Abstract
Blood pressure (BP) control rates among US adults taking antihypertensive medication have not increased over the past decade. Many adults require two or more classes of antihypertensive medication to achieve guideline-recommended BP goals, but the proportion of US adults taking antihypertensive medication monotherapy, versus combination therapy, has not been quantified using contemporary data. We analyzed data from the 2005–2008, 2009–2012, and 2013–2016 National Health and Nutrition Examination Surveys to determine trends in monotherapy and combinations of antihypertensive medication classes among US adults age ≥ 20 years with hypertension taking antihypertensive medication (n=7,837). The proportion of US adults taking antihypertensive medication with uncontrolled BP (i.e., systolic BP ≥140 or diastolic BP ≥90 mm Hg) was 32.3%, 30.2%, and 31.0% in 2005–2008, 2009–2012, and 2013–2016, respectively (Ptrend=0.37). Between 2005–2008 and 2013–2016, there was no evidence of changes in the proportions of US adults taking antihypertensive monotherapy (39.5% to 40.4%, Ptrend=0.67), dual-therapy (37.9% to 38.3%, Ptrend=0.75), triple-therapy (17.6% to 16.5%, Ptrend=0.36), or quadruple-therapy (4.4% to 4.3%, Ptrend=0.93). Between 2005–2008 and 2013–2016, there was no evidence of changes in the proportions of US adults with uncontrolled BP taking antihypertensive monotherapy (39.3% to 40.6%, Ptrend=0.78). A high proportion of US adults with hypertension, including those with uncontrolled BP, are taking one antihypertensive medication class. Increasing the use of dual- and triple-therapy antihypertensive medication regimens may restore the upward trend in BP control rates among US adults.
Keywords: hypertension, blood pressure, cardiovascular diseases, antihypertensive agents, cardiovascular agents
Graphical Abstract
INTRODUCTION
Between 1988-1994 and 2007-2008, the proportion of US adults with hypertension taking antihypertensive medication that had controlled blood pressure (BP) increased from 27.3% to 50.1%.1 However, the proportion of US adults with hypertension taking antihypertensive medication that had controlled BP has not increased over the past decade despite the increasing availability of safe, effective, and low-cost antihypertensive medications.2,3 Combining two or more classes of antihypertensive medication is more efficacious to control BP than monotherapy.4-7 The 2017 American College of Cardiology (ACC)/American Heart Association (AHA) BP guideline recommends initiating antihypertensive medication with dual-therapy, either with separate products or in a fixed-dose combination (FDC) product, in adults with a systolic BP (SBP)/diastolic BP (DBP) ≥ 140/90 mm Hg and an average BP > 20/10 mm Hg above their BP goal.8 Also, the 2018 European Society of Cardiology (ESC)/European Society of Hypertension (ESH) BP guideline recommends initiating dual-therapy with an FDC in all patients with hypertension except in the frail elderly and those with SBP/DBP of 140–160/90–99 mm Hg who have a low risk for cardiovascular disease (CVD).9 The American Society of Hypertension (ASH) recommended FDC antihypertensive medication for most adults initiating antihypertensive medication in 2010.10
Previous studies have assessed trends in the use of individual antihypertensive medication classes among US adults.11-15 However, there are few data on the trends of antihypertensive medication regimens, including the frequency of monotherapy and combination therapy among US adults with hypertension. Determining the proportion of US adults with hypertension taking antihypertensive monotherapy could guide interventions to optimize combination medication use and restore the upward trend in BP control rates among US adults with hypertension. Therefore, we determined trends in antihypertensive monotherapy and combinations of antihypertensive medication classes being taken among US adults ≥ 20 years of age with hypertension between 2005 and 2016 using data from the National Health and Nutrition Examination Survey (NHANES).
METHODS
Study Design and Population
Detailed methods and protocols for NHANES are provided elsewhere.16 All data used in the current analysis are publicly available through the National Center for Health Statistics and can be accessed at https://wwwn.cdc.gov/nchs/nhanes/default.aspx. NHANES consists of a series of cross-sectional surveys conducted in two-year cycles. Participants are selected using a multi-stage probabilistic sampling approach such that the results can be weighted to produce estimates for the non-institutionalized civilian US adult population.17 All participants provided written informed consent, and the survey protocol for each NHANES cycle was approved by the National Center for Health Statistics ethics review board. We analyzed six consecutive two-year cycles (2005–2006 through 2015–2016), and data were grouped into three separate, four-year calendar periods: 2005–2008, 2009–2012, and 2013–2016 to provide more stable estimates.18
Of the 34,180 NHANES participants ≥ 20 years old who were interviewed and examined, we excluded 3,906 participants who did not have three SBP and DBP measurements taken during their medical evaluation (Figure S1 in the online-only supplement). Of the 30,274 participants with complete SBP and DBP data, we excluded another 19,576 participants who did not self-report a prior diagnosis of hypertension and 2,813 participants who were not taking antihypertensive medication or were missing information about antihypertensive medication use in the NHANES BP questionnaire or during the study’s pill bottle review. Finally, we excluded 48 pregnant women. The final analysis included 7,837 participants with complete BP data, self-reported hypertension and who were taking at least one class of antihypertensive medication.
