence can be multifactorial, with successful interventions designed to improve adherence targeting one or more of these factors. These interventions have resulted in a variety of successful strategies to address nonadherence, but the improvements have generally been modest. The objectives of this review are to discuss the potential reasons for medication nonadherence, and then to describe successful strategies designed to address them. We will first define and explore each major factor contributing to medication nonadherence, followed by a discussion of recent interventions that have been employed to address them. Finally, we will explore future areas of research for improving medication adherence in post-ACS patients.
Patient factors There are a variety of patient factors associated with medication nonadherence and a proposed schema classifies nonadherence into “intentional” or “nonintentional” behaviors [7–10]. Intentional nonadherence stems from patient beliefs about medications, including the impact of the costs of medications, influence of side effects, and/or personal valuation of health care. Nonintentional adherence arises from factors that may be external to the patient. These include barriers to access to care, physician factors (lack of education to the patient on the importance or benefits of their medications), or societal factors (cultural or societal variability on the weight of health in day to day life), as well as patient-related factors such as health illiteracy or cognitive impairment. Although behavioral studies have demonstrated overlap between nonadherence because of intentional and nonintentional behaviors [11], this prior work still can serve to organize potentially modifiable factors affecting nonadherence. A number of studies have also assessed the association of specific patient factors and medication nonadherence. In general, these patient factors are similar to factors associated with health disparities and comprise the following: low socioeconomic status, lower education levels, non-White race, female sex, and older age [12–15]. Although these risk factors are associated with nonadherence, it is not clear that these factors are directly actionable but rather may assist in defining specific target groups for interventions. In general, interventions have been designed to target potential modifiable intentional or unintentional nonadherence behaviors and include interventions that limit out-of-pocket costs, decrease regimen complexity, increase access to providers, and education intensification efforts to emphasize the importance of adherence on health. Initial patient-level interventions were designed around education. Patient education can potentially improve health literacy and increase a patient’s understanding of the benefits of therapies compared with any
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perceived disadvantages. Educational efforts aimed directly at patients have demonstrated some success through direct mailings on the benefits of beta blockers post-ACS [16]. Patients receiving these mailings demonstrated an absolute increase of 4.7 % in adherence (defined as 980 % of patient days covered with beta blockers). More recent interventions have targeted other barriers to adherence such as cost of medications and administration complexity (multiple pills, multiple administration times). These newer interventions include simplifying regimens to minimize polypharmacy, decreasing the complexity of the medication taking schedule, or offering direct incentives to encourage regimen adherence and offset the financial costs of medications.
Lottery-based incentives Kimmel et al evaluated a unique lottery system to reward patients for adherence with warfarin. The intervention addressed barriers attributable to perceived value of medication adherence and monetary constraints through the use of monetary incentives [17]. An electronic monitoring system tracked medication administration, offering patients a chance to win cash prizes on a daily basis by following their anticoagulant regimen correctly. The trial randomized 100 patients to this lottery-based system or usual care, and used time out of therapeutic range as its primary endpoint. There was no effect on the time out of therapeutic range in the general population. However, the lottery incentive system decreased time out of therapeutic range in a prespecified subgroup of patients with baseline international normalized ratio out of therapeutic range (ie, nonadherent patients) that was statistically significant. The authors’ findings suggest that an incentive approach targeted toward those patients with poor baseline adherence may be successful. Debate remains over the general applicability of such an incentive scheme. The cost-effectiveness of such an approach is unknown, as is the optimal type of incentive: positive reinforcement like these lottery systems vs negative reinforcement in the form of penalties for poor adherence. In addition, there are questions of fairness for adherent patients when targeting financial incentives to nonadherent patients [18].
Physician/provider factors Physicians and other health care providers can influence patients’ intentional or nonintentional poor adherence behaviors. Provider-led patient education and emphasis on health benefits of prescribed regimens as well as explanation of possible adverse effects can impact a patient’s decision about whether they will adhere to medications [19]. Increases in adherence correlate positively with increased time spent by provider teams and ease of communication between patients and providers [20–22]. Positive patient attitudes toward their providers are also associated with increased adherence [21] in chronic disease states such as HIV infection. These findings support the theory that a healthy providerpatient relationship that fosters open communication between both parties can impact adherence. Concerns that may lead to intentional nonadherence (eg, self-discontinuation of a regimen after experiencing an unexpected side profile or medication adverse effects) may be averted by increased communication with
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Curr Treat Options Cardio Med (2014) 16:349 a provider helping the patient work through the issue or finding an equivalent therapy as opposed to outright discontinuation. Thus, interventions directed at the provider level have the potential to be powerful tools capable of addressing both intentional and nonintentional factors for the multiple patients within each provider’s panel.
