Adhering to medication regimens has the potential to significantly improve clinical outcomes for persons with high blood pressure. A patient-related factor likely to affect adherence to treatment is the convenience of the prescribed drug regimen. The authors hypothesized that medication adherence would be superior and cost benefits would accrue in subjects who receive a once-daily, single-capsule, fixed-dose combination product for blood pressure control, compared with subjects who receive a similar regimen of separate components. A managed care organization that provides benefits for members enrolled in various health plans provided the data for this retrospective analysis. The database was used to assess medication adherence patterns for two groups of hypertensive subjects. Group 1 included subjects who had been prescribed the single-capsule, fixed-dose combination of amlodipine besylate/benazepril HCl. Group 2 comprised subjects who had been prescribed a regimen including an angiotensin-converting enzyme inhibitor and a dihydropyridine calcium channel blocker as separate drugs. Adherence was measured by the medication possession ratio, and medical resource utilization by the two groups was assessed during the study period. Group 1 (n=2754) and Group 2 (n=2978) were balanced with regard to age (mean, 53 years; range, 18–64 years) and sex (men, 50%; women, 50%). The overall medication possession ratio for Group 1 was significantly higher than that for Group 2 (80.8% vs. 73.8%; p<0.001). The average annual cost of cardiovascular-related care per subject was significantly lower in Group 1 compared with Group 2 (p<0.001). Subjects receiving the once-daily, single-capsule, fixed-dose combination of amlodipine/benazepril HCl demonstrated significantly better medication adherence and required fewer medical resources than did subjects receiving an angiotensin-converting enzyme inhibitor and a dihydropyridine calcium channel blocker as separate components.
Controlling blood pressure (BP) in persons with hypertension reduces the burdensome medical and social costs of treating cardiovascular and renal events such as coronary heart disease, stroke, congestive heart failure, and end-stage renal disease.1–5 The relationship between BP and risk of cardiovascular disease events is continuous and independent of other risk factors.6 Thus, risk doubles for each 20 mm Hg systolic BP increment across the BP range of 115/75 mm Hg to 185/115 mm Hg.7 The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) defines normal BP as <120/80 mm Hg and provides a new category of BP, designated prehypertension (BP of 120–139/80–89 mm Hg).6 Because it is not practical to lower BP in the general population to the optimal goal of <120/80 mm Hg, goal BP for persons with uncomplicated hypertension is generally set at 140/90 mm Hg. According to JNC 7, specific groups at high risk, such as persons with type 1 and type 2 diabetes or chronic kidney disease, should receive antihypertensive therapy with a target BP goal of <130/80 mm Hg.6 This BP goal is consistent with that recommended by the American Diabetes Association, the National Kidney Foundation, and the International Society on Hypertension in Blacks.8–10
Physician failure to treat hypertension aggressively is one factor in the larger portrait of inadequate population-level BP control.11 However, a large portion of the difficulty in achieving BP goals can be attributed to patient behavior and a lack of adherence to prescribed medication regimens.12,13 These problems are compounded by the reality that more than half of all hypertensive patients cannot achieve BP control to the currently recommended target of <140/90 mm Hg with a single antihypertensive agent.14–16 Furthermore, a large percentage of high risk patients with hypertension require two or more drugs to control BP to the more stringent goal of <130/80 mm Hg.17
Factors likely to affect medication adherence include the convenience and tolerability of the prescribed drug regimen.12,13 One proposed option for improving patient adherence and BP control in hypertensive patients is the use of fixed-dose combination antihypertensive therapy. The rationale for this approach includes the potential advantages of improved BP control, fewer dose-related adverse effects, and greater convenience.18
We hypothesized that adherence would be superior in persons who receive a once-daily, single-pill, fixed-dose combination product for BP control compared with persons who receive a similar regimen of two separate drugs. We therefore conducted a study to compare medication adherence, resource utilization, and costs in persons who received a once-daily, fixed-dose combination of amlodipine besylate/benazepril HCl with those who received an angiotensin-converting enzyme (ACE) inhibitor and a long-acting dihydropyridine calcium channel blocker (DHP CCB) as separate drugs.
