Therapy-related strategies to improve adherence to cardiovascular medications



by S. Rasheeqa Ismail, Malaysia; S. Tsoli and R. Chowdhury, United Kingdom

Rajiv CHOWDHURY, PhD, FESC
Department of Public Health and
Primary Care, University of
Cambridge, Cambridge
UNITED KINGDOM
Sophia RASHEEQA ISMAIL
MBBS, MSc
Diabetes & Endocrine Unit
Cardiovascular, Diabetes
& Nutrition Research Centre
Institute for Medical Research
MALAYSIA
Stergiani TSOLI, MPhil
Department of Population Health
Faculty of Epidemiology and
Population Health, London School
of Hygiene and Tropical Medicine
UNITED KINGDOM




Objective: To determine the efficacy of various therapy-related strategies in improving adherence to cardiovascular disease (CVD) medications. Design: Systematic review and meta-analysis of prospective interventional studies. Data sources: Medline, Embase, and Cochrane electronic databases, supplemented by a search of the reference lists of relevant studies. Study selection: Randomized controlled trials in adults (age >18 years) on existing CVD medications (antihypertensives, antiplatelets, or statins) that evaluated the effects of three key therapy-related strategies (ie, those related to education and support, technology, and the use of combination pills) on subsequent changes in medication adherence compared with usual care or equivalent. Data extraction and analysis: Two investigators extracted data and a consensus was reached with involvement of a third. Study-specific effect estimates were combined using random-effects meta-analysis. For the studies that could not be quantitatively synthesized, a systematic narrative review was performed. Results: Of the 2383 unique citations retrieved following the initial screening, a total of 27 articles met our inclusion criteria. In these studies, a wide range of interventions was evaluated for each key therapy-related strategy. The included studies vary widely in efficacy and overall quality. Nonetheless, in aggregate, education and support programs increased adherence to nonspecific CVD medications for both short-term (6 months) and longer-term (12 months) interventions. Overall, these strategies were equally effective for improving adherence to specific CVD medications such as statin or clopidogrel, when taken alone. Similarly, technology-based programs as well as the use of fixed-combination pills also improved adherence to CVD medications significantly. Nonetheless, the overall number of trials available for each of these strategies and their quality were generally inadequate. Conclusion: The findings of this review indicate that several therapy-related strategies may significantly improve medication adherence. However, there are significant differences across all types of interventions such as education and support, technology-based interventions, and fixed-combination pills. Since the overall quality and extent of evidence was generally low, further trials are required to reliably quantify the effects of these diverse interventions.

Introduction

Rising cardiovascular burden and lack of adherence to medications
The death and disability burden of cardiovascular diseases (CVD) has increased rapidly worldwide in the past few decades, emphasizing the need to develop effective primary and secondary prevention strategies to halt such rising trends. Meta-analyses of global intervention data have consistently demonstrated that pharmacological interventions with antihypertensives, aspirin, and statins are able to reduce major CVD outcomes and associated premature mortality.1-3 However, as the level of adherence to these CVD medications is generally low,4 optimal measures to improve adherence are essential for maximizing the potential benefit of these therapeutic agents.

Lack of adherence and associated impact on clinical consequences
Adherence is defined as “the extent to which a person’s behavior— taking medication, following a diet, and/or executing lifestyle changes—corresponds with agreed recommendations from a health care provider.”5 Adherence should not be confused with compliance, as the latter lacks the agreement from the patient to the recommendations given.5 Adherence is a complex behavioral process that results from the interplay of various factors, and therefore remains a challenge for health care providers.6 Worldwide, a substantial proportion of people do not adhere adequately to cardiovascular medications. Evidence suggests that good adherence is achieved in only 60% of patients on CVD medications.7 The prevalence of suboptimal adherence has been reported to be significantly high, irrespective of the type of CVD medication, and is on the rise.8,9 Suboptimal drug therapy, often resulting from a lack of adherence to essential CVD medications, leads to inadequate control of symptoms, and subsequently increases the risk of morbidity and mortality.10 The level of optimal adherence to CVD medications has been shown to have an inverse relationship with subsequent adverse CVD outcomes,7,11 with more adherent patients having a lower risk of developing future CVD than poorly adherent patients, for both statins and antihypertensives.

