Abstract
This study sought to identify patterns of antihypertensive drug modifications in initial drug therapy as well as to examine the effect of modifications on costs. The study population included adults who initiated antihypertensive drug therapy during 12 months of therapy. Approximately three‐fourths of study participants had a change in therapy within the first 12 months of treatment. Discontinuation (57.1%) of antihypertensive drug treatment was the most prevalent modification type, followed by titrations (14.6%). Initiating treatment with fixed‐dose combinations was associated with the lowest likelihood of a nondiscontinuation modification (12.5%); the use of 2 separate drugs was associated with the least likelihood of complete discontinuation (28.7%). The presence of therapy changes was associated with increased health services costs in the first 12 months of antihypertensive drug therapy. Clinicians and payers should be aware of the association between starting specific antihypertensive treatment regimens and the likelihood of changes in medication and changing costs.
Antihypertensive medications are widely used for hypertension and other cardiovascular diseases. These affect a significant proportion of the American population (1 in 4 Americans) and have resulted in as many as 931,000 deaths per year, with costs exceeding $300 billion per year. 1 , 2 Recent data suggest that deaths from cardiovascular disease are decreasing. Therapy linked to these conditions is of importance because of the potential complexity of treatment regimens. 3 Part of the complexity arises from the various types of potential drug therapy modifications needed 4 , 5 , 6 This is further magnified by the fact that an increasing number of individuals with hypertension, primarily older adults, also suffer from other chronic conditions that require different drug treatment. 7 , 8
The critical role antihypertensive drug modifications play in achieving optimal blood pressure merits a better understanding of the prevalence and trends of the modifications. The importance of such investigations is magnified by findings from studies that report patient‐ and physician‐related characteristics (eg, reluctance to modify drug therapy) as barriers to achieving optimal blood pressure. 9 Furthermore, recent years have witnessed an increase in prescription drug benefit changes—tiered formularies, drug expenditure caps, and preferred drug lists—in public and private insurance plans. Such changes have made decisions regarding medication regimens more complicated and have been suggested as major reasons for the increased likelihood of nonadherence. 10 , 11 The aim of this study was to explore the prevalence and trend of antihypertensive drug modifications and the potential impact of drug class and patient and provider characteristics on the likelihood of changes in therapy. In addition, the association between health services costs and the occurrence of these was explored. The goal of this investigation was to generate findings that can potentially serve as a resource to clinicians when beginning antihypertensive drug therapy. The examination of health services costs also may help the process of drug benefit design in public and private plans.
METHODS
Study Population
The study population consisted of individuals enrolled in a managed care organization serving a primarily Northeastern state. Eligible participants included (1) individuals aged 18 years and older who started antihypertensive drug therapy during the period between January 1, 2001, through December 31, 2004, and had no claim for an antihypertensive medication in the 6 months before the initial prescription; (2) had a hypertension diagnosis recorded before the initiation of drug therapy; and (3) had 12 months of continuous enrollment after the therapy initiation date. Exclusion criteria used in the study included (1) a diagnosis of ischemic heart disease, myocardial infarction, congestive heart failure, cardiac arrhythmia, or renal disease before or during the first year of treatment for hypertension; (2) the combination of a diagnosis of lower‐extremity edema and a prescription for a diuretic; (3) the combination of a diagnosis of benign prostatic hypertrophy and a prescription for an α1‐adrenergic receptor blocker; and (4) a diagnosis of anxiety or panic disorders combined with a prescription for a β‐blocker or clonidine. 12 By excluding individuals with these diagnoses, it is expected that the study population would be more homogeneous and contain individuals who, at least at the beginning of the index year, had uncomplicated hypertension.