This study was a retrospective database analysis of medical and pharmacy claims for two mutually exclusive groups of subjects. A managed care company that provides benefits for members in health maintenance organizations, preferred provider organizations, and government-based health plans provided the database used in this study. Group 1 consisted of subjects meeting inclusion criteria who had been prescribed the once-daily, fixed-dose combination product amlodipine besylate/benazepril HCl. Group 2 consisted of subjects meeting inclusion criteria who had been prescribed a DHP CCB and an ACE inhibitor as separate drugs concurrently. Assessment of comorbid conditions was made by accessing all diagnosis code fields and identifying subjects with codes for diabetes, hyperlipidemia, coronary heart disease, and congestive heart failure (including cardiomyopathy, disorders of conduction, and other heart disease). Each subject was assigned a severity score, based on the Charlson index.19,20 The Charlson index, widely used to measure patient comorbidities, includes scores of 0 to ≥6, according to the absence or presence of comorbid disorder(s) assessed by International Classification of Disease, Ninth Revision codes.20
Study period. The study period included 2 consecutive years of data (January 1, 2000 to December 31, 2001, inclusive) and was based on a minimum of 12 months of continuous data from the date of first prescription for each subject in the study. The treatment interval extended from day 1 of receipt of the first study prescription to day 1 of receipt of the final prescription.
Inclusion criteria. Subjects with a diagnosis code for hypertension who were between the ages of 18 and 64 years, inclusive, at study entry and who were continuously eligible for medical and pharmacy benefits for at least 12 months following the date of their first prescription were included in the database if they: 1) had been treated with either of the two regimens under investigation; and 2) had filled at least two prescriptions for their regimen on two different dates during the study period.
Data analysis. Demographic and clinical data, including age, comorbid conditions, and use of cardiovascular medications, were collected for all study subjects. Utilization and costs of services attributable to hypertension (also considered cardiovascular-related costs) were calculated using three general categories of claims: facility, professional services, and pharmacy. Types of claims and services assessed for resource utilization are listed in Table I. Annual pharmacy costs were measured per patient for the cost of antihypertensive medications, all other cardiovascular medications, and all other medications. Actual health plan costs were used in the analysis, and pharmacy and medical costs were based on claims. Cost calculations were made for each group to determine the average annual cost per subject of drug therapy, inpatient visits, and office visits. Cost of care was also determined for each group by severity score, based on the Charlson index. Because individual study intervals varied among the population, ratio calculations were used to assess medication adherence and resource utilization.
Table I. Types of Claims and Services Assessed for Resource Utilization
Ambulatory surgical center
Skilled nursing care
Home health care
All other medications
*Analysis reports the number of inpatient hospital claims and not the number of hospitalizations, as there may be more than one claim per hospitalization. Claims for physician visits during hospitalization are reported under professional services.
The primary aim was to assess medication adherence, defined as the medication possession ratio (MPR), represented as a percentage. The MPR for each subject in Group 1 was calculated as the sum of the total days' supply across prescriptions divided by the total number of days from the first prescription fill date to the first day of the last prescription fill date (Figure 1).
The MPR for each subject in Group 2 was calculated based on daily possession of both agents. The beginning of the overlap period started with the first fill date of the second prescription and ended with the last fill date of the last prescription. The subject was considered to be adherent only during the days that both medications were in hand. This number was divided by the total number of calendar days within the specific study period.
The compliance analysis was performed for the total hypertensive population and stratified for selected subgroups, including age groups, sex, and severity score. Data for resource utilization attributable to hypertension were measured during the treatment interval for each subject and prorated to a 12-month period. Utilization of inpatient, outpatient, and pharmacy resources was based on the mean number of respective claims per group. The statistical analysis included the Mantel-Haenszel chi-square and t test, and the significance level was <0.05.
Clinical and demographic characteristics. The total population comprised 5732 subjects; 2754 in Group 1 received a fixed-dose combination of amlodipine besylate/benazepril HCl and 2978 in Group 2 received an ACE inhibitor and a DHP CCB as separate agents. Demographic and clinical variables are listed in Table II. Age and sex were balanced between the two groups. There were more subjects in Group 1 in lower severity score categories. The average severity score, based on the Charlson index, was 2.5 in Group 1 and 2.9 in Group 2 (p<0.001). With the exception of hyperlipidemia, there were a significantly greater number of comorbidities such as diabetes, heart failure, and coronary artery disease in Group 2 than in Group 1. During the study period, more subjects in Group 2 than in Group 1 were hospitalized with a primary cardiovascular diagnosis (11.6% vs. 3.8%, respectively; p<0.001). The number and percentage of subjects taking other therapies including other antihypertensive drugs by class are shown in Table III and IV. In addition to ACE inhibitors and DHP CCBs, Group 2 subjects were taking drugs from other antihypertensive classes more often than those in Group 1 (Table III). As summarized in Table IV, the number of subjects taking drugs from two or more drug classes in addition to ACE inhibitors and DHP CCBs was significantly greater in Group 2 than in Group 1. In contrast, significantly more subjects in Group 1 than in Group 2 (p<0.001) were taking no drugs other than ACE inhibitors and DHP CCBs.
