Initial Monotherapy and Combination Therapy and Hypertension Control the First Year
Initial antihypertensive therapy with single-pill combinations produced more rapid blood pressure control than initial monotherapy in clinical trials. Other studies reported better cardiovascular outcomes in patients achieving lower blood pressure during the first treatment year. We assessed the effectiveness of initial antihypertensive monotherapy, free combinations, and single-pill combinations in controlling untreated, uncontrolled hypertensives during their first treatment year. Electronic record data were obtained from 180 practice sites; 106 621 hypertensive patients seen from January 2004 to June 2009 had uncontrolled blood pressure, were untreated for ≥6 months before therapy, and had ≥1 one-year follow-up blood pressure data. Control was determined by the first follow-up visit with blood pressure <140/<90 mm Hg for patients without diabetes mellitus or chronic kidney disease and <130/<80 mm Hg for patients with either or both conditions. Multivariable hazards regression ratios (HRs) and 95% CIs for time to control were calculated, adjusting for age, sex, baseline blood pressure, body mass index, diabetes mellitus, chronic kidney disease, cardiovascular disease, initial therapy, final blood pressure medication number, and therapeutic inertia. Patients on initial single-pill combinations (N=9194) were more likely to have stage 2 hypertension than those on free combinations (N=18 328) or monotherapy (N=79 099; all P<0.001). Initial therapy with single-pill combinations (HR, 1.53 [95% CI, 1.47–1.58]) provided better hypertension control in the first year than free combinations (HR, 1.34; [95% CI, 1.31–1.37]) or monotherapy (reference) with benefits in black and white patients. Greater use of single-pill combinations as initial therapy may improve hypertension control and cardiovascular outcomes in the first treatment year.
The National Health and Nutrition Examination Survey 2007–2008 data on prevalent hypertension and 2010 population estimates suggest that there are ≈70 million hypertensive patients in the United States.1,2 Although ≈50% of all hypertensive patients have blood pressure (BP) controlled to <140/<90 mm Hg, ≈35 million people have uncontrolled hypertension.
Multiple patient, provider, treatment, and system variables impact BP control.3 One key to progress is to identify modifiable variables that impact hypertension control.4 Prospective clinical efficacy studies first showed in 2003 and then subsequently confirmed that initial treatment with single-pill combinations achieved more rapid BP control during the first 3 to 6 months than initial monotherapy with add-on medications.5–7 Second, adherence is better when medications are given as single-pill combinations than free combinations.8 Third, randomized, clinical studies suggest that hypertensive patients achieving lower BPs in the first 3 to 12 months of treatment experience fewer cardiovascular events during that time period.9,10
A meta-analysis confirmed better adherence with single-pill than free combinations,8 whereas associations with greater persistence on therapy, larger BP reductions, and fewer adverse effects were not statistically significant. Of 15 trials, 9 examined BP changes and/or control as a primary outcome, and all but 1 were <1 year in duration. The authors encouraged the use of single-pill combinations given better adherence, potential for better BP control, and fewer adverse effects.
Although clinical efficacy studies suggest that single-pill combinations improve hypertension control, most studies were short term and conducted in research-intensive settings. The impact of initial therapy with monotherapy, free combinations, and single-pill combinations on BP control during the first treatment year in usual clinical practice is unknown. Our study addressed this gap11,12 among previously uncontrolled, untreated patients receiving care in a community-based practice network.
This retrospective study used electronic record data of patients at 180 clinical sites in the Outpatient Quality Improvement Network.13,14 Each clinic signed a Business Associate Agreement approved by legal counsel and the Medical University of South Carolina Office of Research Protection. The agreement authorized use of deidentified data for research.