Increasing provider team-patient communication A number of interventions targeting providers have focused on improving rates of evidence-based medication prescription prior to the patient’s ACS hospital discharge. However, there have been limited studies of interventions focused on the postdischarge period or interventions targeting provider behaviors to improve the medication adherence of their patients. An intervention consisting of counseling and repeat visits by nurses to assess cardiovascular risk factor modification resulted in improvements in statin adherence (90 %–95 % in the usual care arm, vs 95 %–100 % adherence in the nursing intervention arm, PG0.01) in patients with cardiovascular disease (CVD) or increased CVD risk [23]. Provider-level interventions in other chronic disease states have yielded similar results in terms of improving adherence. In heart failure management, increased provider-patient contact via regular scheduled telephone communications improved adherence to heart failure medications and decreased hospitalizations [24]. Pharmacist-led interventions in the form of counseling, medication reconciliation, or regimen simplification have led to improved medication adherence in noncardiac chronic illnesses such as asthma, hypertension, and diabetes [25–27]. Proponents of these direct provider-to-patient communication strategies (via telephone or in person) point to the flexibility of these strategies to reach the individual patient and tailor the intervention to each patient’s specific needs and barriers to adherence. Detractors question the feasibility and sustainability of these interventions on a larger scale because each of these studies involved small numbers of patients and required development of a strong infrastructure and health care team to execute the intervention.
Societal/environmental factors Societal and environmental factors such as health policy aimed toward reducing barriers to care and community outreach efforts can affect patients’ attitudes toward medication regimens. Policy changes affording easier access to care and medications can remove barriers that often result in nonintentional adherence. National campaigns promoting disease awareness can impact patient attitudes and priorities around their conditions, positively influencing awareness [28] and recognition of time-sensitive conditions such as acute onset of myocardial infarction (MI) and stroke symptoms. It is as yet unknown if these campaigns to promote awareness translate to chronic disease recognition and management. In addition, pharmaceutical advertising campaigns on specific medications have shown positive effects on adherence [29–31], but effect sizes of these efforts are difficult to measure. Although advertising succeeds in reaching a broad audience of patients and
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providers alike, the effectiveness of the messages may be diminished because of the loss of personalization.
Value-based insurance design From a societal/environmental standpoint, value-based insurance plans have been tested to improve patient adherence. Proponents hold that insurance designed to promote use of evidence-based medication regimens through economic rewards (monetary rebates or incentives) can increase adherence through both improved patient access to care (nonintentional adherence) and decreasing costs of prescription medications (intentional adherence). The Full Coverage for Preventative Medications after Myocardial Infarction (MI-FREEE) trial evaluated the effect of a value-based plan for post-MI prescription medications [32]. The investigators randomized 5855 patients following hospital discharge for MI to either full prescription coverage for indicated medications [statin, beta blocker, ACE-I or angiotensin receptor blocker (ARB)] compared with standard insurance plan coverage. The primary outcome in MI-FREEE was unique in that it sought to evaluate “hard” endpoints of cardiovascular events in addition to measuring adherence rates. Full prescription coverage increased adherence by approximately 5 %, but overall cardiovascular events did not significantly differ. A cost analysis did not find a significant change between overall health care costs between full coverage and usual coverage patients.
Interventions aimed at multiple domains Interventions to date have been mainly designed to target specific factors such as patients, providers, or societal/environmental factors. These interventions have resulted in modest improvements in adherence. Given that an individual’s nonadherence may be due to multiple reasons that very likely change over time, interventions targeting multiple factors could be more effective in a synergistic fashion. As such, investigators have started to develop multidisciplinary and multifaceted approaches to cover multiple domains known to impact adherence.
A multifaceted approach In four centers, 253 patients discharged after hospitalization for ACS were randomized to a multifaceted intervention to improve adherence vs usual care [33]. The intervention was directed toward providers and patients, providing follow-up beyond that of usual care. Each patient received education about cardiovascular medications at hospital discharge, as well as postdischarge education through communication with the study pharmacist. In addition, automated voice messages were left at regularly scheduled intervals to both remind patients to take their medications, as well as to remind them of when their medications needed to be refilled. On the provider level, pharmacists who were part of the research team met with patients within 7 10 days of discharge to address adverse effects and to perform medication reconciliation. In addition, they provided pillboxes if needed and discussed
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Curr Treat Options Cardio Med (2014) 16:349 strategies to improve adherence. A second pharmacist-patient interaction occurred at 1 month to further discuss any medication issues and to synchronize cardiac medication refill dates as much as possible to promote ease of refills. Pharmacists also contacted the patients’ primary care physicians and cardiologists on enrollment, leaving contact information to facilitate communication regarding any questions on the medication regimen. The intervention demonstrated a significant benefit in adherence, with an absolute increase in adherence of 15.4 % (89.3 % vs 72.9 %, P=0.003), however, secondary outcomes of achieving lipid and blood pressure goals for cardiovascular risk reduction were not statistically significant between groups. In addition, there were no differences in clinical outcomes of MI, death, or revascularization. Cost analysis did not reveal any significant differences for inpatient, outpatient, medication, or total costs between treatment arms. This multifactorial approach, despite a high baseline adherence rate in the usual treatment arm, displayed one of the most significant increases in adherence amongst secondary prevention CVD patients to date.