Table II. Clinical and Demographic Variables for Subjects Taking Fixed-Dose Amlodipine Besylate/Benazepril HCl (Group 1) or an ACE Inhibitor and a DHP CCB as Separate Components (Group 2)
Group 1 (n=2754)
Group 2 (n=2978)
Women (No. [%])
Men (No. [%])
Mean age (years)
18–39 (No. [%])
40–49 (No. [%])
50–59 (No. [%])
60–64 (No. [%])
Comorbidity (No. [%])
Congestive heart failure
Coronary heart disease
Average severity score*
Number of subjects by severity score* (No. [%])
ACE=angiotensin-converting enzyme; DHP CCB=dihydropyridine calcium channel blocker; *severity score is determined based on the Charlson index19,20
Table III. Number and Percentage of Subjects Taking Other Therapies*
Group 1 (n=2754) (No. [%])
Group 2 (n=2978) (No. [%])
Angiotensin receptor blocker
Other antihypertensive drug
All other drugs
*Includes all drugs other than amlodipine besylate/benazepril HCl, angiotensin-converting enzyme inhibitors, and dihydropyridine calcium channel blockers (CCBs)
Table IV. Number and Percentage of Subjects Receiving Other Drug Classes*
Number of Other Drug Classes
0 (No. [%])
1 (No. [%])
2 (No. [%])
3 (No. [%])
4 (No. [%])
5 (No. [%])
Group 1 (n=2754)
Group 2 (n=2978)
*Drug classes observed during the compliance analysis period include angiotensin receptor blockers, β blockers, diuretics, other antihypertensive drugs, and all other drugs. The 0 column represents “combination class” and indicates the number of subjects in each group taking only their study drug(s). There were zero of 2754 (0%) subjects in Group 1 taking six drug classes, compared with three of 2978 (0.1%) subjects in Group 2 taking six drug classes.
Medication adherence. MPRs for the variables of age group, number of drug classes, and severity score (based on Charlson index) are shown in Table V. Adherence based on MPR was significantly greater in Group 1 than in Group 2 for subjects aged 40–64 years, for subjects taking 1–4 different drug classes, and for subjects who had severity scores of 0–3 and ≥6 (all p<0.001). The overall MPR for Group 1 was 80.8% compared with 73.8% for Group 2 (p<0.001). This represents a 7% absolute increase in the rate of compliance with amlodipine besylate/benazepril HCl compared with taking an ACE inhibitor and a DHP CCB as separate components. This higher MPR rate indicates that subjects who received fixed-dose amlodipine besylate/benazepril HCl were compliant for approximately 26 more days of any given year.
Table V. Medication Possession Ratios (MPRs) for Subjects in Group 1 or Group 2*
Group 1 (n=2754)
Group 2 (n=2978)
Overall MPR (%)
MPR (%): age group
MPR (%): number of drug classes
MPR (%): severity score†
*All medications except amlodipine besylate/benazepril HCl, angiotensin-converting enzyme inhibitors, and dihydropyridine calcium channel blockers (DHP CCBs); subjects in Group 2 had to be compliant with both angiotensin-converting enzyme inhibitors and dihydropyridine calcium channel blockers; †severity score is based on Charlson index19,20
Resource utilization. As shown in Table VI, the average annual cost of amlodipine/benazepril HCl per subject was significantly less than the average per subject cost of the two-component therapy ($427 vs. $574: p<0.001). The average annual cost of other antihypertensive medications per subject (excluding amlodipine besylate/benazepril HCl, ACE inhibitors, and DHP CCBs) was $46 for Group 1 and $92 for Group 2 (p<0.001). The average annual cost of other medications per subject was $796 for Group 1 and $1007 for Group 2 (p<0.001). The average annual cost per subject of physician visits or a cardiovascular diagnosis was similar for Groups 1 and 2 ($90 and $88, respectively; p=0.89). As shown in Table VI and Figure 2, total average annual costs of inpatient care per subject were $164 in Group 1 and $848 in Group 2 (p<0.001). The total average annual costs of cardiovascular-related care per subject were $726 in Group 1 and $1600 in Group 2 (p<0.001), as shown in Table VI and Figure 3. Significant inpatient care cost savings were seen for subjects in Group 1 with severity scores of 3, 5, and ≥6 (Figure 2). As shown in Figure 3, total cost savings for cardiovascular-related care for subjects taking amlodipine besylate/benazepril HCl were seen for severity scores of 0–3 and 5 (Figure 3).