Inclusion and Exclusion Criteria
Patients with uncontrolled hypertension who initiated antihypertensive therapy from January 2004 through June 2008 were eligible. Patients were included if they were ≥18 years old, untreated and uncontrolled for ≥6 months before initial antihypertensive therapy, and had ≥1 year of follow-up data. BP control was determined using the seventh Joint National Committee report definition.15
To facilitate generalization of study findings, exclusion criteria were limited to chronic kidney disease with estimated glomerular filtration rate <30 mL/1.7 m2 per minute or International Classification of Diseases, 9th Revision (ICD9) codes 403, 585, 586, active drug or alcohol abuse (ICD9 303, 303.9X, 304.XX), major psychiatric illness (ICD9 295.XX, 296.3, 297.X, 298.X), and known malignancy (ICD9 140–209).
Nonmodifiable and Modifiable Covariables
The impact of initial antihypertensive therapy on time to control was adjusted for nonmodifiable and modifiable covariables. Nonmodifiable variables included initial BP, age, race, sex, diabetes mellitus (ICD9 250.XX), chronic kidney disease as defined, cardiovascular disease (ICD9 402–414, 425, 428, 431–437, 440–442, 444), depression (300.4, 311), and body mass index. Modifiable variables included therapeutic inertia, mean dose equivalents, number of antihypertensive medication pills and antihypertensive medication classes, tobacco status, number of visits in the 13 months after treatment initiation, and Veterans Affairs versus civilian care site. Although the principal outcome was BP control at 1 year, a 31-day extension to 396 days was allowed given variations of follow-up intervals with an outpatient observational study.
“Time to control” was defined by the number of days between initiation of antihypertensive therapy and the point when 50% of patients were controlled (S[T]50, where S indicates survival and T denotes time in days). BP control was defined as <140/<90 mm Hg for patients without diabetes mellitus or chronic kidney disease and <130/<80 mm Hg for patients with either or both diagnoses.15
Dose equivalents for each antihypertensive medication were determined by dividing the dose prescribed by the maximum recommended dose according to the hypertension guidelines or by the US Food and Drug Administration for medications approved after guideline publication.15 The mean equivalents dose for all of the medications in the final regimen taken by each patient was calculated. Therapeutic inertia was defined as the number of visits with elevated BP in which pharmacotherapy was not changed divided by the number of visits with BP above goal.
Data Reporting and Analysis
Baseline descriptive data presented are presented as mean and SD. Comparative data by group are provided as mean and 95% CI. One-way ANOVA was used to analyze continuous variables (age, body mass index, and BP) among the final therapy groups (monotherapy, free combination, single-pill combination, and none). Bonferroni adjustment was applied to multiple pairwise comparisons of continuous variables between final therapy groups. The χ2 test was performed for categorical variables, for example, male/female, white/black, and diabetes mellitus (yes/no) with the final therapy groups. Fisher combination test was used to adjust for multiple χ2 test comparisons. The Kruskal-Wallis test (P<0.05, true/false) was used to determine whether the numbers of BP medications and medication categories were different among final therapy groups. The median time to 50% BP control was generated from raw data using Kaplan-Meier survival curves. A log-rank test was used to test the homogeneity of time to control across the 3 initial treatment strata for all of the patients and separately in blacks and whites. Univariable and multivariable Cox proportional hazard regression analyses were performed to identify the impact of nonmodifiable and modifiable factors on time to control. Independent variables that were significant in the univariable model were included in multivariable modeling. SAS version 9.2 was used for all of the analyses. Two-sided P values <0.05 were accepted as statistically significant.
Patient Inclusion-Exclusion Diagram
From 1 414 020 adults seen at practices in the Outpatient Quality Improvement Network between January 2004 and June 2009, 106 621 were eligible for analysis based on inclusion and exclusion criteria (Figure 1).
Data are provided separately for groups without and with diabetes mellitus and/or chronic kidney disease (Table 1).15 The 2 groups were divided into 3 initial therapy categories, monotherapy, free combinations, and single-pill combinations. The greatest number of patients is in the monotherapy category. The single-pill combination group is 3 to 5 years younger and has a higher body mass index, proportion of females, patients with stage 2 hypertension, and BP ≥20/≥10 mm Hg above goal and fewer Veterans Affairs patients than other initial therapy groups.