Objective of the present review
Several therapy-related measures can be used to improve adherence to CVD medications; however, they have rarely been systematically reviewed in a single, comprehensive investigation. To help evaluate these strategies, we have attempted to synthesize all available evidence to quantify the efficacy of different types of therapy-related strategies in improving adherence to various CVD medications.

Methods

Data sources, search strategy, and eligibility criteria
We systematically searched Medline, Embase, and Cochrane Central electronic databases to identify relevant published articles (date of last search: March 12, 2017). The computer based searches combined terms related to the medications (eg, antihypertensives, aspirin) and outcomes (eg, adherence, compliance), without any language restriction. Details of the search strategy are provided in Supplementary Table I (online only). We searched for studies that evaluated the effects of adherence-enhancing strategies compared with usual care or equivalent in adults (>18 years old) participants taking any CVD medications. CVD medications were defined as any class of antihypertensive medications, antithrombotics, and statins frequently used for secondary prevention of CVD.

Study selection
We included randomized controlled trials that (i) followed participants prospectively, (ii) evaluated various interventions that provided education and support programs, used technology or combination pills to promote medication adherence, and (iii) had assessed medication adherence using a validated measurement tool. Direct measurement tools were defined as directly observed therapy and measurement of the level of medicines, metabolites, or biologic markers in the blood. Indirect measurement tools were defined as patient questionnaires, self-reports, pill counts, rates of prescription refills, and electronic medication monitors.12 Two independent reviewers screened the titles and abstracts of all identified articles against the inclusion criteria. Full texts were retrieved for articles that satisfied all the selection criteria. The reference lists of the selected articles and relevant reviews identified on the topic were searched for additional publications.

Data extraction
A predesigned data extraction form was used to extract relevant information. Two reviewers piloted the data extraction form for a sample of the included papers until an agreement was reached among reviewers. Extracted data included information on study size, study design, baseline population, country of study, duration of follow-up, type(s) of CVD medications used, description of interventions and control, frequency of interventions, medication adherence scale, definitions of good adherence, and adherence levels. When available, effects of good adherence—such as changes in systolic blood pressure, low-density lipoprotein, and total cholesterol—were obtained.

Data synthesis and analysis
To enable a consistent approach to the meta-analysis and interpretation of findings in this review, effect estimates (expressed as relative risk, RR) for subsequent changes in medication adherence were based on the proportion of participants with good adherence (≥80% adherence), irrespective of the measurement tool used. This proportion is the most widely accepted and reported cut-off for optimum adherence.7,13 Summary RRs were calculated by pooling the study-specific estimates using a random-effects meta-analysis that allows for between-study heterogeneity. All statistical tests were two- sided and used a significance level of 0.05. Analyses were performed using the statistical package Review Manager and STATA release11 (StataCorp, College Station, TX, USA). Where appropriate, a narrative review of the included studies was performed when quantitative synthesis could not be done due to either significant heterogeneity or unavailability of the relevant data.


Figure 1. Search strategy for the included studies.




Assessing the risk of bias and quality of evidence
We used the Cochrane Collaboration tool to assess the risk of bias in the included studies.14 This tool evaluates seven possible sources of bias: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other bias.

