A Retrospective Observational Real-Word Analysis of the Adherence, Healthcare Resource Consumption and Costs in Patients Treated with Bisoprolol/Perindopril as Single-Pill or Free Combination

Cardiovascular disease (CVD) remains the leading cause of mortality worldwide, therefore representing a public health priority [1]. Initiation and evolution of CVD depend on continuous exposure to cardiovascular risk factors, leading to the activation of damaging pathways that promote the accumulation of organ damage, ultimately leading to its clinical manifestations [2, 3]. The sympathetic nervous system (SNS) and renin-angiotensin-aldosterone system (RAAS) have been regarded as central pathways involved in the progression of CVD and its complications [4]. Their upregulation is involved in all steps of the CVD continuum, influencing the control of cardiovascular risk factors, evolution of the subclinical organ damage and early and long-term adaptations which follow acute cardiovascular (CV) events (i.e., myocardial infarction) [2, 3]. Beyond their intrinsic feedback regulation, these two systems also interact with each other as sympathetic activation results in increased renin secretion and upregulation of the RAAS activity, whereas RAAS activation leads to sympathetic overactivity acting at the level of the central nervous system [5]. This creates the pharmacologic rationale for prescribing drugs that target both neurohormonal pathways, slowing down the CVD continuum's evolution.

Angiotensin-converting enzyme inhibitors (ACE-Is) and β-blockers (BB) have been shown to reduce the overactivity of the RAAS and SNS, leading to improved blood pressure control and lower risk of cardiovascular events in patients with and without established CVD [6, 7]. Furthermore, while BBs were previously recommended in hypertensive patients in the presence of a few specific indications/comorbidities, in the most updated European Society of Hypertension (ESH) guidelines [8], use of BBs was extended in the presence of many additional conditions including various cardiac diseases less or not related to hypertension, other vascular conditions and other non-CV diseases [8]. In many of these conditions, BB has been shown to modify the patient's outcome, reducing the risk of cardiovascular complications. However, the benefits for the general population obtained from CV protective drugs are commonly less evident than what could be expected based on the results of randomized controlled trials [1]. Treatment adherence represents one of the most important factors influencing these differences, given that in the highly controlled environment of a clinical trial, high adherence to the treatment is expected [9], at striking variance from real life in which adherence is lower and is an important determinant of subsequent mortality [10]. Limited adherence to treatment represents a substantial issue in patients receiving BB, as previous meta-analyses and real-life studies suggested that adherence to this class of drugs is limited compared to other cardioprotective medications[11, 12]. Given that an elevated pill burden is the most relevant factor influencing medication adherence, recent hypertension guidelines recommend using a single-pill combination (SPC) as the ideal strategy to start and titrate the antihypertensive treatment [13, 14]. SPC has been shown to improve adherence and persistence to the treatment, resulting in enhanced CVD risk factor control and better patient outcomes [14‐17]. Nevertheless, public health systems often consider the use of SPC as an unnecessary increase in healthcare costs, intensely monitoring their prescription. To date, little evidence is available on the drug utilization of patients prescribed ACE-Is and BB in different formulations. In this regard, the only SPC containing both drug classes and currently available in Italy is the one including perindopril and bisoprolol.

In this study, we used a large Italian dataset of administrative data to assess the drug utilization and economic burden of treatment with ACE-Is and BB as SPC or free equivalent combination (FEC). To do so, we adopted a propensity score matching (PSM) approach to evaluate the differences in the level of adherence and economic costs associated with the prescription of the bisoprolol/perindopril combination as SPC or FEC.

According to the inclusion and exclusion criteria, in the entire administrative database we identified 6521 patients taking the FEC and 11,440 subjects taking the SPC bisoprolol/perindopril (Fig. 1). The clinical characteristics and drug prescriptions of the two groups before PSM are reported in Supplementary Tables 3 and 4, respectively. Patients in the SPC group were younger and showed a lower disease burden than those in the FEC group (Supplementary Fig. 2). While the distribution of pill burden was similar between the two groups, the number of tablets was higher in the FEC group (Supplementary Fig. 3). As reported in Table 1, the propensity score matching resulted in a balanced distribution of the clinical characteristics between the two groups (4688 patients in each group), including the pill and disease burden (mean number ± SD of pills: FEC 1.5 ± 1.4 vs SPC 1.6 ± 1.4; mean number ± SD of disease: FEC 0.9 ± 1.1 vs SPC 0.9 ± 1.1). All the following analyses were performed on the two post-PSM cohorts.