The polypill, or fixed-dose combination therapy Polypharmacy with its associated medication costs, and potential dosing complexity can lead to medication nonadherence. To address the issue of polypharmacy, the “polypill,” also known as fixed-dose combination (FDC) therapy was developed. Investigators hypothesized that use of a single polypill could help overcome intentional and nonintentional adherence barriers alike through lowering cost and easing administration as patients would only need to take a single pill once each day. By providing the pill free of cost to study participants (vs patients with usual care being subject to standard fees), investigators also targeted a societal and environmental barrier. The Effects of a Fixed Dose Combination Strategy on Adherence and Risk Factors in Patients with or at High Risk of CVD (UMPIRE) Trial evaluated the use of such a pill (combination of aspirin, simvastatin, lisinopril and atenolol or aspirin, simvastatin, lisinopril and hydrochlorothiazide) in 2004 among patients with either established CVD or elevated 5-year CVD risk, as compared to usual care [34•]. Investigators assessed self-reported adherence, as well as changes from baseline in systolic blood pressure and low-density lipoprotein cholesterol. The study demonstrated significantly improved adherence in the FDC arm compared with usual care (86 % vs 65 %, PG0.001) with small but statistically significant absolute reductions in the other coprimary endpoints of change in systolic blood pressure (–2.6 mm Hg, P= 0.0005) and low-density lipoprotein cholesterol (–4.2 mg/dL, P=0.0005). Cardiovascular events were nonsignificantly greater in the FDC group (50 events vs 35 in usual therapy), although the study was not powered to detect a difference between groups. FDC therapy demonstrated the greatest improvement in medication adherence among patients who were nonadherent prior to study enrollment (77.2 % compared with 23.1 % with standard care; PG0.01). Investigators concluded that FDC therapy demonstrated significant improvements in medication adherence, and suggested that targeted use of FDC therapy among nonadherent patients may result in greater improvements in the surrogate and clinical outcomes. Critics of the FDC hypothesis
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shared concerns about the tradeoff of achieving adherence while losing the ability to tailor therapies to a specific patient.
Future directions Adherence to cardioprotective medications has been associated with decreased risk of adverse cardiovascular events. The majority of interventions tested to date have demonstrated modest improvements. That said, prior studies targeting individual adherence barriers have shown significant improvement in subgroups of patients with poor baseline adherence, suggesting that a targeted approach would potentially be the most beneficial. More successful recent interventions have been multifaceted in nature, targeting provider, social/environmental, and patient barriers [33, 34•; Fig. 1]. It is possible that the most effective of interventions would be a multimodal, patient, and team-based intervention that is appropriately targeted to those patients who are already nonadherent at enrollment. Nonadherence is a nuanced entity, and patients differ greatly in their barriers to following their prescribed regimens. Not only do they differ from each other, but they can also differ in their own rationale over time, as a patient’s circumstances evolve. What may have begun as forgetfulness and poor understanding of their disease process may evolve into monetary constraints as environmental and societal pressures take hold, or prescription coverage changes. This adds a layer of complexity to the concept of a targeted strategy for adherence interventions, as the target is constantly moving and evolving. The optimal approach to patient nonadherence may be the development of a “toolbox” of strategies that can address poor adherence and that can be accessed to match the patient’s current
SOCIETAL/ ENVIRONMENTAL
PATIENT Intentional
PROVIDER
NonIntentional
UMPIRE (Fixed Dose Combination therapy): 21% improvement in adherence
Ho et al. (Provider-patient communication, regimen simplification, counseling): 15.4% improvement in adherence
MI-FREEE (Value-based insurance design): 5% increase in adherence
Kimmel et al (Lottery incentives): 2.9% improvement (NS)*
Nurse-led Counseling (Provider-patient communication): 5% increase in adherence
Educational mailings: 5% increase in adherence
*NS = statistically non-significant
Fig. 1. Intervention effects by targeted adherence barriers.
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Curr Treat Options Cardio Med (2014) 16:349 needs. From the literature, educational, patient incentive, fixed dose combination therapy, value-based, and provider-level interventions have demonstrated benefit. In the future, adherence research should test these interventions as part of a toolbox, specifically targeting nonadherent patients and matching the intervention to their needs. In order to identify the appropriate adherence intervention for a specific patient, it would be helpful to develop a validated tool to identify the most likely causes for nonadherence. Depending on the identified cause for nonadherence, the strategies within the toolbox could be employed for the patient to help them with their specific adherence barrier. This would allow for targeting of specific interventions to an individual’s reasons for nonadherence, allowing for more individualization of an intervention and possibly increase efficiency. Another consistent theme throughout adherence literature, and seen in the reviewed trials [16, 24–28, 34•] is that of ongoing and increased provider-patient communication. Given advances in telecommunications and the internet, communication between individuals has never been easier, whether via telephone, email, text message, or webbased interface. Although limited in evaluation, mobile phone messaging has been associated with some benefit in chronic illness management [35]. An optimal approach to the incorporation of this new technology in medication adherence remains unknown, but mobile technology may be a powerful tool to include in the “toolbox.”