We assessed the quality of evidence of our two main outcomes using the GRADE Working Group framework (Grading of Recommendations, Assessment, Development and Evaluation Working Group). Quality assessment was based on five factors: risk of bias across all studies; indirectness, interventions, and outcomes; outcome reporting; inconsistency among studies; imprecision; and publication bias. The presence of publication bias was assessed using funnel plots, plotting precision against the effect size. Egger’s test was used to quantify asymmetry.15

Results

Studies identified
Our search strategy retrieved 2383 unique citations. Following the initial screening based on titles and abstracts, 421 articles remained for further evaluation. Of these articles, 394 were excluded in the subsequent detailed assessments for reasons shown in Figure 1 or if full texts were not available. The remaining 27 articles that met our inclusion criteria were finally included in the review. Out of these, 14 studies were included in the quantitative synthesis part of our review, which, in aggregate, comprised of 7725 unique individuals.

Adherence achieved by interventions related to education and support
There were 19 studies that evaluated the effects of various education and support strategies. These studies and their individual results are summarized in Table I. The interventions included various pharmacist-, nurse-, and community worker– led programs. Overall, there was a large variability in the methods used, frequency of interventions, and duration of interventions. The interventions were led by pharmacists, nurses, and community health workers, or a combination of them. Interventions were offered for either 6 months or 12 months, with varying frequencies (minimum once, maximum 2 times throughout the study period). The most important components in these interventions were education and behavioral counseling. Out of the 19 articles, 11 did not have a baseline adherence measurement to compare the before and after effects of the interventions. All the articles used usual care as a comparator, except for 4 articles16-19 that added education leaflets or DVDs to the usual care. Differences in the levels of good adherence between the intervention and control arms were more pronounced for interventions lasting 12 months than for those lasting 6 months.

Out of the 19 studies, only 11 articles could be combined in the meta-analysis. We evaluated the overall differences between the two treatment arms for education and support strategies at 6 and 12 months for nonspecific CVD medications (Figure 2 and Figure 3, respectively, page 284). Participants receiving adherence-enhancing education and support programs for 6 months were 1.35 times more likely to achieve good adherence to their CVD medications than those undergoing usual care (6 studies20-25; 1064 participants, RR, 1.35; 95% CI,1.0-1.67; I2=89%; Figure 2). Patients receiving education and support programs to enhance adherence for 12 months were 1.11 times more likely to be adherent to their CVD medications than those receiving usual care (5 studies17,19,26- 28; 3521 participants, RR, 1.11; 95% CI, 1.03-1.21, I2=83%; Figure 3).



Table I. Findings from education and support programs.




Figure 2.
Good adherence
to
educational
and support
strategies
for nonspecific
cardiovascular
medications
at 6 months.




Figure 3.
Good adherence
to
educational
& support
strategies
for non-specific
CVD
medications
at 12
months.




Table II. Findings from technology-based programs.




For adherence to specific CVD medications, while interventions that aimed to improve statin intake were not effective at 6 months, a more significant improvement in adherence was achieved at 12 months (2 studies17,27; 1317 participants; RR, 1.21; 95% CI, 1.05-1.39; I2=72%). There were also a few studies that evaluated adherence to clopidogrel. Education and support strategies, albeit based on 2 trials,16,27 appeared to increase clopidogrel adherence significantly (573 participants; RR, 1.26; 95% CI, 1.11-1.42; I2=0%).

Adherence achieved by technology-based interventions
Three articles were included in the technology group, with none combined for a meta-analysis. The findings from these studies are summarized in Table II. In general, the interventions were mobile phone–based, and consisted of either automated text messages or phone calls. The frequencies of intervention were also highly variable, ranging from once to 52 times during the study period. As the duration of interventions also varied, we were not able to combine the studies to measure a pooled effect of the interventions in a consistent way. However, when the trial results were appraised individually, there appeared to be significant improvements in adherence between the intervention and control arms within each of the included trials.

Adherence achieved by using fixed-dose combination pills
Five trials were identified that sought to evaluate the effects of fixed-dose combination pills use on improving medication adherence (with only 3 available for quantitative synthesis). Their findings are summarized in Supplementary Table II (online only).