Data Sources
Data were extracted from several datasets to satisfy the study objectives. The first step involved extracting antihypertensive medication claim records submitted between January 1, 2000, through December 31, 2005. Subsequently, this dataset was supplemented by other pharmacy claims for those individuals receiving antihypertensive medications during the same period. In addition, membership files were used to identify enrollment patterns. Finally, medical claims data (inpatient, outpatient, physician visits, and emergency department visits) were extracted for this group. The medical claims data files used were also from January 1, 2000, through December 31, 2005. These served a dual purpose: first, they allowed for the identification of comorbid conditions (including hypertension), and second. they enabled the examination of the effect of antihypertensive drug modifications on health services costs.
Dependent Measures
Two groups of outcome measures were examined. The first related to prevalence and trends of antihypertensive drug modifications, and the second investigated health services costs.
Antihypertensive Drug Modifications. Additions or augmentation were identified when an antihypertensive medication from another drug class was added to the initial regimen for ≥60 days without the deletion of any of the existing drug classes from the initial regimen. Deletions were identified when an antihypertensive drug was removed from the regimen for ≥60 days without being replaced by another drug from the same class.
Titrations were defined as the increase or decrease in dose of previously established antihypertensive medication(s) and/or the increase or decrease in the frequency of drug use (From once daily to twice daily, etc). It is worth noting that the percentage of titrations at 12 months includes those at 12 months and beyond (some titrations were counted in the 13th month because of the extension of drug supply beyond 12 months). In addition, gaps were not considered in the estimation of the number of titrations (eg, an individual who had a gap of 4 months and then resumed treatment often resumed it at a different dosage compared with when he or she temporarily discontinued antihypertensive drug treatment; this was counted as a titration for the purposes of study definitions).
Switching was defined as replacing an antihypertensive drug with another from a different class. Switching was identified if a new class was added within 30 days of the termination of another class and continued for at least 60 days. Discontinuation of therapy was defined as a gap in the medication supply of at least 90 days or the expiration date during the follow‐up period, whichever was earlier, and not taking any other antihypertensive medication during that period (ie, stopping all antihypertensive medication therapy). It is also worth noting that events where a deletion of an antihypertensive drug was not followed by the use of any other antihypertensive medication were identified only as discontinuations.
Health Services Costs. Outcome measures related to health services focused on inpatient, outpatient, emergency department visits, physician services, and medication costs. Measures of costs were examined in the first 12 months of treatment.
Independent Measures
The independent measures included antihypertensive drug modifications and antihypertensive class (angiotensin‐converting enzyme inhibitors (ACEIs), angiotensin receptor blockers, β‐blockers, calcium channel blockers (CCBs), and diuretics as well as fixed‐dose combination agents (eg, ACEI/CCB and other classes combined with a diuretic). Diuretic/diuretic combinations (eg, hydrochlorothiazide/triamterene) were considered a single‐class product. A fixed‐dose combination agent constitutes a single medication that is a combination of multiple drugs and/or classes, whereas the other category refers to multiple drugs and/or classes given as separate medications. It is worth noting that this measure was considered independent only when examining health resource utilization as an independent measure. Patient demographic characteristics (age and sex) patient comorbidities, and first prescriber type and specialty were also considered independent measures.
Statistical Analysis
Univariate analyses were conducted that described the patient demographics, comorbidities, and starting antihypertensive drug class. In addition, bivariate analysis was conducted to test the association between modification type and drug class. Furthermore, logistic regression models were developed that examined the effect of antihypertensive drug class, patient demographics (age and sex), comorbidities, and prescriber credentials and specialty on the likelihood of a modification, using a categorical variable (presence/absence of modification). Finally, linear regression analysis was conducted with health services costs (logged function) as the outcome measure; combined starting class and modification type as dummy variables; number of months to first modification, patient demographics, and comorbidities used as independent variables. The analysis was conducted using SAS version 9.1 (SAS Institute Inc, Cary, NC).
