the Harris Corporation, Falls Church, Va (Q.G.), and Division of Health and Nutrition Examination Surveys, National Center for Health Statistics, Centers for Disease Control and Prevention, Hyattsville, Md (R.P.-R., C.D., V.B.).
Abstract
Background— High blood pressure can be controlled through existing antihypertensive drug therapy. This study examined trends in prescribed antihypertensive medication use among US adults with hypertension and compared drug utilization patterns with recommendations of the Sixth Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.
Methods and Results— Persons aged 18 years from the National Health and Nutrition Examination Surveys were identified as hypertensive on the basis of either a blood pressure 140/90 mm Hg or self-reported current treatment for hypertension with a prescription medication. In 1999–2002, 62.9% of US hypertensive adults took a prescription antihypertensive medication compared with 57.3% during 1988–1994 (P<0.01). Men had the greatest increase in antihypertensive medication use (47.5%, 1988–1994 versus 57.9%, 1999–2002 [P<0.001]). In both surveys, antihypertensive medication use increased with age, was lower among men than among women, and was lower among Mexican Americans than among non-Hispanic whites and blacks. Multiple antihypertensive drug use increased from 29.1% to 35.8% (P<0.001). Polytherapy with a calcium channel blocker, -blocker, or angiotensin-converting enzyme inhibitor significantly increased by 30%, 42%, and 68%, respectively, whereas monotherapy with a diuretic or -blocker significantly decreased. For hypertensives with diabetes, congestive heart failure, or a prior heart attack, the utilization patterns closely followed the Sixth Joint National Committee guideline recommendations.
Conclusions— Antihypertensive medication use and multiple antihypertensive medication use among US hypertensive adults increased over the past 10 years, but disparities by sociodemographic factors continue to exist.
Key Words: hypertension population drugs
Introduction
Hypertension or high blood pressure is among the most common chronic medical conditions, affecting >65 million individuals in the United States.1 Approximately $37 billion is spent annually for medications, office visits, and laboratory tests related to hypertension treatment.2 In the past 3 decades, hypertension treatment has contributed to a decrease in morbidity and mortality from cardiovascular disease. Findings from the National Health and Nutrition Examination Surveys (NHANES) during 1960–1991 indicated an upward trend in awareness, treatment, and control rates of hypertension in the United States.3 However, NHANES 1999–2000 data, presented in the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC), showed an increasing prevalence of hypertension.4 These data also showed a continued poor blood pressure control rate (<35%) for US hypertensives, which is far below the Healthy People 2010 goal of 50%.5 It is therefore important to understand current antihypertensive medication utilization patterns and to study their impact on blood pressure control and hypertension-related clinical outcomes.
Editorial p 178
A large number of drugs, including diuretics, -blockers, calcium channel blockers (CCBs), angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARBs), are available for lowering elevated blood pressures. These drugs have been shown to reduce hypertension-related morbidity and mortality.6,7 On the basis of many randomized clinical trials, the 1997 JNC VI recommended diuretics and -blockers as the first-line agents for pharmacological treatment of uncomplicated hypertension; listed compelling indications for CCBs, ACE inhibitors, and -blockers; and discussed additional favorable clinical indications for these and other drug classes.7 However, most previous published data indicated an increasing use of the more expensive CCBs and ACE inhibitors8–10 despite the lack of evidence to support that they are superior to diuretics and -blockers in preventing major forms of cardiovascular disease. To understand current medication utilization patterns among hypertensives, this study compared NHANES III (1988–1994) and NHANES 1999–2002 data to examine trends and patterns of antihypertensive medication use among US adults with hypertension.
Methods
The NHANES III and NHANES 1999–2002 are cross-sectional surveys designed to select a nationally representative sample of the civilian noninstitutionalized US population with oversampling of young children, older persons, black persons, and Mexican Americans. Data collected during NHANES III11 are comparable to NHANES 1999–200212 data. Survey participants received a detailed in-person home interview, followed by a physical examination including blood pressure measurements at a mobile examination center. Informed consent was obtained from all participants, and the protocol was approved by the institutional review board of the National Center for Health Statistics.
