Modes of Delivery for Interventions to Improve Cardiovascular Medication Adherence

Objective:

To determine the optimal modes of delivery for interventions to improve adherence to cardiovascular medications.

Study Design:

Systematic review.

Methods:

We conducted systematic searches of English-language, peer-reviewed publications in MEDLINE and EMBASE, 1966 through December 31, 2008. We selected randomized controlled trials of interventions to improve adherence to medications for preventing or treating cardiovascular disease or diabetes. Articles were classified based on mode of delivery of the main intervention as (1) person-independent interventions (mailed, faxed, or hand distributed; or delivered via electronic interface) or (2) person-dependent interventions (nonautomated phone calls, in-person interventions).

Results:

We identified 6550 articles. Of these, 168 were reviewed in full and 51 met inclusion criteria. Among person-independent interventions (56% successful), electronic interventions were most successful (67%). Among person-dependent interventions (52% successful), phone calls showed low success rates (38%). In-person interventions at hospital discharge were more effective (67%) than clinic interventions (47%). In-person pharmacist interventions were effective when held in a pharmacy (83% successful), but were less effective in clinics (38%).

Conclusions:

Future medication adherence studies should explore new electronic approaches and in-person interventions at the site of medication distribution. Identifying times of increased patient receptivity to the adherence message such as hospital discharge also will be important.

(Am J Manag Care. 2010;16(12):929-942)

Interventions designed to improve adherence to cardiovascular medications may require a person to deliver them (in-person counseling, phone calls), or the delivery may be person independent (mailed information, electronic interface). The mode of delivery directly affects cost and long-term viability.

• Among person-independent interventions, we found electronic approaches to be most effective at improving adherence.

• For interventions delivered by a person, we found high success rates for in-person interventions delivered at a pharmacy or at the time of hospital discharge.

Nonadherence to essential chronic medication therapy for cardiovascular disease and diabetes is common, leading to substantial morbidity, mortality, and healthcare costs.^1-3 Evidence- based efforts to improve adherence are needed. Previous studies have demonstrated the effectiveness of reduced dosing demands and complex, multifactorial interventions,^4,5 but there is little evidence available comparing modes of delivery for adherence interventions.

Evidence-based information on modes of delivery would enhance the construction of adherence interventions in several domains: the communication channel (eg, written, electronic, phone, in person), the purveyor of information (eg, lay person, pharmacist, physician), and the optimal setting (hospital, home, pharmacy, clinic). The mode of delivery is closely linked to an intervention’s cost and therefore to its long-term viability. Careful consideration of the comparative efficacy and intensity of different approaches is needed to develop evidence-based strategies.

We conducted a systematic review of interventions that sought to improve adherence to medications for cardiovascular disease and diabetes, a cardiovascular disease equivalent. We focused on the mechanism of information transfer to patients. By evaluating the effects of (1) the purveyor of information, (2) the channel of information, and (3) the setting of transfer, we offer to payers, providers, and policy makers additional guidance on the development of adherence interventions.

METHODS

We performed a systematic search of articles published in peer-reviewed, healthcare-related journals between 1966 and December 31, 2008. The search was performed using MEDLINE and EMBASE, with the help of a professional librarian. We limited our search to randomized controlled trials.

eAppendix

We used search terms related to the type of study (randomized controlled trial), adherence (ie, “adherence” OR “compliance” OR “medication adherence” or “treatment adherence”), prescription drugs (ie, “drug” OR “medication” OR “antihypertensive” OR “antihyperlipidemic” OR “hypoglycemic agents”), and cardiovascular disease and diabetes (myocardial infarction, coronary heart disease, heart failure; hypertension; hyperlipidemia; and diabetes). Articles with at least 1 search term in 3 of the main categories (study type AND adherence AND either drug OR disease) met criteria for the title/abstract review (see the at www.ajmc.com).

Search terms and parameters were adjusted for both databases while maintaining a common overall architecture. Search results from MEDLINE and EMBASE were combined and screened for duplicate entries.