Data Collection
Trained interviewers administered standardized questionnaires in participants’ homes. Age, sex, race-ethnicity, household income, education, health insurance, smoking status, and history of coronary heart disease (CHD), diabetes, stroke, or heart failure were self-reported. Participants were invited to attend a study visit at a mobile examination center following the interview. During this visit, BP, height, and weight were measured, and blood and urine samples were collected. Body mass index (BMI) was calculated as weight in kilograms divided by height in meters, squared. Participants were categorized as underweight, normal weight, overweight, and obese based on BMI <18.5 kg/m2, 18.5 to <25 kg/m2, 25 to <30 kg/m2, and ≥30 kg/m2, respectively. Chronic kidney disease (CKD) was defined as an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m2 using the CKD-EPI equation19 or a urinary albumin-to-creatinine ratio >30 mg/g. Estimated 10-year CVD risk was calculated among participants without a self-reported history of CHD, myocardial infarction, or stroke using the Pooled Cohort Risk Equations.20
BP measurements were performed by trained physicians following a standardized protocol. After resting for five minutes, three consecutive, seated readings were obtained using a mercury sphygmomanometer and appropriately-sized cuff with 30-second intervals between measurements. The three SBP and DBP measurements were averaged.
Antihypertensive medication use was determined from participant self-report during the in-home questionnaire as an affirmative answer to the questions, “Have you ever been told by a doctor that you had hypertension, also called high BP?” and “Are you now taking prescribed medicine for high BP?”.21 The interviewer reviewed participants’ pill bottles for prescription and non-prescription medications and supplements reported to have been taken in the previous 30 days.22 For the main analysis, FDC products were classified into individual generic compounds (e.g., lisinopril/hydrochlorothiazide was classified as two distinct compounds, “lisinopril” and “hydrochlorothiazide”). Antihypertensive medications were categorized into classes: aldosterone receptor antagonists, alpha-blockers, ACEI, angiotensin receptor blockers (ARB), beta-blockers, CCB, centrally-acting agents (e.g., clonidine), direct vasodilators, diuretics, and renin inhibitors. For ease of presentation, ACEI and ARB were grouped together, and diuretics (i.e., thiazide, loop, and potassium-sparing) were grouped together. In a separate analysis, FDC products were categorized by their unique antihypertensive class components (e.g., ACEI or ARB and diuretic).
Statistical Analyses
Characteristics of the US adult population taking antihypertensive medication were reported for each four-year calendar period: 2005–2008, 2009–2012, and 2013–2016. Trends in participant characteristics across calendar periods were assessed by linear regression for continuous variables and logistic regression for binary variables. The proportions of US adults taking each antihypertensive medication class, distinct combinations of classes, and number of classes used in a regimen (e.g., monotherapy, dual-therapy) were calculated for each four-year calendar period. Trends in the proportion of US adults taking each antihypertensive medication regimen across calendar periods were assessed by modeling each medication regimen as a dependent variable and the four-year calendar periods as a continuous independent variable.
The distribution and combinations of the antihypertensive medication classes being taken may differ by age, sex, race-ethnicity, and for those with and without controlled BP or co-morbid conditions. Therefore, we calculated the proportions of US adults taking each antihypertensive medication class and combinations of classes within subgroups defined by: 1) uncontrolled BP at two thresholds: SBP/DBP ≥140/90 mm Hg and ≥130/80 mm Hg, separately, given the use of JNC7 for defining controlled BP during the study period and the recent lowering of BP treatment targets in the 2017 ACC/AHA BP guidelines8; 2) age less than or greater than/equal to 75 years; 3) sex; 4) race/ethnicity (i.e., Non-Hispanic White, Non-Hispanic Blacks, and Hispanics); and 5) presence or absence of five compelling indications for specific antihypertensive medication classes (i.e., diabetes, CHD, CKD, stroke, or heart failure), separately, because the JNC7 clinical practice guidelines23 recommended specific classes based on the presence of these comorbidities (Table S1 in the online-only Supplement). We also calculated the proportion of the population taking each antihypertensive medication class (i.e., ACEI or ARB, diuretic, beta-blocker, and CCB), independent of whether the medication was taken as monotherapy or combination therapy. Finally, the proportion of US adults taking FDC products were calculated for each four-year calendar period.
The NHANES sampling weights and the complex sampling design were applied in all calculations to obtain US nationally representative prevalence estimates. All analyses were performed using Stata v.13.1 (StataCorp, College Station, TX).
RESULTS
Characteristics of the study population
In each calendar period, the majority of US adults taking antihypertensive medication were female, Non-Hispanic White, and had private health insurance (Table 1). The proportion of US adults taking antihypertensive medication who were high school graduates, obese, had government insurance, or had diabetes increased, and the proportion with private insurance decreased (Ptrend<0.05). The proportion of US adults with uncontrolled BP as defined by SBP ≥ 140 mm Hg or DBP ≥ 90 mm Hg was 32.4%, 30.3%, and 31.1% in 2005–2008, 2009–2012, and 2013–2016, respectively (Ptrend=0.35).