Table VI. Average Annual Cost* of Medications or Services per Subject
Group 1 (n=2754)
Group 2 (n=2978)
Amlodipine besylate/benazepril HCl therapy (fixed-dose combination therapy in Group 1; component therapy in Group 2)
Other antihypertensive medications
All other medications
Physician visit (cardiovascular-related care)
Inpatient care (cardiovascular-related)
Total care (cardiovascular-related)
*Figures (US $) are rounded to the nearest dollar
The total average number of annual physician visits for a primary cardiovascular diagnosis per subject was 0.2 for Group 1 and 0.9 for Group 2 (p<0.001). Fewer visits were made by subjects in Group 1 at Charlson index scores from 1 to ≥6 compared with Group 2; this difference was significant at scores of 5 (0.75 in Group 1 vs. 4.2 in Group 2; p<0.001) and ≥6 (2.0 in Group 1 vs. 4.9 in Group 2; p<0.001).
In this study, hypertensive subjects receiving the fixed-dose combination product amlodipine besylate/benazepril HCl demonstrated greater adherence to their medication regimen and lower overall costs of care, compared with subjects who received a similar regimen containing an ACE inhibitor and a DHP CCB as separate drugs. Adherence, based on MPR, was superior with amlodipine besylate/benazepril HCl for men and women aged 40–64 years, for subjects taking 1–4 different drug classes, and for subjects with severity scores based on the Charlson index of 0–3 and ≥6. On average, medication supply was in the subject's possession 80.8% of the time for those taking fixed-dose combination therapy and 73.8% of the time for subjects taking separate component therapy, meaning that subjects taking a fixed-dose combination had their medication in hand for approximately 26 more days in a year period. In essence, the prescribed therapy—consisting of an ACE inhibitor and a DHP CCB—was identical in both groups; however, adherence to medication differed according to the regimen.
Resource utilization, which was significantly lower in Group 1 compared with Group 2, may have been partly affected by the higher baseline comorbidities noted in Group 2. When the data were stratified according to severity score, utilization costs were lower in Group 1 as expected, since there were more subjects in Group 2 than in Group 1 in higher severity score categories.
We acknowledge that the two study groups were not completely comparable, as there were statistically significant differences in their comorbidity status and no adjustments were made for confounding factors. Retrospective medical or pharmacy claims are not the optimal source of information to determine health outcomes, and factors including the degree of BP control, dosage, or hospitalization for either therapy regimen were outside the scope of this study. To confirm our findings, we recommend a prospective study including the issues of BP control, dosage equalization, and hospitalization rates between the two groups.
Controlling BP with medications is an extremely important priority for reducing premature morbidity and mortality from cardiovascular disease. Blood pressure control among treated patients is known to be poor6,21 and to be greatly affected by patient adherence to medication regimens.13,22 Importantly, adherence improves both long-term BP control and 24-hour BP control, both of which have been shown to be critical in reducing target organ damage.23–26
Because the treatment of hypertension requires daily lifelong treatment, an essential challenge in helping patients achieve BP control is prescribing a medication regimen they can follow easily, without gaps in treatment. Consistent adherence to antihypertensive medication regimens has been evaluated in several studies. Adherence was found to be uncommon among 821 hypertensive subjects who were interviewed during pharmacy visits.12 BP was controlled in 61% of subjects when it was evaluated at the time of the study, but only 37% of subjects reported consistent adherence to their antihypertensive regimens. Monane et al.27 showed that among 8643 hypertensive subjects aged 65–99 years, good adherence (≥80% MPR) was positively associated with the use of ACE inhibitors and CCBs (subclass not specified), compared with thiazide diuretics, and was inversely associated with the overall number of medications prescribed. Thus, the number of pills to be taken each day and the classes of medications prescribed both appear to be important factors in patient adherence. The need for fewer pills per day is likely to be perceived by patients as more convenient, and adherence can be improved by simplification of the medication regimen.13,28
An improvement in antihypertensive medication adherence with resultant better BP control is likely to improve long-term outcome.29 A recent meta-analysis showed that interventions aimed at improving compliance with medication regimens increased patient adherence by up to 11%.30 Steiner and Prochazka,31 in a review of 41 studies that employed measures of refill compliance, found that partial compliance with prescription fills identified important clinical or economic consequences of reduced compliance. For example, hypertensive patients with gaps in acquisition of their antihypertensive drug had an increase in hospitalizations for uncontrolled hypertension and an increase in the overall costs of care.32 Another study found that gaps in treatment with β blockers were associated with an increased rate of acute myocardial infarction.33 Overall costs of medical care were increased for partially compliant patients with peripheral arterial disease34 and hypertension,35 despite the reduction in drug costs due to poor compliance.