Number of Antihypertensive Pills and Medication Categories
Patients initiated on monotherapy (74.2%) received 1 antihypertensive pill and medication category (Table 2). Patients initiated on free combinations (17.2%) were given 2 pills in different medication categories. Patients initiated on single-pill combinations (8.6%) received 1 pill with 2 different antihypertensive medication categories. Roughly half of free combinations coincided with a marketed single-pill combination.
Final Therapy Category for Each Initial Therapy Group
The majority of patients completed the year on their initial treatment category (monotherapy [57%], free combinations [91%], and single-pill combinations [86.2%]; Tables S1 through S3, available in the online-only Data Supplement). A substantial minority begun on monotherapy changed to free combinations (32%) and single-pill combinations (6.2%). Patients who ended on free combinations included both those on free combinations only and those on ≥2 free-dose medications with a single-pill combination.
The percentage of patients with BP controlled as a function of time by initial therapy group (Figure 2) are depicted for all of the patients combined and black and white patients separately. Among all of the patients, 59% initiated on free combinations and monotherapy and 68% begun on single-pill combinations were controlled to goal after 396 days (end of study).15
The percentage of hypertensives controlled at 1 year was significantly higher in whites than blacks, for monotherapy (BP control 65% versus 53%; P<0.001), free combinations (67% versus 51%; P<0.001), and single-pill combinations (73% versus 63%; P<0.001). The disparity in hypertension control between blacks and whites was marginally lower on single pill than free combinations (10% versus 16%; P=0.12). Although free combinations led to better BP control than monotherapy in whites, no difference was observed in blacks in unadjusted analysis (Figure 2).
Clinical Factors That Influence BP Control
For multivariable hazards regression modeling, the 2 groups with goal BP <140/<90 and <130/<80 mm Hg were combined (Figure 3).15 Diabetes mellitus and chronic kidney disease were covariables in the model. Covariables associated with better BP control in the initial treatment year included female sex, increasing number of visits, and patients with cardiovascular disease (all P<0.0001).16 Patients with higher body mass indices and baseline systolic BP, chronic kidney disease, diabetes mellitus, a larger number of prescribed unique BP medication categories, BP pills taken daily, and higher dose equivalents and therapeutic inertia were less often controlled to goal.
For all of the patients, the median time to 50% BP control for the single-pill combination group was 195 days (95% CI, 185- 203), 269 (95% CI, 254–285) for free-dose combinations, and 280 days (95% CI, 273–287) for monotherapy with overall P<0.001. For whites and blacks, respectively, this trend is preserved with the single-pill combination group attaining 50% control at 168 (95% CI, 159–178) and 262 days (95% CI, 240–280), free-dose combination in 197 (95% CI, 188–210) and 391 days (95% CI, 377 to >396), and monotherapy in 224 (95% CI, 217–231) and 377 days (95% CI, 370–385). Whites attained 50% BP control more quickly than blacks in all 3 of the initial therapy groups (P<0.001). Single-pill combinations provided more rapid BP control than free-dose combinations or monotherapy in both racial groups (P<0.01).
In multivariable modeling, patients beginning on single-pill combinations (HR, 1.53 [95% CI, 1.47–1.58]) were more likely to have BP controlled in the first treatment year than patients initiating treatment with free combinations (HR, 1.34 [95% CI, 1.31–1.37]) or monotherapy (reference). Because only ≈50% of patients were identified in the electronic record as black or white (mostly missing, few other race/ethnicity), multivariable models were repeated with black (white reference) as a covariable. The multivariable HRs including race for single-pill combinations (HR, 1.49 [95% CI, 1.43–1.56]), and free combinations (HR, 1.32 [95% CI, 1.28–1.37]) were similar to results excluding race.