In these studies, a fixed-dose combination pill typically contained an angiotensin-converting enzyme inhibitor, an antiplatelet agent, a statin, and either a thiazide diuretic or a β-blocker. A significant overall benefit on adherence was observed with a longer duration of intervention. The use of fixed-dose combination pills did not improve the adherence significantly in the short term (3 months), but appeared to confer significant improvements in medication adherence at 9 months (1 study29; P=0.019) and at 12 months after the intervention (3 studies30-32; 3140 participants;1989 good adherence events; RR, 1.44; 95%CI, 1.20-1.72; I2=83%) (Figure 4, page 285). Nonetheless, the quality of evidence for the use of fixed-dose combination pills for CVD medication adherence was generally low (Table II).


Figure 4.
Good adherence
to
educational
& support
strategies
for nonspecific
CVD
medications
at 12
months.




Assessments of study quality and risk of bias
Only 5 out of the 27 studies included reported a low risk of bias in all 5 domains (Supplementary Table III, online only). The highest risk of bias was reported in 9 out of the 27 included studies. We constructed funnel plots to assess the publication bias of the included studies in the quantitative analysis (Supplementary Figure 1, online only). P values in the Egger’s asymmetry test involving studies that evaluated education and support strategies in relation to CVD medication adherence were 0.17 at 6 months, and 0.46 at 12 months, respectively. We evaluated the overall quality of evidence and presented it in the form of a “summary of findings” table. The quality of evidence for education and support interventions at 6 and 12 months were both graded as very low (Table III).

Discussion

Summary of the key findings
The findings of this review indicate that therapy-related strategies to improve adherence in patients taking CVD medications show a moderate—though significant—benefit. However, significant differences in medication adherence were observed across all types of interventions: education and support, technology- based, and fixed-combination pills. The quality of the evidence reported for education and support as well as polypill strategies was generally very low.


Table III. GRADE Summary of findings table for therapy-related strategies for cardiovascular medication adherence.




Comparison with other reviews
The combination of educational and behavioral strategies has been recommended to ensure persistence of adherence.33,34 There are three aspects of medication administration that are involved in adherence: initiation of the prescribed medication, implementation of the dosing regimen, and discontinuation of the medication.35 The various aspects of medication adherence are strongly influenced by the behavior of the patient. Among the many behavioral change strategies and techniques, motivational interviewing is often administered as a strategy to improve adherence. However, motivational interviewing alone results in a fairly modest improvement in medication adherence.36,37 When looking at individual CVD medication classes, the highest effect size was seen in antithrombotics (2 studies; 387 participants; RR, 2.32; 95% CI, 1.18-4.56), antihypertensives (6 studies; 1362 participants; RR, 2.21; 95% CI, 1.63-2.98) followed by lipid-lowering medications (3 studies; 404 participants; RR, 2.11; 95% CI, 1.00-4.46).38 Even though there is no strong evidence of the effectiveness of using text messaging systems to improve adherence to CVD medications, text messaging has been reported to double the level of medication adherence in chronic diseases.39

The European Society of Cardiology recommends simplifying treatment regimens to the lowest acceptable level, with repetitive monitoring and feedback.33 The dosage and number of medications are often automatically increased when there is failure to control symptoms, but this only worsens the rate of nonadherence. Therefore, using fixed-dose combination pills is a potentially useful strategy to improve medication adherence, especially in patients on multiple medications. The use of combination pills has showed a 50%-60% cumulative risk reduction.40 In a meta-analysis of 32 studies, patients taking twice-daily medications had a 7%-22.6% lower adherence than those on once-daily medications.41 Simplifying dosing regimens can increase the likelihood of adherence between 8% and 19.6%.34

Strength and limitations
The strengths and limitations of this review merit careful consideration. Although we performed an extensive search and systematic synthesis of available evidence by including data from different sources of evidence, there were insufficient numbers of trials for each of the intervention subtypes to meaningfully compare their effects on medication adherence. Additionally, the quality of evidence was limited by the variability of the measurement tools used in the different studies, the indirectness of the methods of adherence assessment, diversity in the components of interventions, and a general insufficiency of high-quality randomized controlled trials. The absence of baseline adherence data in half of the included studies also limited our ability to draw conclusions on the magnitude of change attributed to the intervention.

