John Jarvis, BA

: To assess the economic impact of switching from metoprolol to nebivolol for hypertension treatment.

: Retrospective analysis of a large single-payer administrative claims database (first quarter 2010-first quarter 2013).

: Adult patients with hypertension, who switched from metoprolol to nebivolol were identified. Patients were required to use each treatment for ≥30 days. Switching was defined as a ≤30-day gap or overlap between metoprolol discontinuation and nebivolol initiation. Patients who used other beta-blockers concomitantly with metoprolol or nebivolol, or had compelling indications for metoprolol (angina, myocardial infarction, or congestive heart failure), during the 180-day period before nebivolol initiation were excluded. Monthly all-cause and cardiovascular (CV)-related healthcare resource use (HRU), medical service costs (2013 US dollars), and medication costs were compared between the pre- and postswitching periods. Sensitivity analyses on treatment exposure were conducted.

: Among the 1046 patients identified, the average age was 53 years and 46% were female. Following a switch to nebivolol, there was a significant (

 <.01) decrease in all HRU. Monthly all-cause costs for prescription medications increased by $134 (

 <.01); however, all-cause medical service costs decreased by $211 ($1485 vs $1274; 

 <.01). Total monthly all-cause healthcare costs (medical services and prescription medications) were similar before and after switching ($1780 vs $1702; 

 = .05). Similarly, monthly CV-related medication costs increased while medical costs decreased following the switch. HRU and cost trends were similar in the sensitivity analyses.

: Increases in prescription drug costs may be offset by decreases in medical costs among patients with hypertension who switched from metoprolol to nebivolol.

Hypertension affects about one-third of adults in the United States and is a major risk factor for cardiovascular disease, renal insufficiency, and peripheral vascular disease.1 The cost of treating hypertension is high and increasing. In 2010, US hypertension treatment costs were $93.5 billion

; they are projected to exceed $274 billion by 2030.

 This high spending is largely driven by the consequences of uncontrolled hypertension; currently, only 50% of hypertensive patients have optimal blood pressure (BP) control.

 With increased focus from healthcare systems on treatment efficiency and cost control, identifying cost-saving treatments for hypertension is a critical public health concern.

Beta-blockers are increasingly used to treat hypertension: 32% of patients with hypertension used beta-blockers in 2010, up from 20% in 2001.

 Metoprolol is the most frequently prescribed beta-blocker and the second most frequently prescribed hypertension treatment.

 A generic form of metoprolol has been available since 2006 in the United States. Nebivolol, the most recently available beta-blocker, received FDA approval in 2007.

 Nebivolol is currently brand-protected. Evidence from head-to-head clinical trials and chart reviews has shown that treatment with nebivolol leads to fewer adverse events (AEs), higher rates of BP goal achievement after 6 months of treatment, and improved quality of life (QoL) compared with treatment with metoprolol.

 Health systems often prefer generic over branded medications, as a means to control spending, and may encourage substitution of a generic for a branded drug in the same class to reduce healthcare costs. However, current evidence on the economic impact of switching from branded to generic drugs for the treatment of hypertension is mixed, with studies finding that switching is associated with both long-term savings and cost increases.

 A recent analysis among hypertensive patients conducted using a large, multi-payer health insurance claims database found that switching to nebivolol from metoprolol was associated with increases in medication costs and reductions in medical service costs, resulting in an overall neutral effect on total healthcare costs.

The present study evaluated whether the finding that there is no overall increase in healthcare costs associated with switching from metoprolol to nebivolol extends to large commercial insurance plans. Specifically, this study estimated and compared monthly healthcare resource use (HRU) and costs among hypertensive patients enrolled in 1 large health insurance plan before and after switching from metoprolol, a generic beta-blocker, to nebivolol, a branded beta-blocker.

This study used retrospective insurance claims data from a large, single-payer source of US medical and pharmacy data. The data represent the medical experiences of insured employees and their dependents, and include more than 10 million covered lives. The majority of enrollees resided in the South and North Central (Midwest) census regions, although all states were represented. Healthcare cost data were reported as standard prices, which were estimated based on accounting algorithms determined by the data provider. Such algorithms were used to standardize variability attributed to differences in contractual arrangements, geographic regions, timeframes of data, and the healthcare setting or organization from which services were provided. The present study analyzed data from January 1, 2010, to January 31, 2013.