Conclusions Optimizing medication adherence is a critically important component toward the care of patients following a recent hospitalization as well as those with chronic illnesses. Following acute coronary syndrome hospitalization, there is an abundance of data that have demonstrated an association between poor medication adherence and adverse cardiovascular outcomes. Interventions to improve adherence to date have been more successful when specifically targeting patients who are nonadherent at baseline, and when developed as a multimodal and multifaceted approach. Further steps to improve medication adherence will likely require improved methods of identifying nonadherent patients and tailoring the interventions to meet individual patient needs, particularly as these needs may evolve over time.
Compliance with Ethics Guidelines Conflict of Interest Dr. Javier A. Valle and Dr. P. Michael Ho each declare no potential conflicts of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
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References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1.••
Melloni C, Alexander KP, Ou FS, et al. Predictors of early discontinuation of evidence-based medicine after acute coronary syndrome. Am J Cardiol. 2009;104(2):175–81. Nearly 30% of patients post-ACS discontinued ≥1 evidence based therapy within 3 months, most without provider involvement in termination. Factors involved in self-discontinuation: no prescription coverage, increasing number of medications, lack of use of reminder tools, lower education 2. Ho PM, Spertus JA, Masoudi FA, et al. Impact of medication therapy discontinuation on mortality after myocardial infarction. Arch Int Med. 2006;166:1842–7. 3. Choudhry NK, Glynn RJ, Avorn J, et al. Untangling the relationship between medication adherence and postmyocardial infarction outcomes: medication adherence and clinical outcomes. Am Heart J. 2014;167:51–8. 4. Schroeder K, Fahey T, Ebrahim S. Interventions for improving adherence to treatment in patients with high blood pressure in ambulatory settings. Cochrane Database Syst Rev 2004;(2) p. Cd004804. 5. Yusuf S, Islam S, Chow CK, et al. Use of secondary prevention drugs for cardiovascular disease in the community in high-income, middle-income, and low-income countries (the PURE study): a prospective epidemiological survey. Lancet. 2011;378(9798):1231–3. 6.• Rasmussen JN, Chong A, Alter DA, et al. Relationship between adherence to evidence-based pharmacotherapy and long-term mortality after acute myocardial infarction. JAMA. 2007;297:178–86. Risk of mortality is highest for patients post-ACS with low adherence to evidence based pharmacotherapy, even after adjustment for potential healthy adherer confounders such as socioeconomic factors and comorbidities 7. Wroe AL. Intentional and Unintentional nonadherence: a study of decision-making. J Behav Med. 2002;25(4):355–72. 8. Haynes RB Ackloo R, Sahota N, et al. Interventions for enhancing medication adherence. Cochrane Database Syst Review 2008;(2) p. Cd000011. 9. Lehane S, McCarthy G. Intentional and Unintentional medication nonadherence: a comprehensive framework for clinical research and practice? A discussion paper. Int J Nurs Stud. 2007;44:1468–77. 10. Horne R, Weinman J, Barber N, et al. Concordance, Adherence and compliance in medicine taking. Report for the National Coordinating Centre for NHS Delivery and Organisation R and D 2005.
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Gadkari AS, McHorney CA. Unintentional nonadherence to chronic prescription medications: how unintentional is it? BMC Health Serv Res. 2012;12:98. Wallach-Kildemoes H, Andersen M, Didreichsen F, et al. Adherence to preventive statin therapy according to socioeconomic position. Eur J Clin Pharmacol. 2013;69(8):1553–63. Spertus JA, Kettlecamp R, Vance C, et al. Prevalence, predictors, and outcomes of premature discontinuation of thienopyridine therapy after drug-eluting stent placement. Circulation. 2006;113:2803–9. Jackevicius CA, Li P, Tu JV. Prevalence, predictors, and outcomes of primary nonadherence after acute myocardial infarction. Circulation. 2008;117:1028–36. Lewey J, Shrank WH, Bowry AD, et al. Gender and racial disparities in adherence to statin therapy: a meta-analysis. Am Heart J. 2013;165(5):665–78. Smith DH, Kramer JM, Perrin N, et al. A randomized trial of direct-to-patient communication to enhance adherence to beta-blocker therapy following myocardial infarction. Arch Intern Med. 2008;168:477–83. Kimmel SE, Troxel AB, Loewenstein G, et al. Randomized trial of lottery-based incentives to improve warfarin adherence. Am Heart J. 2012;164:268–74. Volpp KG, Pauly MV, Loewenstein G, et al. P4P4P: an agenda for research on pay-for-performance for patients. Health Aff. 2009;28(1):206–14. Viswanathan M, Golin CE, Jones CD, et al. Interventions to improve adherence to self-administered medications for chronic diseases in the United States: a systematic review. Ann Intern Med. 2012;157(11):785–95. De Geest S, Sabate E. Adherence to Long-term therapies: evidence for action. Eur J Cardiovasc Nurs. 2003;2:323. Russell J, Krantz S, Neville S. The provider-patient relationship and adherence to highly active retroviral therapy. J Assoc Nurs AIDS Care: JANAC. 2005;15:40–7. Horowitz CR, Sb R. Leventhal H. A story of maladies, misconceptions and mishaps: effective management of heart failure. Soc Sci Med. 2004;58:631–43. Nieuwkerk PT, Nieman MC, Vissers MN, et al. Intervention to improve adherence to lipid-lowering medication and lipid-levels in patients with an increased cardiovascular risk. Am J Cardiol. 2012;110(5):666–72. Ferrante D, Varini S, Macchia A, et al. Long-term results after a telephone intervention in chronic heart