Refill compliance using a review of pharmacy records is useful in assessing adherence to medications intended for long-term use such as antihypertensive drugs.31 The MPR has high specificity for identifying individuals who cannot be compliant with the prescribed antihypertensive regimen over a defined time period because they do not have enough pills or capsules to do so.31 The limitations to a retrospective review of claims include an inability to determine clinical outcomes such as BP measurements. Therefore, it is not certain that all compliant subjects were well controlled. In addition, no detailed information was available in regard to when other medications were started or switched during the study period. Using the MPR to assess compliance relies on at least two assumptions regarding patient behavior: 1) that patients who fill prescriptions correctly adhere to their drug therapy36; and 2) that patients fill prescriptions within the pharmacy system.31
On average, monotherapy controls BP in fewer than 50% of hypertensive patients.17 The rationale for use of a combination product rests on the additive effect of BP, allowing the use of lower doses of two drug classes to achieve similar, if not better, BP response than monotherapy and a decreased incidence of adverse effects.37 Using two drugs from two different drug classes targets several of the metabolic pathways that contribute to hypertension. The combination amlodipine besylate/benazepril HCl contains a DHP CCB, thus providing excellent BP control, as well as an ACE inhibitor, offering cardioprotection to patients at the greatest risk of cardiovascular disease events—patients with diabetes and renal disease.38 Importantly, as the number of comorbid conditions increases in a hypertensive individual, the number of daily medications also increases. A fixed-dose combination product such as amlodipine besylate/benazepril HCl simplifies the medical regimen for these patients, which may increase overall medication adherence.
A recent, large, practice-based clinical trial assessed the efficacy and tolerability of amlodipine besylate/benazepril HCl in 7912 subjects with Stage 1 and Stage 2 hypertension who were being treated with amlodipine monotherapy.37 Subjects were enrolled based on either a lack of BP control on amlodipine monotherapy or an inability to tolerate amlodipine monotherapy because of pedal edema, an adverse effect commonly associated with dihydropyridine CCBs. After 4 weeks of therapy, subjects with inadequate BP control on amlodipine monotherapy had mean declines in systolic and diastolic BP of 15.6 mm Hg and 11.2 mm Hg, respectively, after switching to the combination product. For subjects who had experienced pedal edema while on amlodipine monotherapy, 85% experienced improvement after switching to combination therapy with amlodipine besylate/benazepril HCl.
Fixed-dose combination therapy has a proven record of reducing BP and is typically better at effectively reducing BP and dose-limiting adverse effects than monotherapy. It is only speculative whether the sequential addition of antihypertensive medications has comparative efficacy and safety to fixed-dose combination therapy.39 As a combination product, amlodipine besylate/benazepril HCl has been extensively studied and shown to meet the strict criteria of having: 1) superior efficacy than the sum of the effectiveness of either component alone; 2) at least equal safety compared with that of either component used alone; and 3) a risk/benefit ratio lower than that of either component alone.40–43
Subjects who received amlodipine besylate/benazepril HCl as a once-daily, fixed-dose, combination antihypertensive regimen were significantly more adherent to their medication regimens and had fewer physician visits compared with subjects who received an ACE inhibitor and a DHP CCB as separate components. Using amlodipine besylate/benazepril HCl combination therapy is superior to using component ACE inhibitor/DHP CCB therapy in improving patient adherence. This, in turn, has the potential to improve BP control, to reduce adverse health care outcomes, and to lower the cost of cardiovascular care in the hypertensive population.