During the home interview, participants were asked, "Have you taken or used any prescription medicines in the past month" Respondents who answered affirmatively were further asked to report the name, duration, and main reason for each product used. An interviewer recorded the exact product name from the medication container label. If the container was unavailable, the participant verbally reported this information. With the use of the JNC VI and JNC VII list of oral antihypertensive drugs4,7 and the assistance of pharmacists at the Food and Drug Administration, antihypertensive agents reported by participants in NHANES III and NHANES 1999–2002 were identified. Any antihypertensive drug use was defined as a report of using 1 or more of these drugs. Six therapeutic drug classes including -blockers, CCBs, diuretics, ACE inhibitors, ARBs, and other antihypertensive agents (1-blockers, central 2-agonists, direct vasodilators, and other centrally acting drugs) were classified. A person could have used more than 1 antihypertensive medication within the past month or an antihypertensive medication containing more than 1 antihypertensive active ingredient. In both cases, the person was counted once within each antihypertensive drug class used. Persons who used an antihypertensive medication with only 1 active ingredient were defined as receiving monotherapy. Those taking more than 1 active ingredient (either in 1 combination pill or in 2 different single pills) were defined as receiving polytherapy.
Blood pressure was measured with the participant in the sitting position after 5 minutes of rest by a physician at the mobile examination center. The average of up to 3 measurements was used. Hypertension was defined as a mean systolic blood pressure 140 mm Hg, or a mean diastolic blood pressure 90 mm Hg, or current hypertension treatment with prescription medication (affirmative answers to the following sequence of questions: "Has a doctor ever told you that you had high blood pressure"; "Because of your high blood pressure, have you ever been told to take prescribed medicine"; and "Are you now taking prescribed medicine").13
The NHANES III response rate for completion of the interview and health examination was 78%. Of those, 5003 adults aged 18 years were identified as hypertensive on the basis of the aforementioned criteria. Seventy were excluded because of missing prescription medication data. The final analytic sample was 4933. The NHANES 1999–2002 response rate for completion of the interview and health examination was 75%. Of those, 3288 adults aged 18 years were identified as hypertensive, and 39 were excluded because of missing prescription medication data. The final analytic sample was 3249.
A history of physician-diagnosed diabetes, stroke, congestive heart failure, and heart attack was assessed by questionnaire. Diabetes only presenting during pregnancy was defined as no diabetes. Glomerular filtration rate was estimated with the use of the Modification of Diet in Renal Disease (MDRD) equation,14 subtracting 0.23 mg/dL from the NHANES III serum creatinine levels to adjust for calibration differences between NHANES III and the MDRD study.15 Chronic kidney disease (CKD) was defined as either an estimated glomerular filtration rate <60 mL/min per 1.73 m2 or 200 mg albumin per gram urinary creatinine.4 Hypertensives who had none of the aforementioned 5 comorbidities were categorized as uncomplicated hypertensives.
Statistical analyses were conducted with the use of SAS (SAS Institute) and SUDAAN (RTI). Sample weights were used to account for differential probabilities of selection and the complex sample design and to obtain estimates representative of the noninstitutionalized US population aged 18 years. Variance estimates were computed with the Taylor series linearization approximation approach.16,17 An estimate with a relative SE >30% was considered statistically unreliable and noted in the tables. Statistical hypotheses were tested univariately at the 0.05 level with a t statistic. The Bonferroni method was used to adjust for multiple comparisons when differences between age groups were tested (4 comparisons, =0.05/4) and race/ethnicity groups (3 comparisons, =0.05/3). Tests for differences between the 2 study periods were performed at the 0.05 level with 2-sample t tests for comparisons of weighted percentages between the NHANES III and NHANES 1999–2002 data.
Because age structures may be different between surveys or between race/ethnicity groups, we examined the potential impact of age by the direct age-standardized method in which weights corresponding to the NHANES 1999–2002 hypertensive population were used to estimate antihypertensive medication use prevalence during NHANES III. Results in which these adjusted weights were used led to only minor differences in point and variance estimates without changing any comparisons in trends across surveys or race/ethnicity comparisons within surveys. Thus, in this report we present unadjusted estimates. Additionally, we do not present race/ethnicity estimates that are age-adjusted to the standard US population because the age structures of the hypertensive populations for NHANES III and NHANES 1999–2002 are very different from the standard US population (specifically, they are significantly older). By age-standardizing the antihypertensive drug use estimates with the standard US population, the true prevalence of antihypertensive medication use would be significantly underestimated. Instead, we provide unadjusted prevalence estimates that are stratified at multiple levels to increase the precision of estimates in specific demographic subgroups.