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Curr Treat Options Cardio Med (2014) 16:349 ment guidelines for depression. Med Care. 2004;42:1176–85. 30. Prev. Mag. 1998. National Survey of Consumer Reactions to Direct-to-Consumer Advertising. Emmaus, PA 31. Prev. Mag. 1999. Year Two: a National Survey of Consumer Reactions to Direct-to-Consumer Advertising. 32. Choudhry NK, Avorn J, Glynn RJ, et al. Full coverage for preventative medications after myocardial infarction. N Engl J Med. 2011;365:2088–97. 33. Ho PM, Lambert-Kerzner AL, Carey EP, et al. Multifaceted intervention to improve medication adherence and secondary prevention measures after acute coronary syndrome hospital discharge. JAMA. 2014;174(2):186–93. 34.• Thom S, Poulter N, Field J, et al. Effects of a fixeddose combination strategy on adherence and risk factors in patients with or at high risk of CVD: the UMPIRE randomized clinical trial. JAMA. 2013;310(9):918–29. A multifaceted approach to improve medication adherence achieved the largest increase in adherence (21 %), suggesting that strategies targeting multiple adherence barriers may have the most impact 35. De Jongh T, Gurol-Urganci I, Vodopivec-Jamsek V, et al. Mobile Phone messaging for facilitating selfmanagement of long-term illnesses. Cochrane Database Syst Rev 2012;12 p. Cd007459.
Prevention (L Sperling and D Gaita, Section Editors)
Medication Adherence in Secondary Prevention Post-Myocardial Infarction Javier A. Valle, MD1,2,* P. Michael Ho, MD, PhD1,2 Address *,1 University of Colorado, 12631 East 17th Avenue, B130, Aurora, CO 80045, USA Email: [email protected] 2 Veterans Affairs Eastern Colorado Health Care System, Denver, CO, USA
Published online: 25 October 2014 * Springer Science+Business Media New York 2014
This article is part of the Topical Collection on Prevention Keywords Adherence
I
ACS
I
Nonadherence
I
Secondary prevention
Opinion statement Nonadherence to cardiovascular medications is common and has been associated with adverse outcomes. Patient adherence to medications is complex, with multiple factors contributing to the development of nonadherence, and these factors likely evolve over time. Significant efforts have gone into identifying factors that impact patient adherence, including patient, physician, and social/environmental factors. To date, various efforts to improve medication adherence have demonstrated modest results. The most successful interventions have addressed multiple potential reasons for nonadherence, suggesting that an adaptive approach with interventions that are flexible and can address patient-specific needs is important. Future research should be aimed at the development of an adaptive set of tools to identify and address evolving patient barriers to adherence.
Introduction Medical care following acute coronary syndromes (ACS) hospitalization has become more involved for both physicians and patients. Advances in medical therapy have led to declines in mortality and recurrent hospitalizations, while increasing the complexity of the prescribed medication regimen. With beta blockade, angiotensin-converting enzyme (ACE) inhibition, and mineralocorticoid receptor antagonism in addi-
tion to statin and antiplatelet therapy, patients are asked to take up to six new medications following a hospitalization for acute coronary syndrome, in addition to their medications for other chronic conditions. Facing the possibility of a new diagnosis of coronary artery disease and major changes to their medication regimens, patients may be at risk of nonadherence to recommended medications. An analysis by Melloni
349, Page 2 of 10
Curr Treat Options Cardio Med (2014) 16:349
and colleagues found that nearly 30 % of post-ACS patients discontinued one or more of medications within 3 months of their coronary event [1••]. Even though prior studies have demonstrated a consistent association between cardiovascular medication adherence and improved cardiovascular outcomes [2–4], adherence rates remain low, ranging between 50 % and 79 % [5, 6•]. Observational studies have identified a number of factors that can impact the frequency with which a patient is able to comply with a prescribed medication regimen. These factors have been organized into three major groupings: patients (as individuals or groups, eg, ethnic or socioeconomic groupings), physicians or providers, and societal or environmental factors. Prior studies have shown that
medication nonadherence can be multifactorial, with successful interventions designed to improve adherence targeting one or more of these factors. These interventions have resulted in a variety of successful strategies to address nonadherence, but the improvements have generally been modest. The objectives of this review are to discuss the potential reasons for medication nonadherence, and then to describe successful strategies designed to address them. We will first define and explore each major factor contributing to medication nonadherence, followed by a discussion of recent interventions that have been employed to address them. Finally, we will explore future areas of research for improving medication adherence in post-ACS patients.