Table 1.
Characteristics of NHANES participants taking antihypertensive medication regimens in 2005–2008, 2009–2012, 2013–2016.
| Characteristic | Calendar Period | |||
|---|---|---|---|---|
| 2005–2008 | 2009–2012 | 2013–2016 | P-Trend | |
| (n=2,157) | (n=2,840) | (n=2,840) | ||
| Age, years | ||||
| <40 | 5.0 (3.7,6.8) | 4.9 (4.0,6.0) | 5.8 (4.6,7.3) | 0.38 |
| 40 to 49 | 15.3 (13.2,17.7) | 12.9 (11.0,15.1) | 11.8 (10.3,13.5) | 0.01 |
| 50 to 59 | 24.5 (21.8,27.4) | 25.1 (22.6,27.8) | 22.2 (19.6,25.0) | 0.20 |
| 60 to 74 | 36.9 (33.7,40.3) | 37.1 (34.9,39.3) | 41.4 (38.4,44.5) | 0.04 |
| ≥ 75 | 18.3 (16.2,20.6) | 20.1 (18.4,21.8) | 18.8 (16.5,21.4) | 0.83 |
| Female sex | 55.5 (53.0,58.0) | 54.9 (52.6,57.2) | 54.9 (52.3,57.5) | 0.67 |
| Race/ethnicity | ||||
| Non-Hispanic White | 76.6 (71.4,81.0) | 72.3 (66.5,77.5) | 69.9 (65.0,74.4) | 0.04 |
| Non-Hispanic Black | 14.0 (10.4,18.4) | 14.7 (11.3,19.0) | 14.3 (11.1,18.2) | 0.84 |
| Hispanic | 5.6 (4.1,7.7) | 8.0 (5.3,11.8) | 9.2 (6.5,12.7) | 0.05 |
| Household Income <$20K | 18.6 (16.3,21.1) | 18.3 (15.8,21.2) | 17.7 (14.8,21.0) | 0.55 |
| High School Graduate | 78.9 (75.7,81.8) | 78.6 (75.4,81.4) | 83.2 (80.4,85.6) | 0.02 |
| Health Insurance | ||||
| Private | 66.4 (63.7,69.0) | 63.2 (60.0,66.3) | 60.0 (56.9,63.0) | 0.004 |
| Government | 26.9 (24.5,29.5) | 29.2 (26.7,31.9) | 33.5 (31.0,36.2) | 0.001 |
| None | 6.7 (5.3,8.5) | 7.6 (6.3,9.3) | 6.5 (5.3,7.8) | 0.93 |
| Current smoker | 15.8 (13.6,18.2) | 13.1 (11.5,14.8) | 17.8 (16.0,19.9) | 0.06 |
| Body mass index, kg/m2 | ||||
| Underweight | 0.5 (0.3,0.8) | 0.9 (0.5,1.7) | 0.8 (0.5,1.3) | 0.30 |
| Normal weight | 17.6 (15.6,19.9) | 13.9 (12.1,15.9) | 15.1 (13.5,16.8) | 0.05 |
| Overweight | 32.4 (29.8,35.1) | 32.7 (30.5,35.0) | 30.6 (28.0,33.5) | 0.25 |
| Obese | 49.5 (46.8,52.2) | 52.5 (49.8,55.1) | 53.5 (50.6,56.4) | 0.02 |
| Comorbidities | ||||
| Diabetes | 21.2 (18.5,24.2) | 27.7 (25.8,29.6) | 29.0 (26.8,31.3) | <.001 |
| Coronary heart disease | 9.4 (8.2,10.9) | 9.0 (7.8,10.3) | 10.5 (9.0,12.1) | 0.40 |
| Chronic kidney disease | 46.3 (42.7,49.8) | 43.2 (40.2,46.2) | 43.0 (40.4,45.6) | 0.04 |
| Stroke | 8.2 (6.8,9.8) | 7.4 (6.2,8.8) | 7.6 (6.5,8.9) | 0.41 |
| Heart failure | 6.6 (5.7,7.6) | 6.9 (5.5,8.5) | 7.1 (6.1,8.1) | 0.71 |
| Mean 10-year CVD risk, %* | 7.8 (7.2,8.5) | 8.8 (8.1,9.5) | 9.1 (8.3,9.9) | 0.09 |
| Mean systolic blood pressure, mmHg | 131.7 (130.7,132.8) | 130.8 (129.8,131.8) | 131.8 (130.5,133.0) | 0.91 |
| Systolic blood pressure, mm Hg | ||||
| < 130 | 49.7 (46.8,52.6) | 52.9 (50.5,55.2) | 49.1 (46.0,52.1) | 0.86 |
| 130 - 139 | 20.9 (18.6,23.4) | 18.9 (17.6,20.3) | 21.6 (19.0,24.5) | 0.60 |
| 140 - 159 | 20.9 (19.2,22.8) | 21.1 (19.2,23.2) | 21.8 (19.9,23.8) | 0.65 |
| ≥ 160 | 8.5 (7.2,10.0) | 7.1 (5.8,8.7) | 7.5 (6.5,8.6) | 0.20 |
| Mean diastolic blood pressure, mm Hg | 71.4 (70.5,72.2) | 69.9 (68.9,70.9) | 69.8 (69.0,70.6) | 0.03 |
| Diastolic blood pressure, mm Hg | ||||
| < 80 | 73.4 (70.2,76.4) | 78.7 (75.8,81.4) | 79.5 (76.9,81.8) | 0.005 |
| 80 - 89 | 18.7 (16.1,21.5) | 14.9 (13.0,17.1) | 15.0 (13.1,17.1) | 0.07 |
| 90 - 99 | 6.5 (5.1,8.1) | 5.2 (3.9,6.7) | 4.5 (3.7,5.5) | 0.03 |
| ≥ 100 | 1.5 (1.0,2.0) | 1.2 (0.7,1.9) | 1.0 (0.6,1.8) | 0.31 |
