According to the Eighth Joint National Committee, hypertension is a known risk factor for cardiovascular (CV) events, such as stroke, myocardial infarction, and heart failure.1 Hypertension is defined as persistent systolic/diastolic blood pressure of at least 140/90 mm Hg among patients aged <60 years or at least 150/90 mm Hg among patients aged ≥60 years for 6 months.1 The prevalence of hypertension is steadily increasing in the United States and is projected to rise from 29% of the US adult population in 2006 to approximately 38% by 2030, and the associated costs soaring from $70 billion in 2010 to an estimated $200 billion in 2030.2,3 The goal of therapy in patients with hypertension is to decrease the risk for CV events (such as myocardial infarction or stroke) by reducing and controlling blood pressure.1 A recent study showed that within 5 years, patients with hypertension with an average blood pressure reduction of 3.6/2.4 mm Hg can potentially have a 14% lower odds for overall CV events, 28% lower odds for stroke events, 19% lower odds for coronary events, and 20% lower odds for heart failure.4 Despite the numerous treatment options available, the management of patients with hypertension remains inadequate: only approximately 50% of US adults with hypertension achieve optimal control.5 Inadequately managed hypertension may contribute to several adverse health outcomes, including stroke, myocardial infarction, and heart failure.6-8
Metoprolol was the most often prescribed beta-blocker in the United States in 2011, with 72.3 million prescriptions.9 However, metoprolol and other second-generation beta-blockers have lower efficacy than other classes of antihypertensives, which led to the development of third-generation beta-blockers.10 One of these third-generation beta-blockers, nebivolol, is a cardioselective agent with high selectivity for beta1-adrenergic receptors. Nebivolol also causes vasodilation, by interacting with the endothelial L-arginine/nitric oxide pathway.11-13 Cardioselective beta-blockers not only lower the heart rate by blocking the effect of adrenaline in the heart but also relax and widen blood vessels, improving blood flow.13 Having both properties, nebivolol reduces the peripheral vascular resistance and significantly increases stroke volume while preserving cardiac output.13
Clinical trials have shown that nebivolol is efficacious compared with other classes of antihypertensive medications and is well-tolerated among a wide range of patients.13-16 Moreover, in one study, patients receiving nebivolol reported fewer adverse events (eg, sexual dysfunction, fatigue, depression, and metabolic abnormalities) than patients receiving other beta-blockers.17 The presence of fewer adverse events generally is associated with a lower likelihood of treatment discontinuation,18,19 and a recent study by Signorovitch and colleagues demonstrated that patients with hypertension who received nebivolol had better medication persistence compared with patients receiving other beta-blockers (eg, metoprolol).20 The reduction in adverse events among patients with hypertension who receive nebivolol and their subsequent improved medication persistence may also result in better disease management compared with patients receiving other beta-blockers.
Although nebivolol may be a viable treatment alternative for patients with hypertension who do not respond to or cannot tolerate other beta-blockers, little is known about the impact of switching patients from metoprolol to nebivolol on the associated CV-related healthcare resource utilization and costs. This information is especially important to payers, because nebivolol is a branded drug with a significantly higher average wholesale price (listed in the Medi-Span Master Drug Database) than for generic metoprolol.21 Therefore, the aim of this study is to analyze and document the impact on CV-related economic outcomes for patients with hypertension who switch their treatment from metoprolol to nebivolol.
For this retrospective observational study, medical, pharmacy, and eligibility claims data were extracted from the HealthCore Integrated Research Database. This database contains claims from 14 geographically dispersed US commercial health plans representing more than 45 million lives, making it one of the largest data sets of a commercially insured population. Overall, this database is comparable with the US Census data (the American Community Survey) in terms of age and sex, although the population in the database is slightly younger, because all members are commercially insured.
All personally identifiable data used in this study were deidentified and were accessed with protocols that are compliant with the Health Insurance Portability and Accountability Act of 1996. Patient confidentiality was preserved, and the anonymity of all patient data was safeguarded throughout the study. No waiver of informed consent was required from an Institutional Review Board.
Claims were obtained from the HealthCore Integrated Research Database during the study period (July 1, 2007-June 30, 2013). Patients included in the analysis were aged ≥18 years with a diagnosis of hypertension (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] 401.xx-404.xx) in an inpatient or outpatient setting during the patient identification period (January 1, 2008-December 31, 2012). To be included in the analysis, patients had to receive metoprolol for at least 6 months before switching to nebivolol, and then receive nebivolol for at least 6 months after switching from metoprolol. A treatment gap of less than 30 days of prescription supply was considered a continuous or stable drug regimen.
The index date was defined as the date the patient switched from metoprolol to nebivolol; the preperiod (baseline) was defined as the 6 months of treatment with metoprolol before the index date, and the postperiod was the 6 months of continuous treatment with nebivolol after the index date. All patients were continuously enrolled in a health plan during the preperiod and postperiod (Figure 1).