There is a need for larger-scale and higher-quality studies to assess the efficacy of these methods to improve adherence to CVD medications. Future studies should not only explore medication adherence but also medication persistence, and the period of follow-up should, therefore, be planned accordingly.

Conclusion

Adherence to cardiovascular medications is an important component of patient management. Different types of strategies such as education and support, technology, and fixed-dose combination pills, are available but should be tailored to the needs of individual patients. Adherence is a complex and dynamic process; it is, therefore, important for the treating team to thoroughly explore the reasons behind nonadherence and subsequently implement strategies that meet the specific needs of the individual patient. ■


Acknowlegements. The authors would like to thank the Department of Public Health & Primary Care at the University of Cambridge and the Director General Of Health Malaysia.


References
1. Law MR, Morris JK, Wald NJ. Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies. BMJ (Clinical research ed). 2009;338:b1665.
2. Baigent C, Blackwell L, Collins R, et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet. 2009;373(9678):1849-1860.
3. Baigent C, Blackwell L, Emberson J, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376(9753):1670-1681.
4. Abegaz TM, Shehab A, Gebreyohannes EA, Bhagavathula AS, Elnour AA. Nonadherence to antihypertensive drugs: A systematic review and meta-analysis. Medicine. 2017;96(4):e5641.
5. Adherence to Long-Term Therapies: Evidence for action. World Health Organisation; 2003.
6. Tajouri TH, Driver SL, Holmes DR, Jr. ‘Take as directed’—strategies to improve adherence to cardiac medication. Nat Rev Cardiol. 2014;11(5):304-307.
7. Chowdhury R, Khan H, Heydon E, et al. Adherence to cardiovascular therapy: a meta-analysis of prevalence and clinical consequences. Eur Heart J. 2013; 34(38):2940-2948.
8. Chen HY, Saczynski JS, Lapane KL, Kiefe CI, Goldberg RJ. Adherence to evidence- based secondary prevention pharmacotherapy in patients after an acute coronary syndrome: A systematic review. Heart Lung. 2015;44(4):299- 308.
9. Turin A, Pandit J, Stone NJ. Statins and Nonadherence. J Cardiovasc Pharmacol Ther. 2015;20(5):447-456.
10. Al-Ganmi AH, Perry L, Gholizadeh L, Alotaibi AM. Cardiovascular medication adherence among patients with cardiac disease: a systematic review. J Adv Nurs. 2016;72(12):3001-3014.
11. Allonen J, Nieminen MS, Lokki M, et al. Mortality rate increases steeply with nonadherence to statin therapy in patients with acute coronary syndrome. Clin Cardiol. 2012;35(11):E22-E27.
12. Osterberg L, Blaschke T. Adherence to medication. New Engl J Med. 2005; 353(5):487-497.
13. Ho PM, Bryson CL, Rumsfeld JS. Medication Adherence. Its Importance in Cardiovascular Outcomes. Circulation. 2009;119(23):3028-3035.
14. Higgins JP, Altman DG, Gotzsche PC, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928.
15. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315(7109):629-634.
16. Palacio AM, Uribe C, Hazel-Fernandez L, et al. Can Phone-based motivational interviewing improve medication adherence to antiplatelet medications after a coronary stent among racial minorities? A Randomized Trial. J Gen Intern Med. 2015 Apr;30(4):469-475.
17. Doshi JA, Lim R, Li P, et al. A synchronized prescription refill program improved medication adherence. Health Aff (Millwood). 2016;35(8):1504-1512.