Percent of Hypertensive Patients Controlled in Cox Multivariable Modeling
Figure S1 provides data separately for 4 race-sex groups. White men and women were more likely to be controlled than black men and women on initial monotherapy, free combinations, or single-pill combinations (P<0.001 for all 3). In both black and white men and women, single-pill combinations provided the highest percentages of controlled hypertension (P<0.001 for both). In white men and women, initial therapy with free combinations provided better control than monotherapy (P<0.01), whereas the difference between free combinations and monotherapy was not significant in black men and women.
The principal study finding is that untreated, uncontrolled hypertensive patients attained better BP control when treatment was initiated with a single-pill antihypertensive combination than with free combinations or monotherapy (Figure 2). The monotherapy group does not appear to “catch up” during the first treatment year. Our findings in hypertensive patients receiving usual care in a diverse primary care setting confirm shorter-term observations in randomized clinical efficacy studies.5–7 However, in the Aliskiren and the Calcium Channel Blocker Amlodipine Combination as an Initial Treatment Strategy for Hypertension Control Trial,7 BP differences between the initial monotherapy and single-pill combination groups declined when all of the groups received combination treatment.
Hypertensive patients begun on single-pill combinations were ≈53% and on free combination ≈34% more likely than those started on monotherapy to attain BP control in the first year (Figure 3). Other covariables independently associated with better BP control included females sex, higher baseline diastolic BP, cardiovascular disease, depression, and number of visits yearly. None of these other covariables was as strongly related to BP control as initial therapy. Covariables independently associated with worse BP control included higher baseline body mass index and systolic BP, chronic kidney disease and diabetes mellitus, greater therapeutic inertia, and higher mean dose equivalents, unique BP medication categories, and number of BP pills.
Many covariable associations are not surprising.3,5,15,16 The positive link between depression and BP control is inconsistent with the impression that depression impedes control of concomitant health conditions, but this may not apply to cardiovascular risk factors.17 A higher number of BP medications, pills, and dose equivalents was associated with poorer BP control, although up-titration of antihypertensive medications is required to control BP in many patients.15,16 The explanation may be that patients requiring treatment intensification have BP values above goal and a substantial proportion remain uncontrolled even after intensified treatment.
Hypertensive patients initiated on single-pill combinations had higher untreated BP values and were more likely to have stage 2 hypertension than those started on monotherapy, which is consistent with clinical guidelines for initial therapy in patients ≥20/≥10 mm Hg from goal.15 Despite starting with higher untreated BP, patients who began treatment with single-pill combinations were more likely to achieve BP control than those started on free combinations or monotherapy BP (Figure 2).
A second study observation is that patients are most likely to end their first treatment year on the initial treatment strategy of monotherapy, free combinations, or single-pill combinations. Although this may partially reflect therapeutic inertia,16 the highest control rates at 1 year within each initial therapy group occurred in those that remained in the initial treatment category.
In this study, one fourth (25.8%) of patients began treatment on combination therapy. Our data suggest that beginning more patients on combination therapy, especially single-pill combinations, which composed only 8.6% of the total, could improve hypertension control. The growing number of generic single-pill combinations may facilitate greater use as initial therapy. However, high costs including copayments for some proprietary single-pill antihypertensive combinations may limit use.18
Our findings are consistent with the Simplified Intervention to Control Hypertension Study. Single-pill combination use rose from ≈10% at baseline to >80% with the Simplified Intervention to Control Hypertension Study compared with ≈16% with stepped care. Hypertension control at 6 months was better with the Simplified Intervention to Control Hypertension Study than stepped care (64.7% versus 52.7%; P=0.028).19 Medication uptitration occurred more often in patients assigned to the Simplified Intervention to Control Hypertension Study than traditional stepped care, which is consistent with evidence that single-pill combinations reduce therapeutic inertia.20