RESULTS
The study population consisted of 22,821 individuals who met the inclusion criteria (Table I). The average age was 55 years; slightly less than half (47.3%) were female. The antihypertensive drug class on which most study participants were started was ACEIs (29.2%), followed by diuretics (19.1%) and β‐blockers (14.8%). On the other hand, 2 separate medications were the antihypertensive drug class least prescribed as initial drug therapy.
Table I.
Description of the Study Population, All Classes (N=22,821)
| Patient Characteristics | No./Avg. | %/Std. |
|---|---|---|
| Age | 55.0 | 12.4 |
| Female sex | 12,030 | 47.3 |
| Antihypertensive starting class | ||
| Fixed‐dose combination agent | 2931 | 12.8 |
| 2 Separate agents | 1491 | 6.5 |
| Angiotensin‐converting enzyme inhibitor | 6652 | 29.2 |
| Angiotensin receptor blocker | 1561 | 6.8 |
| β‐blocker | 3371 | 14.8 |
| Calcium channel blocker | 2449 | 10.7 |
| Diuretic | 4366 | 19.1 |
Overview of Modifications
A detailed description of the prevalence of modifications by antihypertensive drug class is presented in Figure 1 and Table II. Approximately three‐fourths of study participants (74.6%) had therapy modified at sometime. The least common modification of the initiating drug was switching (4.0%) (Table III). Discontinuation was the most prevalent (57.1%), followed by titrations (14.6%) and deletions (13.7%). ACEI was the class associated with the most modifications (80.4%), and the use of 2 separate agents with the fewest modifications (60.2%). Separating the modifications into discontinuation and nondiscontinuation revealed that fixed‐dose combinations had the least likelihood of a nondiscontinuation modification (12.5%). On the other hand, the use of 2 separate agents was associated with the least likelihood of complete discontinuations (28.7%). Figure 2 presents the time distribution of the percentage of patients discontinuing the initial antihypertensive class (for 2 separate medications, it was on 1 of the initial antihypertensive drug classes) during the first 12 months of drug therapy. The findings revealed that individuals taking 2 separate medications were most likely to discontinue at least 1 of the initial antihypertensive classes in the first few months. On the other hand, those on fixed‐dose combinations tended to discontinue the initially prescribed antihypertensive later.
Figure 1.
Overview of the presence of antihypertensive drug modifications in the first 12 months of drug treatment regimen by antihypertensive starting class. Note: These categories are not mutually exclusive. ACEI indicates angiotensin‐converting enzyme inhibitor; ARB, angiotensin receptor blocker; BB, β‐blocker; CCB, calcium channel blocker; DIU, diuretic.
Table II.
Overview of the Presence of Antihypertensive Drug Modifications in the First 12 Months of Drug Treatment by Antihypertensive Starting Class and Modification Type Among Those With a Modification
| Antihypertensive Starting Class | Addition | Deletion | Titration | Switching | Discontinuation | |||||
|---|---|---|---|---|---|---|---|---|---|---|
| No. | % | No. | % | No. | % | No. | % | No. | % | |
| All classes | 1837 | 8.1 | 3133 | 13.7 | 3330 | 14.6 | 901 | 4.0 | 13,022 | 57.1 |
| Antihypertensive starting class | ||||||||||
| Fixed‐dose | 153 | 5.2a | 242 | 8.3a | 330 | 11.3a | 91 | 3.1a | 1676 | 57.2a |
| 2 Drugs | 116 | 7.8 | 469 | 31.5 | 210 | 14.1 | 9 | 0.6 | 428 | 28.7 |
| Angiotensin‐converting enzyme inhibitor | 318 | 4.8 | 762 | 11.5 | 1185 | 17.8 | 276 | 4.2 | 4351 | 65.4 |
| Angiotensin receptor blocker | 107 | 6.9 | 197 | 12.6 | 188 | 12.0 | 65 | 4.2 | 848 | 54.3 |
| β‐blocker | 388 | 11.5 | 392 | 11.6 | 620 | 18.4 | 106 | 3.1 | 1896 | 56.2 |
| Calcium channel blocker | 303 | 12.4 | 359 | 14.7 | 407 | 16.6 | 132 | 5.4 | 1214 | 49.6 |
| Diuretic | 452 | 10.4 | 712 | 16.3 | 390 | 8.9 | 222 | 5.1 | 2609 | 59.8 |
| a P<.001. Statistical significance was conducted for differences across class by modification type. | ||||||||||
Table III.