Patient factors There are a variety of patient factors associated with medication nonadherence and a proposed schema classifies nonadherence into “intentional” or “nonintentional” behaviors [7–10]. Intentional nonadherence stems from patient beliefs about medications, including the impact of the costs of medications, influence of side effects, and/or personal valuation of health care. Nonintentional adherence arises from factors that may be external to the patient. These include barriers to access to care, physician factors (lack of education to the patient on the importance or benefits of their medications), or societal factors (cultural or societal variability on the weight of health in day to day life), as well as patient-related factors such as health illiteracy or cognitive impairment. Although behavioral studies have demonstrated overlap between nonadherence because of intentional and nonintentional behaviors [11], this prior work still can serve to organize potentially modifiable factors affecting nonadherence. A number of studies have also assessed the association of specific patient factors and medication nonadherence. In general, these patient factors are similar to factors associated with health disparities and comprise the following: low socioeconomic status, lower education levels, non-White race, female sex, and older age [12–15]. Although these risk factors are associated with nonadherence, it is not clear that these factors are directly actionable but rather may assist in defining specific target groups for interventions. In general, interventions have been designed to target potential modifiable intentional or unintentional nonadherence behaviors and include interventions that limit out-of-pocket costs, decrease regimen complexity, increase access to providers, and education intensification efforts to emphasize the importance of adherence on health. Initial patient-level interventions were designed around education. Patient education can potentially improve health literacy and increase a patient’s understanding of the benefits of therapies compared with any
Curr Treat Options Cardio Med (2014) 16:349
Page 3 of 10, 349
perceived disadvantages. Educational efforts aimed directly at patients have demonstrated some success through direct mailings on the benefits of beta blockers post-ACS [16]. Patients receiving these mailings demonstrated an absolute increase of 4.7 % in adherence (defined as 980 % of patient days covered with beta blockers). More recent interventions have targeted other barriers to adherence such as cost of medications and administration complexity (multiple pills, multiple administration times). These newer interventions include simplifying regimens to minimize polypharmacy, decreasing the complexity of the medication taking schedule, or offering direct incentives to encourage regimen adherence and offset the financial costs of medications.
Lottery-based incentives Kimmel et al evaluated a unique lottery system to reward patients for adherence with warfarin. The intervention addressed barriers attributable to perceived value of medication adherence and monetary constraints through the use of monetary incentives [17]. An electronic monitoring system tracked medication administration, offering patients a chance to win cash prizes on a daily basis by following their anticoagulant regimen correctly. The trial randomized 100 patients to this lottery-based system or usual care, and used time out of therapeutic range as its primary endpoint. There was no effect on the time out of therapeutic range in the general population. However, the lottery incentive system decreased time out of therapeutic range in a prespecified subgroup of patients with baseline international normalized ratio out of therapeutic range (ie, nonadherent patients) that was statistically significant. The authors’ findings suggest that an incentive approach targeted toward those patients with poor baseline adherence may be successful. Debate remains over the general applicability of such an incentive scheme. The cost-effectiveness of such an approach is unknown, as is the optimal type of incentive: positive reinforcement like these lottery systems vs negative reinforcement in the form of penalties for poor adherence. In addition, there are questions of fairness for adherent patients when targeting financial incentives to nonadherent patients [18].
Physician/provider factors Physicians and other health care providers can influence patients’ intentional or nonintentional poor adherence behaviors. Provider-led patient education and emphasis on health benefits of prescribed regimens as well as explanation of possible adverse effects can impact a patient’s decision about whether they will adhere to medications [19]. Increases in adherence correlate positively with increased time spent by provider teams and ease of communication between patients and providers [20–22]. Positive patient attitudes toward their providers are also associated with increased adherence [21] in chronic disease states such as HIV infection. These findings support the theory that a healthy providerpatient relationship that fosters open communication between both parties can impact adherence. Concerns that may lead to intentional nonadherence (eg, self-discontinuation of a regimen after experiencing an unexpected side profile or medication adverse effects) may be averted by increased communication with
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Curr Treat Options Cardio Med (2014) 16:349 a provider helping the patient work through the issue or finding an equivalent therapy as opposed to outright discontinuation. Thus, interventions directed at the provider level have the potential to be powerful tools capable of addressing both intentional and nonintentional factors for the multiple patients within each provider’s panel.
Increasing provider team-patient communication A number of interventions targeting providers have focused on improving rates of evidence-based medication prescription prior to the patient’s ACS hospital discharge. However, there have been limited studies of interventions focused on the postdischarge period or interventions targeting provider behaviors to improve the medication adherence of their patients. An intervention consisting of counseling and repeat visits by nurses to assess cardiovascular risk factor modification resulted in improvements in statin adherence (90 %–95 % in the usual care arm, vs 95 %–100 % adherence in the nursing intervention arm, PG0.01) in patients with cardiovascular disease (CVD) or increased CVD risk [23]. Provider-level interventions in other chronic disease states have yielded similar results in terms of improving adherence. In heart failure management, increased provider-patient contact via regular scheduled telephone communications improved adherence to heart failure medications and decreased hospitalizations [24]. Pharmacist-led interventions in the form of counseling, medication reconciliation, or regimen simplification have led to improved medication adherence in noncardiac chronic illnesses such as asthma, hypertension, and diabetes [25–27]. Proponents of these direct provider-to-patient communication strategies (via telephone or in person) point to the flexibility of these strategies to reach the individual patient and tailor the intervention to each patient’s specific needs and barriers to adherence. Detractors question the feasibility and sustainability of these interventions on a larger scale because each of these studies involved small numbers of patients and required development of a strong infrastructure and health care team to execute the intervention.