| Uncontrolled blood pressure | ||||
| SBP ≥ 140 or DBP ≥ 90 mm Hg | 32.4 (30.4,34.5) | 30.3 (28.3,32.4) | 31.1 (28.6,33.7) | 0.35 |
| SBP ≥ 130 or DBP ≥ 80 mm Hg | 58.6 (55.1,62.1) | 54.3 (52.0,56.7) | 55.6 (52.4,58.8) | 0.22 |
Numbers in table are column percents (95% confidence interval) or means (95% confidence interval)
CVD: cardiovascular disease; DBP: diastolic blood pressure; SBP: systolic blood pressure
Cardiovascular disease risk calculated using the Pooled Cohort Risk Equation
Antihypertensive medication use
There was no evidence that the proportion of US adults taking one, two, three, four, or five or more classes of antihypertensive medication changed from 2005–2008 to 2013–2016 (Table 2; see Tables S2-S3 for regimens with <1% prevalence and ACEI categorized separately from ARB). ACEI or ARB monotherapy was the most common antihypertensive medication class being taken as monotherapy in each calendar period and increased from 18.9% to 24.2% between 2005–2008 and 2013–2016 (Ptrend=0.004). Between 2005–2008 to 2013–2016, the proportion of US adults taking a beta-blocker as monotherapy decreased from 9.0% to 5.9% (Ptrend=0.003), and the proportion taking a diuretic as monotherapy decreased from 6.6% to 4.9% (Ptrend=0.06).
Table 2.
Proportion of US adults taking antihypertensive medication regimens in 2005–2008, 2009–2012, 2013–2016.
| Number and specific antihypertensive combinations |
Calendar Year | |||
|---|---|---|---|---|
| 2005–2008 | 2009–2012 | 2013–2016 | P-Trend | |
| (n=2,157) | (n=2,840) | (n=2,840) | ||
| One Medication Class | 39.5 (36.4,42.7) | 40.4 (37.7,43.1) | 40.1 (37.6,42.7) | 0.78 |
| ACEI or ARB | 18.9 (16.4,21.8) | 21.0 (18.8,23.3) | 24.2 (21.7,26.9) | 0.004 |
| BB | 9.0 (7.3,11.1) | 8.2 (6.8,9.7) | 5.9 (4.9,7.1) | 0.003 |
| Diuretic | 6.6 (5.3,8.1) | 5.8 (4.4,7.6) | 4.9 (4.0,6.0) | 0.06 |
| CCB | 4.3 (3.1,5.9) | 4.6 (3.5,6.2) | 4.4 (3.4,5.7) | 0.93 |
| Two Medication Classes, Any Combination | 37.9 (35.5,40.4) | 36.8 (34.7,39.1) | 38.4 (35.8,41.1) | 0.70 |
| ACEI or ARB+Diuretic | 14.3 (12.3,16.5) | 14.2 (12.4,16.3) | 15.9 (13.3,18.9) | 0.30 |
| ACEI or ARB+BB | 6.2 (4.8,8.1) | 5.5 (4.6,6.6) | 6.5 (5.3,8.0) | 0.72 |
| ACEI or ARB+CCB | 5.0 (4.0,6.3) | 6.0 (5.0,7.3) | 7.2 (5.7,9.0) | 0.04 |
| BB+Diuretic | 5.9 (4.9,7.1) | 5.8 (4.6,7.1) | 3.9 (3.0,4.9) | 0.003 |
| CCB+Diuretic | 2.0 (1.4,2.8) | 1.9 (1.3,2.8) | 1.7 (1.2,2.5) | 0.55 |
| BB+CCB | 2.1 (1.5,3.1) | 1.4 (0.9,2.1) | 2.2 (1.5,3.0) | 0.87 |
| Three Medication Classes, Any Combination | 17.6 (15.7,19.8) | 17.9 (16.1,19.9) | 16.6 (14.9,18.5) | 0.43 |
| ACEI or ARB+BB+Diuretic | 7.7 (6.2,9.5) | 7.9 (6.7,9.4) | 5.8 (4.8,7.1) | 0.03 |
| ACEI or ARB+CCB+Diuretic | 4.8 (3.8,6.0) | 3.9 (2.9,5.2) | 4.3 (3.5,5.4) | 0.57 |
| ACEI or ARB+BB+CCB | 2.5 (1.8,3.5) | 2.9 (2.0,4.2) | 3.8 (2.9,5.0) | 0.07 |
| BB+CCB+Diuretic | 1.4 (1.0,2.0) | 1.3 (0.9,1.9) | 1.0 (0.7,1.4) | 0.19 |
| Four Medication Classes, Any Combination | 4.4 (3.4,5.6) | 4.4 (3.3,5.7) | 4.3 (3.4,5.5) | 0.93 |
| ACEI or ARB+BB+CCB+Diuretic | 3.1 (2.3,4.1) | 3.0 (2.1,4.1) | 2.9 (2.1,4.0) | 0.72 |
| Five or More Medication Classes, Any Combination | 0.6 (0.3,1.2) | 0.5 (0.2,1.0) | 0.5 (0.2,1.1) | 0.69 |
Numbers in table are column percentage (95% confidence interval).