Logistic Regression: The Effect of Starting Class and Patient and Provider Characteristics on the Likelihood of Antihypertensive Drug Therapy Modifications During the First 12 Months of Drug Treatment Regimen
| Characteristic | Any Modification a | Discontinuation b | Nondiscontinuation c | |||
|---|---|---|---|---|---|---|
| OR | 95% CI | OR | 95% CI | OR | 95% CI | |
| Antihypertensive Starting Class | ||||||
| Fixed‐Dose Combination | Reference | Reference | Reference | |||
| 2 Drugs | 0.67 | 0.59–0.77 | 0.31 | 0.27–0.35 | 3.14 | 2.69–3.67 |
| Angiotensin‐converting enzyme inhibitor | 1.70 | 1.54–1.88 | 1.33 | 1.22–1.46 | 1.29 | 1.13–1.47 |
| Angiotensin receptor blocker | 0.99 | 0.87–1.14 | 0.84 | 0.74–0.96 | 1.39 | 1.16–1.65 |
| β‐blocker | 1.33 | 1.19–1.49 | 0.98 | 0.88–1.08 | 1.61 | 1.40–1.85 |
| Calcium channel blocker | 1.14 | 1.01–1.28 | 0.73 | 0.66–0.82 | 2.06 | 1.78–2.38 |
| Diuretic | 1.40 | 1.26–1.56 | 1.10 | 1.00–1.21 | 1.42 | 1.24–1.63 |
| Patient Characteristics | ||||||
| Age | 0.99 | 0.99–0.99 | 0.99 | 0.99–0.99 | 1.01 | 1.00–1.01 |
| Female sex | 0.92 | 0.87–0.99 | 0.86 | 0.82–0.91 | 1.14 | 1.06–1.23 |
| Provider Characteristics | ||||||
| Provider credentials | ||||||
| Osteopathic doctor | 1.03 | 0.92–1.16 | 1.11 | 1.00–1.24 | 0.87 | 0.76–1.00 |
| Medical doctor | Reference | Reference | Reference | |||
| Nurse practitioner/physician assistant | 1.59 | 1.38–1.85 | 1.77 | 1.57–2.00 | 0.67 | 0.56–0.79 |
| Other | 0.68 | 0.17–2.71 | 2.23 | 0.55–9.09 | ‐ | ‐ |
| Provider specialty | ||||||
| General internal medicine | 0.91 | 0.84–0.99 | 0.95 | 0.88–1.02 | 0.97 | 0.89–1.07 |
| Cardiology | Reference | Reference | Reference | |||
| Emergency medicine | 1.10 | 0.87–1.38 | 1.04 | 0.85–1.26 | 1.05 | 0.82–1.34 |
| Geriatrics | 1.08 | 0.85–1.37 | 1.19 | 0.96–1.46 | 0.83 | 0.63–1.10 |
| General practitioner | 0.93 | 0.85–1.02 | 0.95 | 0.88–1.03 | 0.98 | 0.89–1.09 |
| Obstetrics and gynecology | 1.68 | 1.04–2.69 | 1.68 | 1.15–2.46 | 0.76 | 0.47–1.24 |
| Surgery | 1.11 | 0.63–1.96 | 1.39 | 0.84–2.30 | 0.65 | 0.32–1.31 |
| Other | 1.01 | 0.78–1.43 | 0.83 | 0.65–1.08 | 1.38 | 1.03–1.87 |
| Comorbidities in the model included valvular disease, pulmonary circulation disorders, peripheral vascular disease, paralysis, other neurologic condition, chronic obstructive pulmonary disease, uncomplicated diabetes, complicated diabetes, hypothyroidism, AIDS, liver disease, peptic ulcer disease, lymphoma, metastatic cancer, solid tumor (no metastasis), rheumatoid arthritis, coagulopathy, obesity, weight loss, fluid and electrolyte disorders, blood loss anemia, deficiency anemia, alcohol abuse, drug abuse, psychoses, and depression. The unit of analysis was the individual. aC statistic=58.5%; bC statistic=60.4%; cC statistic=60.9%. Abbreviations: OR, odds ratio; CI, confidence interval. | ||||||
Figure 2.