A third study finding is that initial therapy with single-pill combinations improved BP control in both black and white hypertensive patients, which may be important for several reasons. First, blacks are more likely than whites to have stage 2 hypertension, which typically requires ≥2 classes of BP medications to obtain control.15,21 Second, adherence to antihypertensive medications appears to be lower in blacks than in whites.21,22 Single-pill combinations improve adherence.5,8,23 Third, blacks have more economic barriers to care than whites.21 For some patients, copayments or cost of purchasing medication may be less for single-pill than for free combinations. Greater use of single-pill combinations in black hypertensive patients with BP ≥15/10 mm Hg from goal may reduce racial differences in hypertension control and time to control.21
In whites, the time to 50% control was ≈1 month longer for free-dose combinations and 2 months longer for monotherapy than for single-pill combinations. For blacks, the time to 50% control was ≈4 months longer for free-dose combinations and monotherapy than for single-pill combinations. Given the greater risk for hypertensive cardiovascular disease in blacks than whites,21 the differences in time to control may magnify racial disparities in outcomes in addition to absolute differences in hypertension control achieved.9
Our study confirms and extends previous reports that initial antihypertensive treatment with single-pill combinations improves BP control compared with free combinations or monotherapy.5–7 The meta-analysis, reporting a favorable trend but nonsignificant difference between single-pill and free combinations, rigorously compared the same medications and doses. In our study, only ≈50% of free combinations corresponded with the medication classes in single-pill combination (Table 2). Available single-pill combinations were rigorously tested to document that the combination provides better BP control than the individual components. Free-dose combinations not corresponding with marketed single-pill combinations may not satisfy this important efficacy criterion.
Limitations of this study include the use of observational, community-based practice data. Patients were not randomized. BP measurements and visit frequency were not standardized. Nearly 9200 patients were initiated on single-pill combinations but composed only 8.6% of patients. In multivariable hazards regression, we controlled for differences that were measured, but potentially important differences, for example, adherence, were not assessed. Prescription information was obtained from various electronic health record systems. These data do not always reflect prescriptions that the patient received.24–26 For example, the comparatively high rates of BP control for patients who were untreated at 1 year (Tables S1–S3) may include patients on medication(s) not captured in the electronic record.25 The available electronic record data precluded an assessment of adverse effects, although previous studies documented that initial therapy with single-pill combinations is well tolerated.5–7,27
Uncontrolled hypertensive patients initiated on combination antihypertensive therapy, especially single-pill combinations, were more likely to obtain BP control to goal15 than patients initiated on monotherapy. However, <10% of previously untreated patients began treatment with single-pill combinations, which may reflect the fact that most physicians have not been trained in this approach. Single-pill combinations are beneficial for improving BP control in black patients who are more likely to have untreated BP ≥15 to 20/≥10 mm Hg from goal than white hypertensive patients.15,21 The findings suggest that initiating antihypertensive therapy more often with combination therapy, and particularly single-pill combinations, could improve BP control and health equity in community-based practices.
Sources of Funding
This work was supported by Novartis Pharmaceuticals Corp, which participated in study design and review of the results. The clinical network and investigative team are also supported by National Institutes of Health grants HL105880, HL091841, DK067615; 1UL1RR029882 from the National Center for Research Resources; and the United States Army grant W81XWH-10-2-0057, which made this analysis possible. D.B. acknowledges support from grant P20 RR-017696 from the National Center for Research Resources, National Institutes of Health.
B.M.E. received support from Novartis (>$50 000), Daiichi-Sankyo (>$50 000), Takeda (>$50 000), and Medtronic (>$50 000); he is a lecturer with honoraria on Continuing Medical Education–accredited programs from the American Society of Hypertension Carolinas-Georgia-Florida Chapter (>$10 000) and the International Society of Hypertension in Blacks (<$10 000); and is a consultant for NicOx (<$10 000). K.S.Y.-I. was an employee for Novartis Pharmaceutical Corp during the time this study was designed and conducted.
The online-only Data Supplement is available with this article at http://hyper.ahajournals.org/lookup/suppl/doi:10.1161/HYPERTENSIONAHA.112.194167/-/DC1.
- Received March 6, 2012.
- Revision received March 14, 2012.
- Accepted April 12, 2012.
- © 2012 American Heart Association, Inc.
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