Societal/environmental factors Societal and environmental factors such as health policy aimed toward reducing barriers to care and community outreach efforts can affect patients’ attitudes toward medication regimens. Policy changes affording easier access to care and medications can remove barriers that often result in nonintentional adherence. National campaigns promoting disease awareness can impact patient attitudes and priorities around their conditions, positively influencing awareness [28] and recognition of time-sensitive conditions such as acute onset of myocardial infarction (MI) and stroke symptoms. It is as yet unknown if these campaigns to promote awareness translate to chronic disease recognition and management. In addition, pharmaceutical advertising campaigns on specific medications have shown positive effects on adherence [29–31], but effect sizes of these efforts are difficult to measure. Although advertising succeeds in reaching a broad audience of patients and
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providers alike, the effectiveness of the messages may be diminished because of the loss of personalization.
Value-based insurance design From a societal/environmental standpoint, value-based insurance plans have been tested to improve patient adherence. Proponents hold that insurance designed to promote use of evidence-based medication regimens through economic rewards (monetary rebates or incentives) can increase adherence through both improved patient access to care (nonintentional adherence) and decreasing costs of prescription medications (intentional adherence). The Full Coverage for Preventative Medications after Myocardial Infarction (MI-FREEE) trial evaluated the effect of a value-based plan for post-MI prescription medications [32]. The investigators randomized 5855 patients following hospital discharge for MI to either full prescription coverage for indicated medications [statin, beta blocker, ACE-I or angiotensin receptor blocker (ARB)] compared with standard insurance plan coverage. The primary outcome in MI-FREEE was unique in that it sought to evaluate “hard” endpoints of cardiovascular events in addition to measuring adherence rates. Full prescription coverage increased adherence by approximately 5 %, but overall cardiovascular events did not significantly differ. A cost analysis did not find a significant change between overall health care costs between full coverage and usual coverage patients.
Interventions aimed at multiple domains Interventions to date have been mainly designed to target specific factors such as patients, providers, or societal/environmental factors. These interventions have resulted in modest improvements in adherence. Given that an individual’s nonadherence may be due to multiple reasons that very likely change over time, interventions targeting multiple factors could be more effective in a synergistic fashion. As such, investigators have started to develop multidisciplinary and multifaceted approaches to cover multiple domains known to impact adherence.
A multifaceted approach In four centers, 253 patients discharged after hospitalization for ACS were randomized to a multifaceted intervention to improve adherence vs usual care [33]. The intervention was directed toward providers and patients, providing follow-up beyond that of usual care. Each patient received education about cardiovascular medications at hospital discharge, as well as postdischarge education through communication with the study pharmacist. In addition, automated voice messages were left at regularly scheduled intervals to both remind patients to take their medications, as well as to remind them of when their medications needed to be refilled. On the provider level, pharmacists who were part of the research team met with patients within 7 10 days of discharge to address adverse effects and to perform medication reconciliation. In addition, they provided pillboxes if needed and discussed
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Curr Treat Options Cardio Med (2014) 16:349 strategies to improve adherence. A second pharmacist-patient interaction occurred at 1 month to further discuss any medication issues and to synchronize cardiac medication refill dates as much as possible to promote ease of refills. Pharmacists also contacted the patients’ primary care physicians and cardiologists on enrollment, leaving contact information to facilitate communication regarding any questions on the medication regimen. The intervention demonstrated a significant benefit in adherence, with an absolute increase in adherence of 15.4 % (89.3 % vs 72.9 %, P=0.003), however, secondary outcomes of achieving lipid and blood pressure goals for cardiovascular risk reduction were not statistically significant between groups. In addition, there were no differences in clinical outcomes of MI, death, or revascularization. Cost analysis did not reveal any significant differences for inpatient, outpatient, medication, or total costs between treatment arms. This multifactorial approach, despite a high baseline adherence rate in the usual treatment arm, displayed one of the most significant increases in adherence amongst secondary prevention CVD patients to date.