The time distribution of the percentage of patients discontinuing the initial antihypertensive class during the first 12 months of antihypertensive drug treatment (of individuals who dropped initial antihypertensive class). DIU indicates diuretic; CCB, calcium channel blocker; BB, β‐blocker; ARB, angiotensin receptor blocker; ACEI, angiotensin‐converting enzyme inhibitor.
Multivariate regression results revealed that compared with fixed‐dose combinations, only the use of 2 separate agents had a lower likelihood of a modification (odds ratio [OR], 0.67; 95% confidence interval [CI], 0.59–0.77). Categorizing modifications as an outcome measure into discontinuations and nondiscontinuations revealed that this group had a lower likelihood of discontinuations (OR, 0.31; 95% CI, 0.27–0.35); however, fixed‐dose combinations were associated with the lowest likelihood of nondiscontinuation modifications. Female sex was associated with a lower likelihood of discontinuation (OR, 0.86; 95% CI, 0.82–0.91) and a higher association with nondiscontinuation modification (OR, 1.14; 95% CI, 1.06–1.23). With respect to provider credentials, nurse practitioners/physician assistants were associated with a higher likelihood of a patient discontinuing antihypertensive drug therapy as compared with medical doctors (OR, 1.77; 95% CI, 1.57–2.00) and a lower likelihood of other types of modifications (OR, 0.67; 95% CI, 0.56–0.79).
Associated Health Services Costs
Individuals who had drug therapy modified or changed, irrespective of starting antihypertensive drug class, had higher health services costs during the first 12 months of antihypertensive drug therapy (Figure 3). Compared with individuals on fixed‐dose combinations who had no modification, those on ACEIs who had no modification (coefficient=−0.17; P<.01), on β‐blockers who had no modification (coefficient=−0.30; P<.001), and on diuretics who had no modification (coefficient=−0.21; P<.001) had lower health services costs. Categorizing modifications into discontinuations and nondiscontinuations, however, revealed that those who discontinued therapy had lower health services costs among all antihypertensive drug classes. On the other hand, modifications in treatment without discontinuation were associated with higher health services costs.
Figure 3.
The effect of modification status, antihypertensive class and patient characteristics on health services costs during the first 12 months of the drug treatment regimen, all classes The model included age, sex, and comorbidities. The unit of analysis was the individual. All class/modification combinations were significant at P<.05 except ARB/no modification and CC/no modification. ARB indicates angiotensin receptor blocker; CCB, calcium channel blocker; ACEI, angiotensin‐converting enzyme inhibitor; BB, β‐blocker; DIU, diuretic.
DISCUSSION
The latest guidelines issued by the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) highlight the importance of aggressively controlling blood pressure to reduce the risk of morbidity and mortality. 13 Following such guidelines requires active and informed providers. Studies that have surveyed hypertension treatment practices have reported a need for physicians to be more familiar with guidelines to enhance treatment effectiveness 14 and to be aware of therapy recommendations. 9 This study examined the prevalence and trends of antihypertensive drug therapy modifications during the first 12 months of drug treatment and health resource utilization associated with such modifications.