Results
Table 1 provides baseline characteristics of the sample populations, weighted to be representative of the US hypertensive adult population. The gender and race/ethnicity distributions of the hypertensive populations were similar during 1988–1994 and 1999–2002. The average ages of the hypertensive populations were 59.6 years. By 1999–2002, the percentage of hypertensives aged 50 to 59 years increased, and those aged 18 to 39 years decreased. The proportions of hypertensives with stroke, congestive heart failure, or a heart attack were also similar between 1988–1994 and 1999–2002. Approximately 70% of hypertensives had none of the 5 major comorbidities. Compared with NHANES III, the current hypertensive population had a higher body mass index value, higher diabetes prevalence, and lower CKD prevalence. Both the NHANES III and NHANES 1999–2002 hypertensive populations had similar mean systolic blood pressure, but hypertensives in NHANES 1999–2002 had a lower mean diastolic blood pressure value than those in NHANES III. The proportion of the hypertensive populations with normal blood pressure (<140/90 mm Hg) significantly increased, whereas the proportion with stage 1 hypertension significantly decreased. In both surveys, &20% had stage 2 hypertension (160/100 mm Hg).
Prescription Antihypertensive Medication Use by Demographic Factors
Between 1988–1994 and 1999–2002, antihypertensive medication use prevalence among hypertensive adults significantly increased from 57.3% to 62.9% (Table 2). Antihypertensive medication use increased for men (47.5% versus 57.9%); non-Hispanic whites (58.8% versus 64.5%); non-Hispanic blacks (56.6% versus 65.2%); and hypertensives aged 70 years (65.3% versus 70.7%). Specifically, antihypertensive medication use increased for non-Hispanic white men aged 60 years, non-Hispanic black men aged 50 years, and Mexican American men aged 60 to 69 years. For women, a significant increase in use was observed only for Mexican American women aged 70 years (45.3% versus 61.7%).
Overall, during both surveys, antihypertensive medication use was greater among hypertensive women than men, older adults than younger persons, and non-Hispanic whites and non-Hispanic blacks than Mexican Americans. When race/ethnicity differences were further examined by gender and age groups, a different pattern emerged. By 1999–2002, Mexican American men had lower utilization than non-Hispanic whites at 40 to 59 years of age and non-Hispanic blacks at 50 to 69 years of age, but there were no differences by 70 years of age. For women, Mexican Americans had significantly lower utilization compared with non-Hispanic blacks at 50 to 69 years of age, but there were no differences compared with either race/ethnic group at 40 to 49 and 70 years.
Drug Classes, Monotherapy Versus Polytherapy
When monotherapy and polytherapy were considered together, diuretics remained the most commonly used antihypertensive drug class during 1988–1994 (27.8%; Figure 1) and 1999–2002 (28.7%). Use remained stable across both time periods for most drug classes, except for ACE inhibitors, for which there was a significant increase in use (15.2% versus 23.8%). During 1988–1994, ARBs were not in general clinical use, but by 1999–2002, ARB use among hypertensive adults had reached 9.0% (SE, 0.71; data not shown).
Overall, antihypertensive polytherapy use among hypertensives increased significantly between 1988–1994 and 1999–2002 from 29.1% to 35.8% (Figure 1). Specifically, the use of polytherapies containing a CCB, -blocker, or ACE inhibitor substantially increased by 30%, 42%, and 68%, respectively. Between 1988–1994 and 1999–2002, ACE inhibitor monotherapy use significantly increased from 6.2% to 8.5%, whereas monotherapy use of a diuretic or -blocker decreased from 4.9% and 7.1% to 2.7% and 5.1%, respectively.
Diuretics (including the use of multiple diuretics or a diuretic combined with another drug class) remained the most commonly used polytherapy during both time periods. A diuretic plus a -blocker, ACE inhibitor, or CCB each accounted for 20% of all polytherapy medication users, respectively, in both surveys (Figure 2). Between 1988–1994 and 1999 to 2002, significant increases were only observed for polytherapies containing an ACE inhibitor. Specifically, the use of an ACE inhibitor with a diuretic, CCB, or -blocker significantly increased by 23%, 45%, and 142%, respectively.