The analytical sample consisted of adult hypertensive patients who switched from treatment with metoprolol to treatment with nebivolol. Patients were defined as having hypertension if they had at least 1 medical claim with a recorded primary or secondary diagnosis for hypertension (

International Classification of Diseases, Ninth Revision, Clinical Modification

]: 401.x - 404.xx). Patients included in the analytical sample were required to initiate metoprolol on or after their hypertension was first diagnosed and to initiate nebivolol within 30 days of discontinuing metoprolol (defined as a gap in metoprolol treatment of at least 30 days).

Patients were also required to have at least 30 days of continuous treatment with metoprolol prior to their first prescription fill date for nebivolol (index date) and at least 30 days of continuous treatment with nebivolol following the index date. Additionally, patients were required to have 180 days of continuous enrollment in a health plan prior to the index date (baseline period) and at least 30 days of continuous enrollment following the index date.

Patients were excluded if they received treatment with other beta-blockers during the baseline or study periods; such patients may have used 1 of the beta-blockers to treat a condition other than hypertension. Similarly, patients with a compelling indication for metoprolol use (angina: 

 411.1x, 411.13.xx; myocardial infarction: 

 410.xx, 412.xx; congestive heart failure: 

 402.01, 402.11, 402.91, 404.x1, 404.x3, 428.xx) during the baseline period were also excluded to ensure that metoprolol was used to treat hypertension.

Changes in monthly HRU and healthcare costs after switching from metoprolol to nebivolol were assessed using a pre-/poststudy design. Each patient’s metoprolol treatment period (pre-switching period) was defined as the period between the last occurrence of: (a) 180 days prior to the index date, (b) metoprolol initiation date, or (c) start of continuous enrollment in their healthcare plan and the index date. Similarly, each patient’s nebivolol treatment period (postswitching period) was defined as the period from the index date until the first occurrence of the following: (a) 180 days after the index date, (b) end of continuous enrollment in their healthcare plan, or (c) end of data availability. The pre- and postswitching periods were both capped at a maximum of 180 days and restricted to periods of continuous health plan enrollment and continuous treatment with metoprolol/nebivolol.

Given that the durations of the pre- and postswitching periods differed among patients, HRU and healthcare costs were calculated in terms of average daily HRU or healthcare costs, then aggregated as monthly HRU and healthcare costs during each patient’s study period. HRU was measured as the average number of visits and inpatient admissions per month during the pre- and postswitching periods. The average length of stay (LOS) per all-cause and cardiovascular (CV)-related inpatient admission was also compared between the 2 periods. Medical service costs were assessed using standard prices inflated to 2013 US dollars using the medical care component of the Consumer Price Index.

 Monthly HRU and medical service costs were compared during the pre- and postswitching periods for both all-cause and CV-related conditions, defined as any medical visit with a CV-related diagnosis (

 cardiovascular disease: 430.xx-438.xx; congestive heart failure: 402.01, 402.11, 402.91, 404.x1, 404.x3, 428.xx; chronic ischemic heart disease: 412.xx, 414.xx; acute coronary syndrome: 410.xx, 411.xx, 413.xx; peripheral vascular disease: 440.xx, 443.9; valvular disease: 394.0x; arrhythmia: 427.xx; aortic aneurysm: 250.xx).

Outcomes were also specifically assessed for inpatient admissions, outpatient visits, emergency department (ED) visits, and other visits (home, outpatient hospital, ambulatory surgery center, birthing center, skilled nursing facility, hospice, residential substance abuse facility, and mass immunization center visits), which were identified using place-of-service and revenue codes. The use and costs of all-cause and antihypertensive medications, including metoprolol and nebivolol, were compared between the pre- and postswitching periods. Antihypertensive medications included angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, calcium channel blockers, loop diuretics, thiazide diuretics, and miscellaneous antihypertensives. All-cause and antihypertensive medications were identified using Generic Product Identifier codes.