The findings revealed that approximately three‐fourths of individuals starting an antihypertensive drug treatment regimen had therapy modified within the first 12 months of treatment. A considerable proportion of these modifications would be expected since providers generally attempt to adjust drug treatment (eg, dosage, frequency, antihypertensive class) to achieve blood pressure goals. 5 , 6 The question, however, is whether starting individuals on any particular antihypertensive class is associated with a lower likelihood of modifications and, second, whether the occurrence of these changes was associated with additional health resource use.
Findings revealed that beginning treatment with diuretics and ACEIs was associated with the highest likelihood of a modification; it is worth noting that many patients with high blood pressure are started on one of these classes. 5 , 14 On the other hand, the use of 2 separate medications was associated with the least likelihood of a modification, followed by fixed‐dose combination drugs, even after controlling for patient and provider characteristics. Separating the modifications into discontinuation and nondiscontinuation modifications revealed a different pattern, however; fixed‐dose combinations were least likely to be associated with modifications other than discontinuation (12.5%), while 2‐drug regimens were associated with the least likelihood of discontinuation (28.7%). One reason for such a finding is that patients started on 2 medications may perceive their hypertension to be more severe (requiring more pills) than those receiving fixed‐dose combinations and, hence, may be more compliant. Alternatively, a noncompliant patient may stop only 1 drug in the regimen, an event recorded as a deletion rather than a discontinuation, but would have to stop all drugs in a fixed‐dose combination to have a discontinuation event recorded. The finding that fixed‐dose combination therapy was associated with the least likelihood of a nondiscontinuation modification may possibly be due to the clinical effectiveness of such therapy in controlling blood pressure resulting in a lesser need for a modification 15 , 16 , 17 , 18 , 19 compared with monotherapy and the use of 2 separate medications.
Another interesting finding of the study relates to the effect of modifications on health services costs. The presence of nondiscontinuation modifications was associated with increased health services costs in the first 12 months of antihypertensive drug treatment, after controlling for patient and provider characteristics. This is to be expected because the changing of medications requires more physician and outpatient (eg, laboratory) visits for monitoring. On the other hand, discontinuations were associated with lower costs primarily as a result of decreased need for follow‐up services. This finding highlights the importance of avoiding random drug and dose changes, because this is associated with increased resource use.
Several limitations of the study merit consideration. First, the lack of baseline blood pressure data prevents the assessment of the severity of an individual's condition. We are also unable to assess when or whether the blood pressure goal was achieved in individuals and whether therapy had proved effective. The absence of such important clinical indicators limits the ability for a full assessment of factors, resulting in modifications or initiation of different treatment regimens. Second, the study did not examine the long‐term adverse effects of discontinuing a drug, specifically as it relates to health services costs. Third, the study population comprised many benefit groups that had different formulary structures. As such, it was challenging to introduce the issue of formulary composition/switches as a factor affecting modifications. Fourth, we are unable to determine what percentage of the modifications decisions initiated by the provider or the patient were initiated by the promotional activities addressed to both parties. Fifth, the study design does not allow the identification of whether discontinuation was initiated by the provider or the patient. Furthermore, in the case that the modification was initiated by the provider, it was not possible to detect whether it was due to an adverse event or a suboptimal response in the patient. Finally, when examining the prescriber credentials and specialty, the study only examined the first prescriber. Although the first prescriber may continue to serve in that role, it is possible that patients with more difficult to control hypertension were more likely to be referred to other providers (eg, specialists) for drug management.
CONCLUSIONS
The likelihood of antihypertensive drug modification in initial hypertension treatment was detected to be common and to vary by initiating drug class/type of therapy. Health resource utilization was found to be associated with the presence of modifications (nondiscontinuation and discontinuation‐related) and initiating drug class/type of therapy. The findings from this study could constitute a resource for clinicians and purchasers to consider when making clinical judgement and in policy formulation.
Disclosure:
This research was sponsored by Novartis Pharmaceuticals Corporation. Two of the authors are employees of Novartis Pharmaceuticals Corporation.
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