ACEI=angiotensin converting enzyme inhibitor; ARB=angiotensin-II receptor blocker; BB=beta-blocker; CCB=calcium channel blocker
Use of an ACEI or ARB with a diuretic was the most common dual-therapy combination in each calendar period. Dual-therapy with a beta-blocker and a diuretic decreased from 5.9% to 3.9% between 2005–2008 to 2013–2016 (Ptrend=0.003). Dual-therapy with an ACEI or ARB and beta-blocker increased from 5.0% to 7.2% between 2005–2008 to 2013–2016 (Ptrend=0.04). The combination of an ACEI or ARB, a beta-blocker, and a diuretic was the most common triple-therapy regimen in each calendar period but decreased from 7.7% to 5.8% between 2005–2008 and 2013–2016 (Ptrend=0.03).
As a group, ACEI or ARB were the most common medication classes taken within each calendar period, followed by diuretics, beta-blockers, then CCBs (Table S4). From 2005–2008 to 2013–2016, the proportion of US adults with hypertension taking antihypertensive medication who were on an ACEI or ARB, alone or as part of combination therapy, increased from 66.0% to 74.1% (Ptrend<0.001). Diuretic use, as monotherapy or combination therapy, decreased from 48.4% to 43.3% (Ptrend=0.015) and beta-blocker use decreased from 39.4% to 35.1% (Ptrend=0.021) over this time period.
Antihypertensive medication use among US adults with uncontrolled BP
There was no evidence that the number of antihypertensive medication classes being taken changed between 2005–2008 and 2013–2016 among US adults taking antihypertensive medication with uncontrolled BP defined as SBP ≥140 mm Hg or DBP ≥90 mm Hg (Table 3) or SBP ≥130 mm Hg or DBP ≥80 mm Hg (Table 4). Among those with SBP ≥140 mm Hg or DBP ≥90 mm Hg, 40.2% and 35.1% were taking one and two classes of antihypertensive medication, respectively, in 2013–2016.
Table 3.
Proportion of US adults with uncontrolled blood pressure (SBP ≥140 mmHg or DBP ≥90 mmHg) taking antihypertensive medication regimens in 2005–2008, 2009–2012, 2013–2016.
| Number and specific antihypertensive combinations |
Calendar Year | |||
|---|---|---|---|---|
| 2005–2008 | 2009–2012 | 2013–2016 | P-Trend | |
| (n=759) | (n=964) | (n=976) | ||
| One Medication Class | 39.3 (34.0,45.0) | 42.6 (37.7,47.7) | 40.2 (36.3,44.2) | 0.87 |
| ACEI or ARB | 18.2 (14.3,22.8) | 19.7 (15.7,24.4) | 20.9 (17.9,24.2) | 0.28 |
| BB | 8.0 (6.1,10.4) | 10.7 (8.0,14.2) | 7.1 (5.4,9.2) | 0.38 |
| Diuretic | 6.5 (4.5,9.4) | 4.7 (2.9,7.6) | 4.9 (3.4,7.0) | 0.35 |
| CCB | 5.2 (3.2,8.3) | 6.1 (4.4,8.4) | 6.2 (4.6,8.2) | 0.52 |
| Two Medication Classes, Any Combination | 34.4 (30.8,38.3) | 32.2 (28.6,36.1) | 35.1 (32.3,38.0) | 0.69 |
| ACEI or ARB+Diuretic | 9.9 (7.7,12.6) | 8.8 (6.8,11.2) | 12.8 (10.0,16.3) | 0.11 |
| ACEI or ARB+BB | 6.3 (4.3,9.1) | 5.9 (4.2,8.2) | 5.9 (4.0,8.7) | 0.87 |
| ACEI or ARB+CCB | 5.6 (3.5,8.8) | 5.8 (4.4,7.6) | 6.9 (5.0,9.6) | 0.48 |
| BB+Diuretic | 6.3 (4.3,9.2) | 6.0 (4.1,8.7) | 3.8 (2.4,6.0) | 0.07 |
| CCB+Diuretic | 2.1 (1.2,3.5) | 1.6 (0.9,2.8) | 2.0 (1.3,3.2) | 1.00 |