The polypill, or fixed-dose combination therapy Polypharmacy with its associated medication costs, and potential dosing complexity can lead to medication nonadherence. To address the issue of polypharmacy, the “polypill,” also known as fixed-dose combination (FDC) therapy was developed. Investigators hypothesized that use of a single polypill could help overcome intentional and nonintentional adherence barriers alike through lowering cost and easing administration as patients would only need to take a single pill once each day. By providing the pill free of cost to study participants (vs patients with usual care being subject to standard fees), investigators also targeted a societal and environmental barrier. The Effects of a Fixed Dose Combination Strategy on Adherence and Risk Factors in Patients with or at High Risk of CVD (UMPIRE) Trial evaluated the use of such a pill (combination of aspirin, simvastatin, lisinopril and atenolol or aspirin, simvastatin, lisinopril and hydrochlorothiazide) in 2004 among patients with either established CVD or elevated 5-year CVD risk, as compared to usual care [34•]. Investigators assessed self-reported adherence, as well as changes from baseline in systolic blood pressure and low-density lipoprotein cholesterol. The study demonstrated significantly improved adherence in the FDC arm compared with usual care (86 % vs 65 %, PG0.001) with small but statistically significant absolute reductions in the other coprimary endpoints of change in systolic blood pressure (–2.6 mm Hg, P= 0.0005) and low-density lipoprotein cholesterol (–4.2 mg/dL, P=0.0005). Cardiovascular events were nonsignificantly greater in the FDC group (50 events vs 35 in usual therapy), although the study was not powered to detect a difference between groups. FDC therapy demonstrated the greatest improvement in medication adherence among patients who were nonadherent prior to study enrollment (77.2 % compared with 23.1 % with standard care; PG0.01). Investigators concluded that FDC therapy demonstrated significant improvements in medication adherence, and suggested that targeted use of FDC therapy among nonadherent patients may result in greater improvements in the surrogate and clinical outcomes. Critics of the FDC hypothesis
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shared concerns about the tradeoff of achieving adherence while losing the ability to tailor therapies to a specific patient.
Future directions Adherence to cardioprotective medications has been associated with decreased risk of adverse cardiovascular events. The majority of interventions tested to date have demonstrated modest improvements. That said, prior studies targeting individual adherence barriers have shown significant improvement in subgroups of patients with poor baseline adherence, suggesting that a targeted approach would potentially be the most beneficial. More successful recent interventions have been multifaceted in nature, targeting provider, social/environmental, and patient barriers [33, 34•; Fig. 1]. It is possible that the most effective of interventions would be a multimodal, patient, and team-based intervention that is appropriately targeted to those patients who are already nonadherent at enrollment. Nonadherence is a nuanced entity, and patients differ greatly in their barriers to following their prescribed regimens. Not only do they differ from each other, but they can also differ in their own rationale over time, as a patient’s circumstances evolve. What may have begun as forgetfulness and poor understanding of their disease process may evolve into monetary constraints as environmental and societal pressures take hold, or prescription coverage changes. This adds a layer of complexity to the concept of a targeted strategy for adherence interventions, as the target is constantly moving and evolving. The optimal approach to patient nonadherence may be the development of a “toolbox” of strategies that can address poor adherence and that can be accessed to match the patient’s current
SOCIETAL/ ENVIRONMENTAL
PATIENT Intentional
PROVIDER
NonIntentional
UMPIRE (Fixed Dose Combination therapy): 21% improvement in adherence
Ho et al. (Provider-patient communication, regimen simplification, counseling): 15.4% improvement in adherence
MI-FREEE (Value-based insurance design): 5% increase in adherence
Kimmel et al (Lottery incentives): 2.9% improvement (NS)*
Nurse-led Counseling (Provider-patient communication): 5% increase in adherence
Educational mailings: 5% increase in adherence
*NS = statistically non-significant
Fig. 1. Intervention effects by targeted adherence barriers.
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Curr Treat Options Cardio Med (2014) 16:349 needs. From the literature, educational, patient incentive, fixed dose combination therapy, value-based, and provider-level interventions have demonstrated benefit. In the future, adherence research should test these interventions as part of a toolbox, specifically targeting nonadherent patients and matching the intervention to their needs. In order to identify the appropriate adherence intervention for a specific patient, it would be helpful to develop a validated tool to identify the most likely causes for nonadherence. Depending on the identified cause for nonadherence, the strategies within the toolbox could be employed for the patient to help them with their specific adherence barrier. This would allow for targeting of specific interventions to an individual’s reasons for nonadherence, allowing for more individualization of an intervention and possibly increase efficiency. Another consistent theme throughout adherence literature, and seen in the reviewed trials [16, 24–28, 34•] is that of ongoing and increased provider-patient communication. Given advances in telecommunications and the internet, communication between individuals has never been easier, whether via telephone, email, text message, or webbased interface. Although limited in evaluation, mobile phone messaging has been associated with some benefit in chronic illness management [35]. An optimal approach to the incorporation of this new technology in medication adherence remains unknown, but mobile technology may be a powerful tool to include in the “toolbox.”
Conclusions Optimizing medication adherence is a critically important component toward the care of patients following a recent hospitalization as well as those with chronic illnesses. Following acute coronary syndrome hospitalization, there is an abundance of data that have demonstrated an association between poor medication adherence and adverse cardiovascular outcomes. Interventions to improve adherence to date have been more successful when specifically targeting patients who are nonadherent at baseline, and when developed as a multimodal and multifaceted approach. Further steps to improve medication adherence will likely require improved methods of identifying nonadherent patients and tailoring the interventions to meet individual patient needs, particularly as these needs may evolve over time.
Compliance with Ethics Guidelines Conflict of Interest Dr. Javier A. Valle and Dr. P. Michael Ho each declare no potential conflicts of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
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References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1.••
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