Study Selection

Studies were included if they reported the results of randomized controlled trials that examined interventions to improve adherence to medications used for the prevention or treatment of cardiovascular disease or diabetes. Studies were limited to adult subjects (aged ≥18 years) in either the outpatient setting or at the inpatient/ outpatient transition. Data were gathered on outpatient adherence for all patients. Studies were excluded if they described an intervention characterized by regimen simplification (either unit-of-use packaging or changes in dose frequency or formulation), as they could not be placed into the study categorization, and previous studies have demonstrated their effectiveness.⁴ Studies were excluded if they were written in a language other than English. Those with a duration of less than 24 weeks were excluded because cardiovascular medications typically require long-term adherence.

Figure

After exclusions, 51 articles () were classified by the mode of delivery of the intervention. Person-independent interventions included (1) mailed, faxed, or hand-distributed interventions and (2) interventions delivered via electronic system. Person-dependent interventions included (1) interventions delivered via nonautomated phone calls and (2) in-person interventions (classified based on site of delivery, ie, home, work site, pharmacy, clinic, or hospital). Persondependent interventions were further classified based on the level of training required of the person administering the intervention: (1) trained lay person, (2) nurse, (3) pharmacist, (4) physician, or (5) not specified.

For those studies that incorporated 2 or more modes of intervention, we assigned categories based on what appeared to be the main mode of intervention. Where categories appeared to be equivalent, we assigned priority in the following order: person dependent (in person, followed by phone) and person independent (electronic system, followed by mailed, faxed, or hand distributed).

Data Extraction

Data were extracted by 2 investigators (SLC, WHS) with disagreements resolved by consensus. We assessed a number of variables related to the organization and outcome of studies, including the study design, setting, characteristics of population studied, the number of participants, characteristics of intervention, methods used to measure medication adherence, clinical outcomes, and medication adherence outcomes. We report confidence intervals (CIs) when available and P values when no CIs were available.

RESULTS

Table 1

Table 2

Our search retrieved a total of 6550 articles. Of these articles, 168 were reviewed in full and 51 met inclusion criteria^6-56 (Figure, , ). The majority (55%) of interventions were aimed at subjects with hypertension. Other patient populations studied included those with diabetes (8%), coronary artery disease (8%), congestive heart failure (14%), and dyslipidemia (10%); 6% of the studies evaluated patients with a mix of cardiovascular and noncardiovascular diseases.

Person-Independent Interventions: Mailed, Faxed, or Hand-Distributed Material

There were 3 studies^6-8 in which the main intervention was delivered via mail, fax, or hand distribution of paper or video information; 1 was successful.⁶ Smith et al followed 907 patients after discharge from a hospital stay for myocardial infarction; 2 letters sent to patients and to primary care providers describing the importance of beta-blocker use yielded improved adherence as measured by pharmacy claims data. Patients receiving mailings were 17% more likely to have 80% of days covered (relative risk = 1.17; 95% CI = 1.02, 1.29). The 2 unsuccessful studies described direct patient mailings of written information on hypertension⁷ or video information on 1 of 4 medications (2 blood pressure agents, an antihyperlidemic, and transdermal estrogen).⁸ Takala defined adherent patients as those still under treatment after 2 years,⁷ and Powell and Edgren studied mean medication possession ratios.⁸

Person-Independent Interventions: Electronic Systems

There were 6 studies^9-14 that examined a range of electronic interventions, including use of electronic pillboxes with programmable reminders, automated phone calls with interactive components, computer-generated individualized interventions, and home automatic blood pressure monitoring. Overall, this group included more positive studies than the mailed/faxed/hand-delivered group (4 out of 6 showed improved adherence).

Rosen et al¹⁴ studied 33 people with diabetes whose baseline adherence was less than 80%. This study tested use of electronic pill caps with a time display and programmable beeper compared with electronic pill caps alone. Participants with programmable beeper pill caps showed improved adherence (80% intervention vs 60% control; P = .017).

