Monday, March 20, 2023
One of the major themes discussed at the American Heart Association (AHA) 2006 Annual Scientific Sessions dealt with "America's other drug problem"[1] -- that is, nonadherence. Many different methods to improve adherence to medication regimens have been proposed and tested. These include fixed-dose combination drugs, once-daily or once-weekly dosing schedules, unit-dose packaging, educational counseling by telephone, case management by pharmacists, treatment in pharmacist- or nurse-operated disease management clinics, mailed refill reminders, self-monitoring, dose-tailoring, rewards, and various combination strategies.
In 2005, a meta-analysis led by analysts at ValueMedics (Falls Church, Virginia) reported that 12 different interventions had been shown to significantly improve patient compliance with antihypertensive or lipid-lowering medications.[2] The most effective were personalized, patient-focused programs that involved frequent contact with health professionals or a combination of interventions. Less-intensive strategies, such as prescribing products that simplified the medication regimen or sending refill reminders, appeared to achieve smaller improvements in compliance but cost less. Most researchers believe that the answer to what the best methods are for improving adherence will come from combining clinical trial results with results from longitudinal studies.
The Federal Study of Adherence to Medications in the Elderly (FAME) was the first prospective randomized trial to specifically address medication adherence in patients aged ≥ 65 years. Using a program combining patient education, regular follow-up, and customized blister packs for administration of blood pressure and lipid-lowering regimens was associated with increased adherence over 6 months from 61% to ≥96% and clinically significant reductions in systolic blood pressure (SBP) and low-density lipoprotein cholesterol (LDL-C).
The results of FAME were presented at the 2006 AHA by senior investigator Allen J. Taylor, MD (Walter Reed Army Medical Center, Washington, DC).[3] A report of the study was also published simultaneously in the Journal of the American Medical Association (JAMA)[4] The study was partially funded by the American Society of Health-System Pharmacists Research and Education Foundation, managed under the auspices of the TRUE Research Foundation for the Advancement of Military Medicine.
Elderly patients are generally less adherent to medication than younger patients, Dr. Taylor explained. They often have multiple chronic health problems (65% of adults aged ≥ 65 years have been reported as having ≥ 2 chronic conditions[5]), leading to use of multiple medications (studies suggest an average of 4 chronic medications) and more complex regimens, all of which promote nonadherence. No fully effective strategies to improve adherence are currently in widespread clinical use, and no previous study had been carried out in the elderly. FAME investigated the impact of a comprehensive pharmacy care program on medication adherence and control of blood pressure and LDL-C.
The study was carried out between June 2004 and August 2006 at the Walter Reed Army Medical Center, a tertiary-care US-military facility. Subjects recruited into FAME were men and women aged ≥ 65 years, taking ≥ 4 chronic medications, and living independently. People living in assisted living facilities or nursing homes or who had any serious medical condition with an expected survival of ≤ 1 year were excluded from the study. Of 208 patients approached about the study, 200 (155 men and 45 women, mean age 78 years) agreed to participate. Of the patients who started the study, 184 (91.5%) had drug-treated hypertension and 162 (80.6%) had drug-treated hyperlipidemia. The patients were taking an average of 9 different chronic medications daily.
FAME consisted of 3 phases, as shown in Table 1.
| Phase | Description |
|---|---|
| Run-in phase | Over a 2-mo run-in period, all patients were assessed for baseline medication adherence and their LDL-C and blood pressure were measured. |
| Phase 1 (N = 200) | During this 6-mo intervention phase:
|
| Phase 2 (N = 159) | Patients successfully completing phase 1 were randomized to either:
|
Medication adherence, measured by pill count, was the primary endpoint of both phases of the study. At the end of phase 1 (8 months), medication adherence showed a 35.5% increase over baseline (Table 2). At this point in the study, there was a 16-fold increase (5.0% to 98.7%) in patients ≥ 80% adherent to all medications, the commonly accepted definition of an acceptable level of adherence.
| N | Baseline | End of Phase 1 | P Value | |
|---|---|---|---|---|
| Medication adherence | 159 | 61.5 ± 13.5% | 96.9 ± 5.2% | < .001 |
At the end of phase 2 (14 months), mean medication adherence was maintained in the patients who continued on pharmacy care (Table 3). In the patients who returned to usual care, mean adherence declined, although it was still slightly higher than adherence at study entry (baseline).
| Usual Care (n = 76) |
Pharmacy Care (n = 83) |
P Value | |
|---|---|---|---|
| Medication adherence | 69.1 ± 16.4% | 95.5 ± 7.7% | < .001 |
Analysis controlling for differences in the study groups at baseline showed that assignment to usual care and taking medications for psychiatric or memory problems were independently related to changes in medication adherence during phase 2.