Two sensitivity analyses of medical service costs based on treatment exposure time were conducted. The first sensitivity analysis was conducted among the subgroup of patients with at least 90 days of continuous metoprolol use during the pre-switching period and at least 90 days of continuous nebivolol use during the postswitching period. The second sensitivity analysis was conducted among the subgroup of patients with at least 180 days of continuous metoprolol use during the pre-switching period and at least 180 days of continuous nebivolol use during the postswitching period.

Wilcoxon signed-rank tests were used to compare HRU, medical service costs, and medication costs between the pre- and postswitching periods. McNemar’s tests were used to compare the percentage of patients prescribed antihypertensive medications in the pre- and postswitching periods. All statistical analyses were performed using SAS version 9.3 (SAS Institute, Inc, Cary, NC).

Of 3,109,008 patients with hypertension in the database, 1046 met all eligibility criteria (Figure 1). Among these patients, the average age was 53 years and 46% were female. Slightly more than half of the patients resided in the South. The majority (73%) were covered by a point-of-service health insurance plan. Before switching to nebivolol, 63% of patients were treated with metoprolol succinate and 37% were treated with metoprolol tartrate.

Other antihypertensive medications frequently used during the pre-switching period included ACE inhibitors (24%), calcium channel blockers (25%), thiazide diuretics (15%), angiotensin receptor blockers (14%), and loop diuretics (7%). The most common comorbidities assessed during the baseline period were diabetes (20%), chronic ischemic heart disease (20%), and arrhythmia (19%) (Table).

Average all-cause monthly HRU decreased across all places of service after switching from metoprolol to nebivolol (all 

 <.01). The most notable change was a decrease of 0.26 visits per month in outpatient office/lab visits (Figure 2). The average LOS for all-cause inpatient admissions and the average number of all-cause medications did not differ between the pre- and postswitching periods.

The average number of CV-related outpatient/office lab visits decreased by 0.05 visits per month (

 <.01) while the number of other CV-related visits decreased by 0.02 visits (

 = .01). ED visits, CV-related inpatient admissions, and LOS for CV-related inpatient admissions were similar in the pre- and postswitching periods (Supplemental Figure 1; available at eAppendix at 

). Although the percentage of patients using antihypertensive medications other than metoprolol or nebivolol did not change significantly between the pre- and postswitching periods, the average number of antihypertensive prescriptions decreased by 0.06 after switching from metoprolol to nebivolol (

Average total medical service costs decreased by $211 per patient per month (from $1485 to $1274; 

 <.01) after patients switched from metoprolol to nebivolol. Reductions in monthly outpatient office/lab costs (

 = .03) influenced the decrease in total medical service costs. There were no significant differences in other monthly costs between the pre- and postswitching periods. Average costs for medications increased by $134 per patient per month (from $294 to $428; 

 <.01). There was no significant difference in total monthly healthcare costs (both medical service and medication costs) before and after switching to nebivolol (Figure 3).

CV-related medical service costs decreased by $123 per patient per month (from $323 to $200; 

 <.01) after patients switched from metoprolol to nebivolol. This change was primarily driven by a monthly decrease of $81 in other CV-related costs (

 = .02); there were also significant reductions in monthly CV-related outpatient office/lab costs (

 <.01). There were no significant differences in monthly CV-related ED or inpatient admission costs. Antihypertensive medication costs increased by $50 ($46 to $96; 

 <.01; Supplemental Figure 2, available at eAppendix at 

Sensitivity analyses that varied treatment exposure time exhibited a similar pattern: Despite higher medication costs, all-cause total healthcare costs did not differ significantly between the pre- and postswitching periods. CV-related medical service costs did not differ in the sensitivity analyses after patients switched from metoprolol to nebivolol.

This study found that overall healthcare expenditures were similar before and after switching from metoprolol to nebivolol for the treatment of hypertension. Although nebivolol is brand-protected and metoprolol is available as a generic, increases in prescription medication costs were offset by decreases in medical expenditures. Additionally, average monthly CV-related costs decreased after patients switched from metoprolol to nebivolol. Overall healthcare expenditure findings were robust to sensitivity analyses that varied treatment duration. All-cause total healthcare and CV-related medical service costs in the sensitivity analyses did not differ between the pre- and postswitching periods.