Friedman et al¹⁰ and Piette et al¹³ studied the effect of automated phone calls. Friedman and colleagues followed 299 hypertensive patients, randomizing patients to an interactive computer-based home telemonitoring system versus usual care. Patients called in weekly, shared information by phone regarding automated blood pressure readings and adherence, and received targeted education and motivational counseling (all automated), with responses forwarded to doctors. Adherence, measured by pill count, was not significantly different between groups in unadjusted analysis; adjustment for age, sex, and baseline adherence yielded significant differences (17.7% adherence in intervention group vs 11.7% in control group; P = .03). Piette et al randomized 280 patients to biweekly automated interactive phone calls with structured messages that were adjusted based on patient responses, followed by targeted nurse calls versus usual care. Differences from Friedman et al’s intervention include outgoing calls to patients (Friedman et al required patients to call in) and limited nonautomated phone follow-up. Piette and colleagues found that intervention patients were “substantially less likely to report adherence problems” (based on self-report using modified Morisky scale) (P = .003, no adherence percentages given) but did not provide baseline adherence (56% reported “any medication problem” at baseline).

Johnson et al¹¹ followed 404 adults, describing the impact of a computer program designed to mimic the reasoning and problem-solving of humans based on an integrative model of behavioral change (the transtheoretical model) and incorporating an individualized computer-generated report mailed to patients. They found an improvement in adherence at 18 months (odds ratio = 2.86, P <.05). Emmett et al⁹ studied 217 patients newly diagnosed with hypertension who were randomized in a factorial manner to a computerized decision analysis intervention, mailed video and leaflet, both, or neither. Neither the decision analysis nor the mailed video and leaflet resulted in significant improvement. Marquez-Contreras et al¹² examined use of home automatic blood pressure monitoring (along with a phone call with instructions on use) in 250 patients with uncontrolled or newly diagnosed hypertension. At the end of 6 months, 92% of the intervention group had adherence greater than 80% (assessed using electronic pillboxes) compared with 74% of the control group (P <.05).

Person-Dependent Interventions: Nonautomated Phone Calls

Eight studies described the use of nonautomated phone calls to improve adherence. Calls were made by trained lay people,^15,16 nurses,¹⁷ pharmacists,^18,19 or a nonspecified caller.^20-22 Overall, 5 of these studies showed a nonsignificant improvement in adherence, a single study²⁰ showed significant improvement but did not clearly define its adherence outcome measure, and 2 showed significant improvement with clearly defined outcomes.

Neither phone calls by trained lay people nor calls by a nurse yielded significant improvements in adherence. Pharmacist calls showed mixed results. Faulkner et al¹⁸ described 12 weeks of weekly phone calls from a pharmacist for patients after cardiac surgery or angioplasty and found a significant improvement in adherence as measured by pharmacy refills (60% adherence for the phone call group vs 27% adherence for the control group at 2 years for lovastatin). Mehos et al19 evaluated the effect of monthly pharmacist phone calls in conjunction with home blood pressure monitoring in a group of hypertensive patients who all received direct clinical services from a pharmacist, and found no significant improvement.

Three studies did not specify the identity of the caller. Antonicelli et al²⁰ described a home telemonitoring intervention managed by a specialized congestive heart failure team that included doctors and nurses, without specifying the actual caller. The study reported significant improvement in adherence (91% in the intervention group vs 46% in the control group, P <.03), but did not adequately define how adherence was measured. Sclar et al21 used phone calls in which adherence was reinforced and monthly mailings delivered to patients with previously treated and newly diagnosed hypertension, and found statistically significant improvements in both intervention groups (previously treated, 82% adherence intervention vs 48% control; newly treated, 93% vs 52%; P <.05 for both). Guthrie22 used phone reminders along with mailings to patients with elevated cholesterol and found no significant difference in self-reported pravastatin use.

Person-Dependent Interventions: In-Person Meetings

We identified 34 in-person interventions^23-56 (Table 2). These interventions included those conducted in the home,^23-26 at work sites,^27-29 at pharmacies,^30-35 and at medical facilities.^36-56 Overall, in-person interventions were more likely (56%) than phone calls (38%) to result in significant improvement.