Most Frequently Used Antihypertensive Drugs
During 1988–1994, the diuretic drug triamterene and hydrochlorothiazide (a single pill combination) was the most commonly used antihypertensive agent, with a 14.4% prevalence of use among antihypertensive drug users (Table 3). However, its use significantly declined after 1988–1994 to 7.5%, making it the seventh most commonly used antihypertensive in 1999–2002. Additionally, the use of propranolol, verapamil, nifedipine, and enalapril maleate also decreased significantly over the past decade. By 1999–2002, the use of lisinopril significantly increased from 6.8% to 13.6%, making this ACE inhibitor the most commonly used antihypertensive agent, followed by the -blocker atenolol and the diuretic hydrochlorothiazide. During 1988–1994, only a few hypertensives reported amlodipine besylate use, and a statistically reliable percentage of use could not be estimated on the basis of this small sample size. However, by 1999–2002, amlodipine besylate use accounted for 9.2% of all antihypertensive medication users, making it the fifth most commonly used antihypertensive medication.
Antihypertensive Drug Use by Comorbidities
During 1988–1994 and 1999–2002, more than three quarters of hypertensive adults with CKD, diabetes, stroke, or congestive heart failure used an antihypertensive medication, with no significant differences in overall utilization between the 2 time periods (Table 4). Antihypertensive medication use among those with a prior heart attack increased by 10% (82.2% versus 90.7%), mainly because of a near doubling in the use of -blockers (24.6% versus 47.9%). -Blocker use also increased by 93% among those with congestive heart failure and by 48% among those with CKD. There were also significant increases in ACE inhibitor use for certain comorbidities. Between 1988–1994 and 1999–2002, ACE inhibitor use increased by 64% among those with CKD, by 86% among diabetic hypertensives, and by 55% among those with congestive heart failure.
More than 70% of hypertensives reported none of the 5 major chronic conditions identified above (Table 1): 48.5% of these persons reported antihypertensive medication use during 1988–1994 (Table 4), and this number significantly increased to 54.6% during 1999–2002 partly because of a significant increase in ACE inhibitor use (12.2% versus 17.8%).
Discussion
The benefit of blood pressure reduction with antihypertensive drug treatment has become increasingly evident, with decreases in both all-cause mortality and coronary artery disease as shown by multiple clinical trials and epidemiological studies, with the greater absolute benefit in older patients.7,18,19 This study found that antihypertensive medication use among US hypertensive adults significantly increased over the past decade, primarily because of an increase in antihypertensive medication use among men. Older non-Hispanic white and black men had the greatest increase in antihypertensive medication use. Increased cardiovascular disease risk among older men may have contributed to the increased prescribing of antihypertensive drugs to those aged 60 years.20
Overall, Mexican American hypertensives had lower antihypertensive medication use than non-Hispanic whites or blacks. These differences, however, were less apparent when use by specific age-groups and gender was examined. Specifically, for women there were minimal race/ethnic disparities in 1999–2002. The differences that existed at 50 to 69 years of age can be explained by increased use among non-Hispanic black hypertensive women (>80% utilization). This could indicate that efforts to increase antihypertensive prescribing and use among non-Hispanic black hypertensive women have been successful and that similar efforts could be made with the other groups. For men, although Mexican American hypertensives aged 60 to 69 years had a significant increase in antihypertensive drug use between 1988–1994 and 1999–2002, race/ethnic disparities continued to exist in this age group as well as at 40 to 59 years of age. Continued efforts are needed among hypertensive men of all race/ethnic groups and specifically among the younger age groups.
On the basis of evidence from epidemiological studies and clinical trials, JNC VI and JNC VII recommended that diuretics and -blockers be used as first-line antihypertensive agents for uncomplicated hypertension.4,7 Our study found that although diuretics were the most frequently prescribed drug class for management of hypertension during both surveys, ACE inhibitor use increased markedly. This trend was also observed among uncomplicated hypertensives. If we consider ACE inhibitors and ARB as 1 class, that is, as agents that block the renin-angiotensin-aldosterone system, renin-angiotensin-aldosterone system medication use doubled over this time period, making it the most frequently used drug class in 1999–2002. In contrast, monotherapy with diuretics or -blockers significantly decreased over the past decade. The rising use of ACE inhibitors may be explained by their substantial benefits in congestive heart failure and diabetes as JNC VI recommends this drug class as the first-line treatment for hypertensives with these conditions.7 However, it is difficult to explain the increased use among uncomplicated hypertensives. The decreasing use of diuretics or -blockers may be explained by physician misperceptions that diuretics are less effective and that -blockers are less well tolerated than other medications.21–23
Recently, several large clinical trials demonstrated that most patients with hypertension can achieve and sustain adequate blood pressure control only with the use of multiple antihypertensive drugs.24,25 Initiating drug therapy with a diuretic, either alone or in combination with an agent from another drug class, apparently provides the best outcomes for hypertension management, and these findings have been incorporated into the current JNC VII guidelines.4 Our study found that the use of multiple antihypertensive drugs either in a single combination pill or in >1 pill significantly increased and accounted for use by more than half of all antihypertensive medication users by 1999–2002. The most common combinations were a diuretic plus an ACE inhibitor, -blocker, or CCB. Diuretic polytherapy accounted for >80% of total diuretic use in 1988–1994 and >90% in 1999–2002.