The results of the present study are consistent with those of a previous analysis conducted in a multi-payer database, which found that switching from metoprolol to nebivolol for the treatment of hypertension did not lead to increases in overall healthcare costs (from $1310 to $1241; 

 Together, these study results suggest that healthcare payers should consider the overall impact of a treatment on healthcare expenditures rather than the cost of that treatment in isolation when creating formulary policies aimed at lowering healthcare spending.

The reduction in medical expenditures following a switch from metoprolol to nebivolol could be due to nebivolol’s superior efficacy and/or tolerability. A chart review study found that patients treated with nebivolol had higher rates of BP goal achievement after 6 months of treatment than patients treated with metoprolol.

 A head-to-head clinical trial found that treatment with nebivolol resulted in a greater decrease in systolic and diastolic BP than treatment with metoprolol.

 Additionally, both clinical trials and real-world evidence studies found that patients treated with nebivolol had fewer AEs compared with patients treated with metoprolol.

Because nebivolol provides BP control comparable to other beta-blockers with potentially fewer AEs, treatment with nebivolol may decrease the need for additional healthcare services and costs for hypertensive patients. Additionally, patients who switch to nebivolol often report improved QoL. Treatment with nebivolol was associated with significant improvements in QoL measures such as AE frequency, personal and professional satisfaction, and satisfaction with hypertension therapy.

 These QoL-related improvements may also contribute to reductions in HRU and medical service costs after switching from metoprolol to nebivolol.

The results of this study should be interpreted in light of its limitations. First, the database did not contain clinical measures, such as specific AEs attributable to the treatment of hypertension, which could have indicated whether patients switched from metoprolol to nebivolol for reasons related to efficacy or tolerability. Without these clinical measures, it was not possible to construct a representative control group.

Second, as in all administrative healthcare claims database analyses, oral medications were identified using prescription fill records; therefore, it was not possible to confirm that the full course of medication was consumed. However, this limitation was mitigated by sensitivity analyses among patients with longer recorded treatment durations with both metoprolol and nebivolol.

Third, the database did not report reimbursed amounts for medical services; standard prices established by the data provider were thus used as a proxy for costs. Fourth, because indirect costs, such as productivity loss and disability, were not available in the analytical database, the present study could not evaluate the impact of switching from metoprolol to nebivolol on indirect costs.

Additionally, costs were assessed during the pre- and postswitching periods (a maximum of 180 days each per patient) and may not be representative of the costs incurred by patients for different time horizons. In particular, few patients in this database who met the sample selection criteria had continuous health plan enrollment for longer durations, and patients with longer health plan enrollment may be systematically different from a real-world sample of hypertension patients. A future study in a separate database should assess the long-term impact of switching from metoprolol to nebivolol on HRU and healthcare costs.

Finally, the results from the present analysis represent a privately insured patient population from a single insurance payer. Study findings may not be generalizable to other populations in the United States, including patient populations insured by Medicaid and Medicare.

This study found that switching from metoprolol, a generic beta-blocker, to nebivolol, a branded beta-blocker, for the treatment of hypertension was not associated with an increase in overall healthcare expenditures. Increases in prescription drug costs following the switch were offset by decreases in medical services and associated medical service costs.

These findings suggest that healthcare payers should consider the overall cost of hypertension treatment when setting formulary policies aimed at decreasing medical expenditures.

 Actavis (SC), Jersey City, NJ; Analysis Group (ES, JJ, EO, CK, EW), Boston, MA; Analysis Group (JX), New York, NY.

 The authors are employees of Analysis Group, a consulting company that received funding from Actavis to conduct this study.

 Concept and design (SC, ES, JJ, EO, CK, JX, EW); acquisition of data (ES, JJ, EO, EW); analysis and interpretation of data (SC, ES, JJ, EO, CK, JX, EW); drafting of the manuscript (ES, JJ, EO, CK); critical revision of the manuscript for important intellectual content (SC, ES, JJ, CK, JX, EW); statistical analysis (SC, ES, JJ, EO, CK, EW); obtaining funding (SC); administrative, technical, or logistic support (SC, EO); supervision (SC, JX)

 Elyse Swallow, Analysis Group, 111 Huntington Ave, 10th Fl, Boston, MA 02199. E-mail: 

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Articles

A large single-payer administrative claims database was used to assess the economic impact of switching from metoprolol to nebivolol for the treatment of hypertension.