Morisky et al²⁵ examined the effect of a trained lay person (a health educator) visiting the home of a patient to provide education to both family members and the patient, and found a significant improvement in self-reported adherence scores. Saunders et al²³ also incorporated visits by trained lay persons. They sent reminder letters to patients with hypertension and used patient-recorded blood pressure and medication records, adding field worker home visits after 2 reminder letters went unanswered, but did not find significant improvement. Kirscht et al²⁶ applied a factorial design to multiple educational and behavioral strategies (Table 2) and found a significant improvement in adherence among patients who received nurse-administered home visits aimed at a support person as well as the patient (adherence 65% vs control 55%, P <.05). Johnson et al²⁴ examined monthly home visits with or without home blood pressure monitoring (the training of the home visitor was not identified) and found no significant improvement. Both effective in-home interventions incorporated family member involvement, in contrast to the 2 unsuccessful interventions.

The 3 work site interventions provided hypertension care by a nurse^27,28 or a physician²⁹; improvement was shown only in the study in which a nurse acted with relative autonomy.²⁷ Logan et al²⁷ examined the effect of hypertension care administered to 457 patients by a specially trained nurse at the work site. All aspects of blood pressure management were handled directly by the nurse, and the intervention demonstrated improved adherence (68% vs 49% had at least 80% of medications consumed based on pill count).

We identified 6 interventions^30-35 that were conducted in pharmacies, all administered by pharmacists. All but 1 study in this group showed success at improving adherence. Although methods of measuring adherence differed between studies, the successful interventions improved adherence by 7% to 27% (Table 2). Interventions in this group were similar, involving an in-person meeting with a pharmacist in which patient-centered medication histories were obtained, medication knowledge was elicited and expanded upon, and disease and lifestyle teaching was conducted, sometimes with accompanying written information. All 6 studies lasted between 6 and 12 months.

Lee et al³⁰ made use of blister packaging in addition to clinical pharmacist meetings and medication education for 159 patients with hypertension, hyperlipidemia, and other diseases, and found 96% adherence at 6 months in intervention patients compared with 69% in controls (P <.001). Murray et al³¹ found an adherence improvement of 11% (95% CI = 5%, 17%) among 314 patients with hypertension over 12 months, but noted that the difference declined to a nonsignificant level after the intervention was discontinued. Blenkinsopp et al³² followed 282 patients with hypertension recruited by community pharmacists over 6 months (63% adherence in intervention group vs 50% in control group, P <.05). Bouvy et al³⁵ followed 152 patients with congestive heart failure, defining nonadherence as fewer than 80% of days without opening the electronic pill bottle, and found all patients in the intervention group took pills more than 80% of days, whereas 86% in the control group reached that threshold (relative risk = 0.5, 95% CI = 0.4, 0.6). Vrijens et al33 followed 392 patients with hyperlipidemia and found that intervention patients had higher adherence at follow-up (96% vs 89%, P <.001). The study of patients with coronary artery disease³⁴ used a self-reported score to measure adherence (making comparison with other studies difficult) and reported very high baseline and follow-up adherence scores. For this reason, the nonsignificant findings in this study may not be representative of the group of pharmacist interventions.

We identified 15 in-person studies^36-50 that were conducted in a clinic setting. Among in-person clinic interventions conducted by a lay person or nurse,^36-39 50% of studies showed significant improvement over the control group (Table 2). Whereas inperson pharmacist interventions showed high success rates when conducted in a pharmacy, in-person pharmacist interventions in clinics^40-47 showed the lowest rate of success among clinic interventions (38% compared with 50% to 67% for other in-clinic interventions). All 3 successful clinic interventions^41,46,47 were carried out at clinics that also had medication-dispensing capabilities. The 5 unsuccessful clinic interventions^40,42-45 were carried out at primary care offices and neighborhood clinics that did not dispense medications.