Patients were excluded from the analysis if they had any compelling indications identified by ICD-9-CM diagnosis codes, for which metoprolol but not nebivolol is an approved treatment (eg, angina [ICD-9-CM codes 411.1x and 413.xx], myocardial infarction [410.xx and 412.xx], or congestive heart failure [428.xx, 402.01, 402.11, 402.91, 404.x1, and 404.x3]). Patients were also excluded if they did not maintain a stable background treatment of other classes of antihypertensive medications (eg, angiotensin-II receptor blockers) during the preperiod and postperiod (Figure 2).
The primary outcome measures were healthcare resource utilization and costs associated with specific CV events, including cerebrovascular disease (including stroke), chronic ischemic heart disease, acute coronary syndrome, peripheral vascular disease, valvular disease, arrhythmia, and aortic aneurysm.
CV-related resource utilization was calculated as the number of times a healthcare resource was utilized divided by the number of months of follow-up during the preperiod or postperiod, multiplied by 100 patients, to reach the healthcare resource utilization per 100 patients per month. The CV-related healthcare costs were presented in 2013 US dollars per patient per month (PPPM); that is, the costs were calculated by dividing the CV-related cost (the total, inpatient, and outpatient costs) by the number of months during the preperiod or postperiod (6 months each).
Healthcare resource utilization and costs were then categorized by the setting of service (ie, inpatient, emergency department visit, and outpatient office visit). CV-related events in the inpatient or emergency department settings were identified from the primary diagnosis; because the primary diagnosis was unavailable in outpatient claims, patients receiving care in outpatient settings were identified using all diagnosis positions.
In the main analysis, the change in the healthcare resource utilization and costs of patients with hypertension who switched from metoprolol to nebivolol were analyzed. The results of the main analysis may overstate the impact of switching to nebivolol, because only the patients who are likely to benefit the most from switching are included. To evaluate this possibility, a sensitivity analysis was conducted, in which the same outcomes were evaluated and compared between matched cohorts of patients who switched from metoprolol to nebivolol and those who did not switch but continued to receive metoprolol. The patients who switched from metoprolol to nebivolol were matched to those who did not switch and continued treatment with metoprolol, using propensity score matching on baseline demographic and clinical characteristics.
Unadjusted differences between the preperiod and postperiod were assessed using McNemar’s test for nominal variables and a bootstrap paired t-test for continuous variables. All data analyses were conducted using SAS version 9.2 (SAS Institute; Cary, NC) or Stata version 12.0 (Stata Corporation; College Station, TX). All statistical tests were 2-sided hypothesis tests performed at a 5% level of significance.
A total of 765 patients were included in the analysis; the patients’ mean age was 55 years, and 59% were men (Table 1). At baseline, the majority (70%) of patients had a Charlson Deyo Comorbidity Index score of 022; only 12% had a score of 2 or higher (Table 2). The most common comorbidities of interest at baseline were chronic ischemic heart disease and fatigue (17% each), followed by arrhythmia and diabetes (14% each).
Medication Use and Resource Utilization
The mean (standard deviation [SD]) number of all prescription medications increased from 21 (14%) in the preperiod to 23 (14%; P <.001) in the postperiod (Table 3). Fewer treatment gaps were observed in the postperiod during treatment with nebivolol than in the preperiod while patients were receiving metoprolol (mean, 12.8 days vs 15.9 days, respectively).
Compared with the preperiod, patients switching to nebivolol in the postperiod had significantly fewer CV-related emergency department visits (0.2 [SD, 1.9] vs 0.04 [SD, 0.8], respectively; P = .012) and CV-related outpatient visits (9.2 [SD, 19.9] vs 6.7 [SD, 17.5], respectively; P <.001). These results are shown in Figure 3.
The number of inpatient visits in the preperiod and postperiod were similar (0.3 [SD, 2.4] vs 0.1 [SD, 1.5], respectively; P = .164). The proportion of patients with at least 1 CV-related outpatient visit was significantly lower in the postperiod than in the preperiod (21% vs 27%, respectively; P <.001), as shown in Figure 4.
CV-related healthcare costs followed a pattern similar to healthcare utilization (Table 4). Compared with the preperiod, patients switching to nebivolol had significantly lower CV-related emergency department mean costs ($6 [SD, $78] vs $1 [SD, $27] PPPM, respectively; P = .028) and lower CV-related total medical costs ($94 [SD, $526] vs $54 [SD, $266] PPPM, respectively; P = .020), as shown in Figure 5.
The CV-related inpatient costs were similar between the preperiod and postperiod ($29 [SD, $324] vs $13 [SD, $161] PPPM, respectively; P =.173), as were the CV-related outpatient costs ($59 [SD, $400] vs $40 [SD, $206] PPPM, respectively; P = .130).
The sensitivity analysis produced results similar to the primary analysis, although the differences between the patients who switched to nebivolol and those who did not switch were not statistically significant (Table 5).