18. Adeyemo A, Tayo B, Luke A, Ogedegbe O, Durazo-Arvizu R, Cooper R. The Nigerian antihypertensive adherence trial: a community-based randomized trial. J Hypertens. 2013;31(1):201-207.
19. Keyserling TC, Sheridan SL, Draeger LB, et al. A comparison of live counseling with a web-based lifestyle and medication intervention to reduce coronary heart disease risk: a randomized clinical trial. JAMA Intern Med. 2014;174(7):1144- 1157.
20. Bisharat B, Hafi L, Baron-Epel O, Armaly Z, Bowirrat A. Pharmacist counseling to cardiac patients in Israel prior to discharge from hospital contribute to increasing patient’s medication adherence closing gaps and improving outcomes. J Transl Med. 2012;10:34.
21. Damush TM, Myers L, Anderson JA, et al. The effect of a locally adapted, secondary stroke risk factor self-management program on medication adherence among veterans with stroke/TIA. Transl Behav Med. 2016;6(3):457-468.
22. Fikri-Benbrahim N, Faus M, Martínez-Martínez F, Sabater-Hernández D. Impact of a community pharmacists’ hypertension-care service on medication adherence. The AFenPA study. Res Social Adm Pharm. 2013;9(6):797-805.
23. Lee JK, Grace KA, Taylor AJ. Effect of a pharmacy care program on medication adherence and persistence, blood pressure, and low-density lipoprotein cholesterol: A randomized controlled trial. JAMA. 2006;296(21):2563-2571.
24. Sookaneknun P, Richards RME, Sanguansermsri J, Teerasut C. Pharmacist Involvement in Primary Care Improves Hypertensive Patient Clinical Outcomes. Ann Pharmacother. 2004;38(12):2023-2028.
25. Wald DS, Bestwick JP, Raiman L, Brendell R, Wald NJ. Randomised trial of text messaging on adherence to cardiovascular preventive treatment (INTERACT Trial). PloS One. 2014;9(12):e114268.
26. Garcia BH, Giverhaug T, Hogli JU, Skjold F, Smabrekke L. A pharmacist-led follow-up program for patients with established coronary heart disease in North Norway—A randomized controlled trial. Pharm Pract. 2015;13(2):1-10.
27. Ho P, Lambert-Kerzner A, Carey E, et al. Multifaceted intervention to improve medication adherence and secondary prevention measures after acute coronary syndrome hospital discharge: a randomized clinical trial. JAMA Intern Med. 2014;174(2):186-193.
28. Xavier D, Gupta R, Kamath D, et al. Community health worker-based intervention for adherence to drugs and lifestyle change after acute coronary syndrome: a multicentre, open, randomised controlled trial. Lancet Diabetes Endocrinol. 2016;4(3):244-253.
29. Castellano J, Sanz G, Peñalvo J, et al. A polypill strategy to improve adherence: results from the FOCUS project. J Am Coll Cardiol. 2014;64(20):2071-2082.
30. Patel A, Cass A, Peiris D, et al. A pragmatic randomized trial of a polypill-based strategy to improve use of indicated preventive treatments in people at high cardiovascular disease risk. Eur J Prev Cardiol. 2015;22(7):920-930.
31. Selak V, Elley C, Bullen C, et al. Effect of fixed dose combination treatment on adherence and risk factor control among patients at high risk of cardiovascular disease: randomised controlled trial in primary care. BMJ. 2014;348:g3318.
32. Thom S, Poulter N, Field J, et al. Effects of a fixed-dose 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):918-929.
33. Piepoli MF, Hoes AW, Agewall S, et al. 2016 European Guideline on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts)Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J. 2016;37(29):2315-2381.