Three in-person clinic interventions were carried out by physicians.^48-50 Although 2 of these studies were successful,^49,50 neither used a rigorous method of assessing adherence. Yilmaz et al⁴⁹ studied the impact of verbal advice on statin benefits from an “expert physician.” At the end of the study there was an increased likelihood of being on continuous statin therapy (63% intervention vs 46% control), but the authors did not define the outcome or the data source. Avanzini et al⁵⁰ studied 1771 patients with hypertension, randomized to care by (1) doctors who had the opportunity to educate themselves extensively on hypertension and then designed and implemented hypertension management guidelines or (2) doctors without this experience. At follow-up, 4% of intervention vs 10% of control patients “admitted poor compliance,” but the authors give no further information on how this outcome was calculated. Birtwhistle et al⁴⁸ randomized patients with hypertension to every-3-month versus every-6-month physician follow-up and found no significant difference in adherence. In-person interventions for patients at the point of hospital discharge^51-56 (67% successful) showed lower success rates than interventions carried out in a pharmacy (83%) but higher success rates than those carried out in a clinic setting (47%). However, although 4 out of 6 studies showed significant improvement in adherence,^52,54-56 2 of the successful studies had unclear definitions of adherence.

Of the 6 studies, 4 recruited in-hospital patients exclusively and followed them after discharge. Two studies recruited patients from both in-hospital sites and outpatient clinics.

Tsuyuki et al⁵¹ found a nonsignificant effect of educational meetings with a research assistant prior to hospital discharge, accompanied by adherence aids, and phone and mail follow-up. Krantz et al⁵² found a significantly higher rate of beta-blocker utilization (96% intervention vs 48% control) after predischarge nurse counseling and outpatient nurse follow-up, but the term “utilization” was not clearly defined. Significant improvement was shown by 2 of the 3 pharmacist interventions,^54,55 although Sadik et al,⁵⁴ who evaluated pharmacist education for congestive heart failure, did not clearly define the way self-reported adherence was calculated. The study by Varma et al,⁵⁵ a successful pharmacist intervention that defined adherence as 80% to 120% of all congestive heart failure drugs taken at 12 months, found a significant effect (77% intervention vs 30% control). Edworthy et al⁵⁶ followed 2643 cardiac patients after hospitalization, giving in-hospital counsel on medications and medical conditions by nurses and pharmacists along with video, printed material, and phone follow-up by both a nurse and a pharmacist. Significant improvement in adherence was seen for both beta-blockers (intervention 89% vs control 80%, P <.01) and lipid-lowering agents (intervention 83% vs control 78%, P < .05).

DISCUSSION

Our review of interventions to improve adherence to cardiovascular and diabetes medications yielded a highly diverse group of interventions. Several themes arose regarding the effectiveness of different approaches that may inform future intervention development.

Among person-independent interventions, those that used electronic interventions showed promise. Effective electronic interventions included those that were designed to be individualized using either computer-generated algorithms or hierarchically structured messages, and 1 study effectively combined hierarchical phone messages and targeted phone follow-up by a nurse. Home automatic blood pressure monitoring and programmable pill caps with reminder cues also demonstrated promising results. Adherence interventions delivered via paper or video showed minimal effectiveness unless targeted at a group (in this case, hospitalized patients after myocardial infarction) that was especially likely to be sensitive to the message.

Among person-dependent interventions, the results of phone call interventions were not encouraging. Only a minority were effective. These interventions targeted groups at a time in their lives when they should have been particularly sensitive to the message (eg, immediately after bypass surgery, percutaneous intervention, or hospitalization for congestive heart failure, or after a new diagnosis of hypertension).

In-person interventions yielded some interesting patterns. Home visits, an expensive intervention, were only effective in half the studies identified; both of the effective studies sought to target a family member as a support person, whereas neither of the ineffective studies did so. The data on worksite interventions were limited, and no recent studies were identified. Interventions carried out in the pharmacy (all by pharmacists) were almost uniformly effective and were a fairly homogenous group in both the nature of the services rendered and in duration of follow-up. Interestingly, when we looked at the group of interventions carried out in the clinic by pharmacists, only 3 out of 8 were effective. All 3 of these were carried out in clinics that also had dispensing abilities and therefore may have been more similar to the group of in-person pharmacy interventions. Interventions that targeted patients at the point of hospital discharge were more effective than those that focused on clinic patients, although the lower number of in-person hospital studies should be noted (6 com pared with 15 clinic studies).