| BB+CCB | 1.9 (1.1,3.3) | 1.2 (0.6,2.3) | 2.8 (1.7,4.5) | 0.26 |
| Three Medication Classes, Any Combination | 20.0 (16.3,24.4) | 19.7 (16.3,23.5) | 19.4 (16.0,23.2) | 0.80 |
| ACEI or ARB+BB+Diuretic | 7.9 (5.9,10.4) | 9.0 (6.5,12.2) | 5.6 (4.1,7.5) | 0.05 |
| ACEI or ARB+CCB+Diuretic | 5.4 (3.6,8.0) | 2.6 (1.8,3.8) | 5.1 (3.0,8.5) | 0.97 |
| ACEI or ARB+BB+CCB | 3.0 (1.9,4.9) | 4.4 (2.8,6.8) | 5.3 (3.7,7.4) | 0.09 |
| BB+CCB+Diuretic | 1.4 (0.7,2.7) | 1.0 (0.5,2.1) | 0.8 (0.4,1.5) | 0.18 |
| Four Medication Classes, Any Combination | 4.9 (3.3,7.1) | 4.5 (2.8,7.0) | 5.1 (3.5,7.4) | 0.84 |
| ACEI or ARB+BB+CCB+Diuretic | 3.1 (0.1,1.2) | 3.3 (0.0,0.5) | 3.2 (0.0,0.6) | 1.00 |
| Five or More Medication Classes, Any Combination | 1.4 (0.7,2.7) | 1.1 (0.5,2.5) | 0.3 (0.1,1.3) | 0.04 |
Numbers in table are column percentage (95% confidence interval).
ACEI=angiotensin converting enzyme inhibitor; ARB=angiotensin-II receptor blocker; BB=beta-blocker; CCB=calcium channel blocker
Table 4.
Proportion of US adults with uncontrolled blood pressure defined as SBP ≥130 mmHg or DBP ≥80 mmHg taking antihypertensive medication regimens in 2005–2008, 2009–2012, 2013–2016.
| Number and specific antihypertensive combinations |
Calendar Year | |||
|---|---|---|---|---|
| 2005-2008 | 2009-2012 | 2013-2016 | P Trend | |
| (n=1,284) | (n=1,658) | (n=1,669) | ||
| One Drug Class, Any Combination | 40.6 (37.1,44.1) | 44.1 (41.0,47.2) | 41.6 (38.5,44.7) | 0.77 |
| ACEI or ARB | 19.3 (16.4,22.7) | 21.0 (18.2,24.1) | 23.3 (20.6,26.2) | 0.04 |
| BB | 8.6 (6.7,11.0) | 11.0 (8.9,13.7) | 6.2 (4.9,7.9) | 0.03 |
| Diuretic | 6.6 (5.1,8.4) | 5.4 (4.0,7.4) | 5.7 (4.5,7.3) | 0.55 |
| CCB | 4.9 (3.2,7.4) | 5.6 (4.1,7.6) | 5.5 (4.3,7.1) | 0.60 |
| Two Drug Classes, Any Combination | 35.6 (32.8,38.6) | 33.4 (30.2,36.6) | 36.0 (33.2,39.0) | 0.76 |
| ACEI or ARB+Diuretic | 13.4 (11.6,15.4) | 10.5 (8.9,12.4) | 14.0 (11.8,16.6) | 0.50 |
| ACEI or ARB+CCB | 5.9 (4.3,7.9) | 5.7 (4.6,7.1) | 6.5 (4.8,8.7) | 0.62 |
| ACEI or ARB+BB | 4.1 (2.8,5.9) | 5.9 (4.5,7.7) | 6.7 (5.4,8.4) | 0.03 |
| BB+Diuretic | 5.7 (4.2,7.6) | 5.6 (4.3,7.3) | 3.6 (2.5,5.1) | 0.03 |
| CCB+Diuretic | 2.5 (1.6,3.8) | 2.2 (1.3,3.6) | 2.2 (1.6,3.1) | 0.67 |
| BB+CCB | 1.8 (1.1,2.8) | 1.4 (0.9,2.2) | 2.1 (1.4,3.1) | 0.61 |
| Three Drug Classes, Any Combination | 18.1 (15.6,21.0) | 17.5 (14.8,20.6) | 17.1 (14.9,19.5) | 0.56 |
| ACEI or ARB+BB+Diuretic | 7.2 (5.8,8.9) | 7.5 (5.9,9.5) | 4.7 (3.7,5.9) | 0.01 |
| ACEI or ARB+CCB+Diuretic | 5.3 (3.8,7.4) | 3.5 (2.6,4.5) | 4.7 (3.3,6.6) | 0.67 |
| ACEI or ARB+BB+CCB | 2.5 (1.6,3.8) | 3.2 (2.2,4.7) | 4.5 (3.2,6.3) | 0.05 |
| BB+CCB+Diuretic | 1.7 (1.1,2.6) | 1.2 (0.6,2.1) | 0.9 (0.6,1.4) | 0.05 |
| Four Drug Classes, Any Combination | 4.9 (3.6,6.5) | 4.3 (3.0,6.2) | 4.8 (3.5,6.5) | 1.00 |
| ACEI or ARB+BB+CCB+Diuretic | 3.3 (2.4,4.5) | 2.9 (1.8,4.5) | 3.3 (2.3,4.6) | 0.89 |
| Five or More Drug Classes, Any Combination | 0.8 (0.4,1.6) | 0.7 (0.3,1.6) | 0.5 (0.2,1.4) | 0.47 |
Numbers in table are column percentage (95% confidence interval).