Hypertension is a major risk factor for stroke, heart failure, coronary heart disease, and end-stage renal disease. Hypertension is also commonly associated with diabetes and chronic renal failure generally. For management of hypertensives with these comorbidities, both JNC VI and JNC VII guidelines recommend ACE inhibitors as the preferred drug for hypertension in the setting of CKD, diabetes, or congestive heart failure; ACE inhibitors or diuretics for recurrent stroke prevention; and -blockers for those with prior myocardial infarction.4,7 In accordance with these recommendations, our study found that between 1988–1994 and 1999–2002, ACE inhibitor use significantly increased in patients with CKD, diabetes, and congestive heart failure, and -blocker use significantly increased in patients with a history of heart attack. Similar prescribing patterns for those with diabetes, congestive heart failure, or a history of heart attack were also reported by Mehta et al.26
The percentage of hypertensive adults using antihypertensive drugs reported in this study is different than the hypertension treatment estimates published by Glover et al27 using NHANES 1999–2002 for several reasons, including differences in sample exclusion criteria, antihypertensive medication use definitions, and analysis methods (age-adjusted versus unadjusted estimates). In the present study we used the prescription medication data that were collected as part of the household questionnaire. These data allowed us to identify all antihypertensive medications used in the past month with their specific drug names rather than using the self-reported response to the following question: "Because of your high blood pressure/hypertension, are you now taking prescribed medicine" Using the specific drug data also allowed us to more completely examine drug utilization patterns and illustrate how the JNC VI recommendations for antihypertensive therapy were being applied to US hypertensives. Additionally, we presented unadjusted and stratified subgroup estimates rather than age-adjusted ones to estimate the true prevalence of antihypertensive medication use among US hypertensives rather than simply examining relative differences in drug use across time periods.
The primary strength of this study is the use of the NHANES data with its nationally representative samples and oversampling of key demographic subgroups such as older persons and ethnic subgroups. Additionally, blood pressure was obtained by standardized examinations. Finally, prescription data were collected by trained interviewers, with the use of an in-person, household interview protocol, with verification of drugs by inspection of medication containers.
However, several potential limitations of our study should be noted. First, while the auscultatory method of blood pressure measurement in NHANES is fully consistent with JNC VI standards, NHANES measurements are performed only at a single time point. By contrast, the clinical application of the JNC VI classification of hypertension is based on the average of 2 properly measured blood pressure readings on 2 separate occasions. It is therefore possible that in our study, some subjects were misclassified with regard to hypertension status. This potential problem was minimized to some extent by taking the average of 3 separate measurements obtained under the same standardized conditions in both surveys. Furthermore, NHANES is a cross-sectional study, and participants were asked to recall only medications used in the past month, thus identifying the set of hypertensives currently on drug therapy. Those who used an antihypertensive drug at any time before the 1-month recall period are classified as a hypertensive but without current antihypertensive medication use. The particular choice of a study recall period will affect prevalence estimates. The NHANES 1-month recall period is reasonable, and a short recall period increases the validity of the data collected by minimizing recall bias. The data collected also do not allow us to determine whether the drug reported was the first prescribed and used or whether other drugs were prescribed and used earlier. This limited our ability to address compliance with JNC VI recommendations regarding drug classes for initial treatment of uncomplicated hypertension. In addition, NHANES did not include collection of drug dosage and strength information, and therefore no such data were available for analysis.
We conclude that among US adults with hypertension, antihypertensive medication use significantly increased over the past decade. During 1999–2002, >60% of adults with hypertension used an antihypertensive drug in the past month. Although significant increases have occurred for certain hypertensive groups, disparities by demographic factors continue to exist. Continued efforts are needed to improve antihypertensive medication use, especially among younger hypertensives and racial and ethnic minorities in certain gender and age groups. By 1999–2002, antihypertensive utilization patterns among those with diabetes, congestive heart failure, and heart attack were consistent with JNC VI recommendations. These NHANES data reflect the most broadly representative trends in antihypertensive medication use patterns estimated to date.
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