The results of this analysis of real-world data demonstrates that patients with hypertension who switched from metoprolol to nebivolol and who continued the drug regimen for at least 6 months had significantly fewer CV-related emergency department and outpatient visits, as well as lower CV-related emergency department and total medical costs in the 6 months after switching. Our results add to clinical studies,16 and suggest that the use of nebivolol has a role in improving hypertension disease management by reducing the likelihood of CV-related utilization and costs when patients switched from metoprolol for any reasons.
The reduction in CV-related emergency department and outpatient visits after the treatment regimen switch could be in part a result of the pharmacologic features of nebivolol. This third-generation medication has been shown to activate endothelial nitric oxide production, which helps to reduce the peripheral resistance of the blood vessels, leading to improved stroke volume with a neutral impact on cardiac output.16,23,24 This effect is useful in the treatment of hypertension, heart failure, ischemia reperfusion injury, and stroke.
It is possible that the observed reduction in the CV-related emergency department and outpatient visits for patients who switched to nebivolol may be related to better management of hypertension and CV disease, which is consistent with previously published clinical trials.25
In addition, the higher treatment persistence observed among patients receiving nebivolol, as measured by fewer days of treatment gaps compared with patients receiving metoprolol, may also contribute to better disease management and potentially lower CV-related emergency department and outpatient visits after switching drugs. Consistent with the results of this present study, in a previously published study, patients receiving nebivolol were found to have better persistence relative to metoprolol.20 Yang and colleagues recently showed that patients with hypertension who were nonpersistent with therapy had significantly more CV-related hospitalizations and emergency department visits than patients who were persistent with therapy.26
Together, the lower CV-related healthcare resource utilization and lower CV-related emergency department costs observed with nebivolol may translate into the significantly lower CV-related medical costs seen after switching from metoprolol. Hypertension is a known risk factor for severe CV diseases such as stroke, myocardial infarction, and heart failure, which result in substantial medical expenditures and account for a large proportion of the total healthcare costs. For example, the estimated direct costs of CV disease-related complications that were attributable to hypertension were predicted to increase from $130.7 billion in 2010 to $389 billion in 2030.3 Added to that were indirect costs (eg, lost productivity) that were estimated to be $25.4 billion in 2010 and were expected to rise to $42.8 billion by 2030.3 The more effectively a treatment can manage hypertension, the lower the risk for severe CV diseases in the near future,26 which can possibly lead to better health and can minimize CV-related resource utilization as well as overall healthcare resource utilization and costs.
In this study, we evaluated the CV-related healthcare resource utilization and the costs of patients with hypertension who switched from metoprolol to nebivolol; therefore, the preperiod and postperiod approach was the appropriate study design for the main analysis. Although the reasons for switching from metoprolol to nebivolol were not evaluated, it was recognized that only patients who were likely to benefit the most from switching were likely to switch.
To test the importance of this assumption, we performed a sensitivity analysis to evaluate the outcomes that were the same between matched patients receiving metoprolol and those receiving nebivolol. The results of the sensitivity analysis were similar to those of the primary analysis, although the differences were not statistically significant. In other words, the point estimate of reduction in the healthcare resource utilization and costs were consistent with that of the main analysis, but with larger variation, and were therefore statistically insignificant.
Taken together, these results demonstrate that switching from the second-generation beta-blocker metoprolol to the third-generation beta-blocker nebivolol is likely to reduce CV-related resource utilization and costs.
To quantify the impact of switching to nebivolol, this study was limited to patients who consistently took metoprolol and nebivolol for 6 months or more.
The findings of this study may also not be generalizable to patients who are not taking metoprolol and nebivolol consistently.
It is possible that the observed effect of cost-saving in this study is more applicable to patients who respond and adhere to their antihypertension medications.
This study is subject to limitations similar to other retrospective database studies, including coding errors or omissions, incomplete claims, unreliable clinical coding, and unobservable factors that may have influenced the outcomes.
However, there is no evidence that this potential measurement error would be nonrandom between the periods that patients were receiving metoprolol and nebivolol. The impact of the measurement error is likely to increase the confidence interval of the estimate (results toward nonsignificant), but the point estimate is likely to be robust.
Because this study was based on a commercially insured population in the United States, the results may not be generalizable to patients with other types of health insurance or those living outside of the United States.
In this analysis, which was based on real-world data, patients with hypertension who switched from metoprolol to nebivolol had significantly lower CV-related healthcare resource utilization (eg, emergency department and outpatient visits) and lower CV-related healthcare costs. The lower CV-related resource utilization and costs may indicate improved disease management of hypertension. Additional studies are needed to identify these key drivers and to quantify the long-term economic impact of switching from other antihypertensive agents to nebivolol.
Funding for this study was provided by Forest Research Institute, Inc.
Author Disclosure Statement
Dr Chen was an employee of Forest Research Institute at the time of this study; Ms Fu, Dr Jain, and Mr Tan are employees of HealthCore, Inc, a consultancy whose activities on the project were funded by Forest Research Institute.
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