34. Schroeder K, Fahey T, Ebrahim S. How can we improve adherence to blood pressure-lowering medication in ambulatory care? Systematic review of randomized controlled trials. Arch Intern Med. 2004;164(7):722-732.
35. Rash JA, Lavoie KL, Feldman RD, Campbell TS. Adherence to Antihypertensive Medications: Current Status and Future Directions. Curr Cardiovasc Risk Rep. 2014;8(12):1-13.
36. Ogedegbe GO, Boutin-Foster C, Wells MT, et al. A randomized controlled trial of positive-affect intervention and medication adherence in hypertensive african americans. Arch Intern Med. 2012;172(4):322-326.
37. Hedegaard U, Kjeldsen LJ, Pottegard A, et al. Improving Medication Adherence in Patients with Hypertension: A Randomized Trial. Am J Med. 2015;128(12): 1351-1361.
38. Al AlShaikh S, Quinn T, Dunn W, Walters M, Dawson J. Multimodal Interventions to Enhance Adherence to Secondary Preventive Medication after Stroke: A Systematic Review and Meta-Analyses. Cardiovasc Ther. 2016;34(2):85-93.
39. Thakkar J, Kurup R, Laba TL, et al. Mobile Telephone Text Messaging for Medication Adherence in Chronic Disease: A Meta-analysis. JAMA Intern Med. 2016;176(3):340-349.
40. Yusuf S, Amir A, Jackie B, et al. Combination pharmacotherapy to prevent cardiovascular disease: Present status and challenges. Eur Heart J. 2014;35(6): 353-364.
41. Weeda E, Sobieraj D, McHorney C, Crivera C, Schein J, Coleman C. Impact of dosing frequency on adherence to chronic cardiovascular medications: a metaregression analysis. J Am Coll Cardiol. 2016;67(13, Supplement):1886.
42. Svarstad BL, Kotchen JM, Shireman TI, et al. Improving refill adherence and hypertension control in black patients: Wisconsin TEAM trial. J Am Pharm Assoc. 2013;53(5):520-529.
43. Robinson JD, Segal R, Lopez LM, Doty RE. Impact of a pharmaceutical care intervention on blood pressure control in a chain pharmacy practice. Ann Pharmacother. 2010;44(1):88-96.
44. Eussen S, Elst M, Klungel O, et al. A pharmaceutical care program to improve adherence to statin therapy: a randomized controlled trial. Ann Pharmacother. 2010;44(12):1905-1913.
45. Park H, Adeyemi A, Wang W, Roane TE. Impact of a telephonic outreach program on medication adherence in Medicare Advantage Prescription Drug (MAPD) plan beneficiaries. J Am Pharm Assoc. 2017;57(1):62-66.e62.
46. Amado GE, Pujol RE, Pacheco HV, Borras J. Knowledge and adherence to antihypertensive therapy in primary care: results of a randomized trial. Gac Sanit. 2011;25(1):62-67.
47. Goswami NJ, DeKoven M, Kuznik A, et al. Impact of an integrated intervention program on atorvastatin adherence: A randomized controlled trial. Int J Gen Med. 2013;6:647-655.
48. Kim KB, Han HR, Huh B, Nguyen T, Lee H, Kim MT. The effect of a communitybased self-help multimodal behavioral intervention in Korean American seniors with high blood pressure. Am J Hypertens. 2014;27(9):1199-1208.
49. Bobrow K, Farmer AJ, Springer D, et al. Mobile Phone Text Messages to Support Treatment Adherence in Adults With High Blood Pressure (SMS-Text Adherence Support [StAR]): A Single-Blind, Randomized Trial. Circulation. 2016; 133(6):592-600.
50. Derose S, Green K, Marrett E, et al. Automated outreach to increase primary adherence to cholesterol-lowering medications. JAMA Intern Med. 2013;173 (1):38-43.
51. PILL Collaborative Group; Rodgers A, Patel A, Berwanger O, et al. An international randomised placebo-controlled trial of a four-component combination pill (“polypill”) in people with raised cardiovascular risk. PloS One. 2011;6:e19857.


Keywords: adherence; cardiovascular disease; fixed-combination pill; therapy-related strategy