ACEI=angiotensin converting enzyme inhibitor; ARB=angiotensin-II receptor blocker; BB=beta-blocker; CCB=calcium channel blocker
Age, race, and ethnicity subgroups
There was no evidence that, among US adults taking antihypertensive medication, the number of antihypertensive medication classes being taken changed between 2005–2008 and 2013–2016 for any age, sex, or race-ethnicity subgroup investigated (Tables S5-11), except for Non-Hispanic Blacks, in whom monotherapy with an ACEI or ARB increased, and dual-therapy with a beta-blocker and a CCB increased (Table S10, each Ptrend<0.05). Among Hispanics, the use of five or more antihypertensive medication classes decreased (Table S11, Ptrend=0.03).
US adults with and without compelling indications
Among US adults without compelling indications, there were no trends in the number of antihypertensive medication classes being taken between 2005–2008 and 2013–2016 (Table S12). Between 2005–2008 and 2013–2016, ACEI or ARB monotherapy increased from 22.4% to 30.0% (Ptrend=0.006), and beta-blocker monotherapy decreased from 12.1% to 6.4% (Ptrend=0.003).
There was no evidence that the number of antihypertensive medication classes being taken changed between 2005–2008 and 2013–2016 for US adults with compelling indications (i.e., diabetes, CHD, CKD, stroke history, or heart failure history; Tables S13-17), except there was a decrease in US adults with diabetes taking five or more antihypertensive classes from 1.3% to 0.4% (Table S13, Ptrend=0.03).
FDC use
There was no evidence that the proportion of US adults taking FDC antihypertensive products changed from 2005–2008 to 2013–2016 (Tables S18-S19).
DISCUSSION
In the current study, a high proportion of US adults with hypertension taking antihypertensive medication had uncontrolled BP, which was unchanged between 2005–2008 and 2013–2016. Over the same time period, the proportion of US adults with hypertension taking antihypertensive medication who were taking one antihypertensive medication class was unchanged. Also, a high proportion of US adults with uncontrolled BP were taking only one class of antihypertensive medication. Although national efforts to increase the proportion of US adults diagnosed hypertension who take antihypertensive medication likely contributed to the dramatic improvements in BP control observed between 1988 and 2008,1 achieving population-wide BP control in the future will be difficult if the high prevalence of monotherapy persists.
A substantial proportion of US adults taking antihypertensive medication, including those with uncontrolled BP, were taking antihypertensive monotherapy, which has repeatedly been shown to have less BP-lowering efficacy compared to dual- and triple-therapy regimens.4,24 It is well-established that achieving and maintaining intensive BP control often requires combining two or more antihypertensive medication classes.4-6 Based on the cross-sectional design of the current analysis, we could not determine if the high prevalence of monotherapy was due to patient or prescriber factors. The persistently high proportion of US adults with uncontrolled BP who are only taking one antihypertensive medication class represents a missed opportunity to lower BP and CVD risk. In conjunction with previous evidence,4-6 the current analysis suggests that to restore an upward trend in BP control rates, initiatives should focus on increasing the use of dual- and triple-therapy regimens.
Patient preferences, cost, and pill-taking disutility may be barriers to combination medication use.25 The patient’s perception of “medication burden,” in which the patient does not want to take more medications, should be distinguished clinically from “pill burden,” in which the patient does not want to take more pills. FDC products represent an attractive option to reduce pill burden, increase patient acceptance, achieve BP goals, improve adherence, and prevent CVD events with a more favorable adverse event profile than individually-formulated products at standard doses.24,26-28 The World Health Organization recently added FDC antihypertensive medications to their Essential Medicines List, further underscoring the international and national figort for combination antihypertensive therapy.29 Beyond initial management with lifestyle modifications, a paradigm shift may be needed in how medical educators promote initial pharmacologic hypertension management from a monotherapy-dependent strategy (i.e., starting with one medication and increasing the dose as tolerated before adding another medication) to a lower-dose combination-dependent strategy (i.e., starting with low doses of multiple medications and increasing the dose of the total combination in a stepwise fashion as needed). Guideline recommendations may further influence the use of FDCs when initiating or intensifying antihypertensive treatment.