Person-dependent administration of an adherence intervention can be costly, whether carried out by a lay person, nurse, pharmacist, or physician. We found the success rate of person-dependent interventions comparable to or lower than that of person-independent interventions. We interpret this result cautiously, given the presence of fewer person-independent interventions overall.

The wide heterogeneity of the adherence intervention studies that we identified should prompt us to interpret all comparisons with caution. We included studies with differing populations (patients from different countries and with different cardiovascular diseases; nonadherent vs all patients; hospitalized vs outpatient patients), and we encountered a wide variety of study designs, including some with idiosyncracies that limited their generalizability. In addition, although a detailed discussion of comparative adherence measurement methods is outside the scope of this study, we found inconsistencies in methods of adherence measurement across the studies reviewed, demonstrated most clearly in our tables. Direct comparison of the magnitude of the intervention effects is complicated by this heterogeneity. Although we were able to consider some aspects of healthcare setting in our analysis, stratification by healthcare facility size was not possible because of inconsistencies in reporting. Finally, although more than 40% of the identified studies reported no significant improvement, publication bias also may be playing a role in our findings.

We suggest that future research focus on (1) the life events causing increased patient receptiveness to the adherence message (ie, hospital stays, particularly after a serious cardiac event); (2) the psychological factors present during an acute illness and hospital stay as they relate to a patient’s willingness to modify adherence behavior; (3) in-person pharmacist counsel delivered at the site of medication dispensing (so that arriving for an appointment to discuss adherence can be combined with retrieving the medication); and (4) new and innovative ways to take advantage of electronic technologies.

We saw few interventions that capitalized on lay-person social networks, either electronic or in person. Research on adherence to other medically recommended behaviors including cancer screening has indicated that this may be a promising direction,⁵⁷ and the same may be true for medication adherence interventions.

In conclusion, among interventions to improve adherence to cardiovascular medications, electronic interventions, in-person pharmacist interventions held at a site of medication dispensing, and in-person interventions targeted to patients at the point of hospital discharge showed the highest rates of success. Future studies should explore new electronic approaches and in-person interventions at the site of medication distribution. A focus on identifying times of increased patient receptivity to the adherence message also will be important.

Author Affiliations: From the Division of Pharmacoepidemiology and Pharmacoeconomics (SLC, NKC, MAF, AS, WHS), Brigham and Women's Hospital, Boston, MA; Tri County Medical Associates Hospitalist Group (SLC) Milford Regional Medical Center, Milford, MA; Division of Strategic Research (JNL, TAB), CVS Caremark, Hunt Valley, MD; and Center for American Political Studies (WHS), Harvard University, Boston, MA.

Funding Source: This work was supported by a research grant from CVS Caremark. Dr Shrank is supported by a career development award from the National Heart, Lung and Blood Institute (HL-090505).

Author Disclosures: Drs Liberman and Brennan are employees of CVS Caremark, the funder of the study. Dr Brennan also reports holding options and stock in the company. Dr Choudhry reports receiving multiple grants to conduct studies on patterns and predictors of medication adherence. Dr Fischer reports a potential study of adherence with Surescripts. Dr Shrank reports receiving grants from CVS Caremark. The other authors (SLC, AS) report no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

Authorship Information: Concept and design (SLC, NKC, MAF, AS, TAB, WHS); acquisition of data (SLC, AS, TAB, WHS); analysis and interpretation of data (SLC, NKC, MAF, AS, JNL, WHS); drafting of the manuscript (SLC, TAB, WHS); critical revision of the manuscript for important intellectual content (SLC, NKC, MAF, AS, JNL, WHS); statistical analysis (WHS); obtaining funding (JNL, WHS); and administrative, technical, or logistic support (AS, WHS).

Address correspondence to: Sarah L. Cutrona, MD, Milford Regional Medical Center, TCMA Hospitalists, 14 Prospect St, Milford, MA 01757. Email: slcutrona@gmail.com.

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