Changes in blood pressure and LDL-C or blood pressure among the participants with pharmacologically treated hypertension or hyperlipidemia were prespecified secondary endpoints for phase 1. At the end of phase 1, significant reductions were seen in LDL-C and systolic blood pressure (SBP), but not diastolic blood pressure (DBP) (Table 4). There was no change in the number of antihypertensive medications taken up during the first 8 months of the study.
| N | Baseline | End of Phase 1 | P Value | |
|---|---|---|---|---|
| SBP (mm Hg) | 142 | 133.2 ± 14.9 | 129.9 ± 16.0 | .02 |
| DBP (mm Hg) | 142 | 70.5 ± 9.2 | 69.7 ± 10.5 | .30 |
| LDL-C | 122 | 91.7 ± 26.1 | 86.9 ± 23.4 | .001 |
DBP = diastolic blood pressure; LDL-C = low-density lipoprotein cholesterol; SBP = systolic blood pressure
Prespecified analyses of changes in blood pressure and LDL-C during phase 2 in the patients who continued on pharmacy care showed significant reductions in SBP, but not DBP or LDL-C (Table 5). The number of antihypertensive medications used was similar in the 2 groups during Phase 2.
| Mean Change | P Value (between groups) | ||
|---|---|---|---|
| Usual Care | Pharmacy Care | ||
| SBP (mm Hg) | -1.0 | -6.9 | .04 |
| DBP (mm Hg) | -1.2 | -2.5 | .39 |
| LDL-C (mg/dL) | -5.8 | -2.8 | .85 |
DBP = diastolic blood pressure; LDL-C = low-density lipoprotein cholesterol; SBP = systolic blood pressure
On the basis of this study and previous recommendations, Dr. Taylor and his colleagues believe that "medication adherence interventions should follow the FAME strategy of addressing underlying reasons for nonadherence, educating patients, providing serial follow-up, and promoting convenience through reminder packaging." Dr. Taylor stressed the need for teamwork and the importance of the participation of pharmacists in the process of evaluation and follow-up. "FAME calls for greater emphasis within healthcare delivery systems and policy organizations on the development and promotion of clinical programs to enhance medication adherence among the at-risk elderly," he said.
AHA-designated discussant Harlan M. Krumholz, MD, SM (Yale University School of Medicine, New Haven, Connecticut) called the FAME study "remarkable." He praised the FAME trial, describing it as "the kind of real-world study we should be focusing research today." Among several reservations, however, were the "relatively small numbers" in the trial and the fact that it was a single-center study done within a military hospital. The types of patients in this hospital might be a little different from those seen in other settings, Dr. Krumholz suggested, noting that almost all of the patients initially approached agreed to participate, and that they appeared more likely to comply with interventions. An educational intervention depends in large part on having a talented educator, he added.
Noting that aside from medication adherence, the other endpoints in the FAME study were surrogates, Dr. Krumholz stressed that research is needed as to whether patients do better when given such an intervention.
Overall, FAME was an important study and ought to stimulate further research focusing on how patients should take their medications and what can be done to help them, he concluded.
At a press conference, Dr. Taylor contrasted "the immense effort that is put into determining that drugs are efficacious" with "how little effort is put into demonstrating how to make patients take their pills." He went on to say that "If we can invest millions and millions of dollars to determine what works... we can invest a little to get this operational."
Timothy J. Gardner, MD (Christiana Care Health Service's Center for Heart and Vascular Health, Wilmington, Delaware), Chairman of the AHA Committee on Scientific Sessions Program, said that the AHA recognizes that researchers need to be engaged in behavioral studies as well as pharmacology.
Christopher Cannon, MD (Brigham & Women's Hospital, Boston, Massachusetts) called the FAME study "a major advance." He also stressed the importance of ensuring that patients actually take the pharmaceuticals that have been shown to be effective in clinical trials. He noted that in Massachusetts there is already a program for educational follow-up in some patients taking statins. "This is happening in bits and pieces," he said, "but we now have a randomized trial to say that we should be doing this more frequently."
In a JAMA editorial commenting on the FAME study,[6] Ross J. Simpson, Jr, MD, PhD (University of North Carolina at Chapel Hill) declared that the results of FAME showed that "multifaceted interventions that incorporate structural and counseling components and include appropriately skilled and motivated pharmacists appear useful to promote medication adherence and persistence." Although, he also noted that further studies will be needed to confirm whether such interventions result in increased and sustained patient adherence and whether they improve outcomes. The study also confirmed the value of the part that pharmacists play in providing patient counseling, Dr. Simpson noted.
He also pointed out several "important" limitations of the study. "A major concern," he believes, is how well the results might apply to the general population of elderly patients. Like Dr. Krumholz, he pointed out that FAME was conducted in a homogeneous group of patients in a military-affiliated facility where medication was free, and that few eligible patients approached for consent refused to participate, "suggesting either a remarkably high success rate at recruitment or preselection of potentially eligible patients." Patient populations in which cost considerations, cultural issues, and more extensive or more varied disease burden are prevalent might not show such good results, Dr. Simpson suggested.
As designed, the intervention also had some weaknesses, he added. It was not based on any specific behavioral model, and counseling appeared intense and time consuming. The individual components of the counseling or the intervention could not be assessed, so it was unclear whether pharmacist involvement, blister packs, or both together were most important. A more important concern, he suggested, was that the 2 groups in the randomized trial phase of the study had different levels of observation and different frequency of visits to the health facility after randomization, and patients in the usual care group had an intervention that they had been receiving for 6 months removed, an unusual design feature in clinical trials. This introduced a potential observation bias favoring the intervention group that should have been controlled for.
Despite these concerns, Dr. Simpson concluded that the FAME study "adds important information about improving medication adherence in elderly patients and also highlights the challenges inherent in designing and conducting high-quality research in this critically important area."