The current analysis revealed several trends in antihypertensive medication use that may reflect changes in practice patterns after publication of landmark trials and clinical practice guideline recommendations. For example, the current analysis observed a 53% decrease in the proportion of US adults with hypertension but without compelling indications taking beta-blocker monotherapy from 12.1% in 2005–2008 to 6.4% in 2013–2016. This may reflect the results of several trials which suggested superior BP reduction and CVD risk reduction with an ACEI and CCB combination compared to a beta-blocker and diuretic combination.30-32 Consequently, the Eighth Panel Report of the Joint National Committee recommended that beta-blockers not be used as initial therapy for essential hypertension,33 which may have influenced the decrease in beta-blocker mono- and combination therapy observed during the study period. Additionally, a high proportion of US adults taking antihypertensive medication were taking medication classes that were preferred in a 2011 ASH position paper (i.e., an ACEI or ARB plus either a CCB or a diuretic).10 Efforts should be made to reduce the proportion of adults taking less effective, harmful, or non-preferential regimens, such as beta-blocker use in patients without compelling indications (20% prevalence overall in most recent year of analysis).
In the current analysis, the most common dual-therapy was an ACEI or ARB combined with a diuretic. In 2009, The Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial showed that dual-therapy with an ACEI and a CCB had superior CVD risk reduction compared to dual-therapy with an ACEI and a diuretic despite similar achieved SBP between the groups.34 These results should be interpreted within the context that the daily dose of hydrochlorothiazide studied may have been suboptimal at 12.5 mg. Over the past decade, more combination products have become available that contain an ACEI or ARB and a thiazide diuretic than products containing an ACEI or ARB and a CCB (16 products versus 6 products, respectively).35 Additionally, most ACEI/thiazide combination products became generically available by 2005.36 In contrast, the first ACEI/CCB combination product did not become generically available until 2010. The higher prevalence of dual-therapy with an ACEI or ARB and a diuretic instead of an ACEI or ARB and a CCB in the current analysis may represent the overall availability and generic cost of available combination products rather than implementation of evidence-based recommendations. These data highlight that prescribers choose to utilize specific combinations of antihypertensive medication classes commensurate with evidence and practical considerations (e.g., availability and cost of combination products). Providers must balance the demonstrated safety and efficacy of combination use within the context of patient-specific drivers of benefit and risk of harm with combinations.37
The current study has several strengths. The sampling design utilized by NHANES allows for prevalence estimates representative of the US population. NHANES collected detailed medication data to allow in-depth analyses of antihypertensive medication monotherapy and combination use. One limitation of the current study is that medication doses are not available in NHANES, which could distinguish the intensity of regimens. Although combining two-year study periods led to more stable estimates with small sample sizes, this may have led to dilution of any effects. Finally, although validated with pill bottle review, medication use was based on self-report and may not reflect actual use.
PERSPECTIVES
In conclusion, between 2005–2008 and 2013–2016, a high proportion of US adults with hypertension were taking only one class of antihypertensive medication, even among those with uncontrolled BP. Use of ACEI or ARB monotherapy increased while the use of beta-blocker monotherapy decreased. The current analysis suggests that a high proportion of uncontrolled BP among US adults with hypertension taking antihypertensive medication may be the result of an inadequate antihypertensive medication regimen. Therefore, initiatives to increase the use of dual- and triple-therapy antihypertensive medication regimens may present an opportunity to restore the upward trend in BP control rates in US adults.
Supplementary Material
NOVELTY AND SIGNIFICANCE.
1). What Is New?
In a nationally-representative survey from 2005–2016, a large proportion of adults with hypertension taking antihypertensive medication were using one antihypertensive medication class.
Monotherapy and combinations with ACEI or ARB were most prevalent; monotherapy and combinations with beta-blockers decreased.
2). What Is Relevant?
Over the past two decades, new evidence has significantly impacted the guideline-directed management of adults with hypertension.
Uncontrolled BP rates may be due to inadequate prevalence of combination therapy.
Characterizing trends in antihypertensive medication use may be one way to examine how evidence-based literature and guidelines are being implemented in clinical practice, informing targeted public health initiative to improve BP control and patient outcomes.
Summary.
With the more intensive SBP goals recommended in current guidelines, more research is needed to investigate: 1) use of effective medication combinations to control hypertension in real-world settings; 2) barriers to use of more antihypertensive medications for BP control (e.g., clinical inertia); and 3) patient preferences for antihypertensive regimens.
Acknowledgements:
Dr. Bress had full access to the study data and takes responsibility for the integrity of the data and accuracy of the analysis.
Sources of Funding:
Dr. Bress is supported by K01HL133468 from the National Heart, Lung, and Blood Institute. Dr. Moran is supported by R01HL130500–01A1 from the National Heart, Lung, and Blood Institute. Dr. Kronish is supported by UL1-TR001873 from the National Center for Advancing Translational Sciences. Dr. Shimbo receives support through R01-HL117323 and K24-HL125704 from the National Heart, Lung, and Blood Institute. Dr. Muntner receives research support through the American Heart Association grant SFRN 15SFRN2390002. Dr. Derington is supported by American Heart Association Grant # 19POST34380226/Derington/2019.
Footnotes
Conflicts of Interest/Disclosures:
Dr. Muntner is a consultant for Kaiser Permanente Southern California on a project funded by Vital Strategies, and he receives grant support through his institution from Amgen Inc. Dr. Bress receives support to his institution from Amarin Corporation, Novartis, and Amgen unrelated to the current manuscript.
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