This study uses a large administrative dataset, including around 11% of the Italian population, to explore the treatment adherence of patients taking a combination of two commonly prescribed drugs in primary and secondary CVD prevention (perindopril and bisoprolol) in the format of FEC or SPC. It also reports the economic burden in terms of hospitalizations, CV visits and overall direct costs related to these two different treatment strategies. The first important finding emerging from the current analysis is that adherence and persistence to cardiovascular drugs remain suboptimal, with a PDC > 80% detectable in < 50% of patients taking the two-drug combination and > 40% of patients in the FEC group discontinuing the drugs during the first year of treatment. The SPC is associated with a significant improvement in medication adherence and persistence compared to the use of FEC. This is likely the main reason explaining the lower risk of hospitalization and lower number of cardiovascular specialist visits observed in patients treated with the SPC than FEC during follow-up. The lower utilization of healthcare resources might explain the lower healthcare costs related to the use of SPC compared to those associated with the prescription of the FEC. In summary, our data suggest that the use of bisoprolol/perindopril SPC might lead to substantial health benefits and considerable reduction of healthcare costs compared to the prescription of both drugs as FEC.

Cardiovascular disease evolves through several subclinical stages, leading to the progressive accumulation of cardiovascular damage, ultimately resulting in the emergence of its clinical manifestations. The RAAS and SNS are the two major systems involved in all stages of CVD evolution, stimulating the heart and vessels remodeling, inducing a faster progression of the subclinical cardiovascular damage and promoting the processes that lead to CVD complications [2, 3]. For these reasons, several guidelines now consider the combination of ACE-Is and BB among the pillars of the treatments for patients at different stages of the CVD continuum, including subjects with hypertension, ischemic heart disease and heart failure [14, 21, 22]. Particularly, the recently published guidelines on the management of arterial hypertension (the most important mortality risk factor worldwide) emphasized that ACE-Is and BB should be considered among first-line agents for the treatment of the disease, based on results from RCTs and their meta-analyses [8] showing they effectively reduce SBP and DBP and, consequently, result in a similar or only slightly different reduction in the risk of major CV outcomes and mortality when given as the initial treatment step (while recognizing a lesser stroke prevention for these drugs). In the same guidelines, the indications for the use of BB as preferred treatment strategy in patients with hypertension were largely expanded compared to previous guidelines, including 26 clinical conditions [8]. Furthermore, the guidelines emphasized the importance of using specific molecules, including BB with high B1 selectivity such as bisoprolol, given they might have a more favorable side effect profile than other BBs [8]. This has been recently confirmed also by a non-interventional study based on routinely collected data from the UK Clinical Practice Research Datalink (CPRD). In a population of > 267,000 patients, Fotch et al. showed that the prescription of bisoprolol in this dataset was associated with a risk for type 2 diabetes mellitus, obesity and erectile dysfunction similar to other antihypertensive durgs, with increased risk for dyslipidemia only when compared to diuretics [23]. Another analysis conducted on the same dataset demonstrated that the prescription of bisoprolol was associated with a lower long-term risk of mortality and cardiovascular events in patients with angina compared to the use of other BBs [24]. Despite these clear recommendations from guidelines supported by real-world data, the benefits obtained from prescribing these classes of drugs remain limited at a population level [25, 26], and hypertension has remained the leading risk factor for morbidity and mortality worldwide in the last 3 decades [27]. Similar issues can be described for ischemic heart diseases and heart failure, which remain leading causes of mortality and disability in subjects > 50 years old [28]. A significant factor that accounts for these alarming statistics is the limited adherence of patients to medical treatment, which is associated with a persistent increase in the mortality risk [29]. This is particularly relevant in subjects with advanced diseases, such as those with established CVD or heart failure, given they are at extremely elevated mortality risk. In these conditions, the combination of BB and ACE-I represents the foundation of the medical treatment. Still, adherence to these medications remains poor, with important mortality and economic costs [30, 31]. To improve patient adherence, current guidelines strongly recommend using SPC wherever possible to reduce the pill burden and simplify the treatment regimen [8]. Our results support this recommendation, showing that adherence and persistence to combination treatment with ACE-I and BB remain suboptimal in > 50% of the population and might be substantially improved by SPC. This might translate into potential clinical benefits, as documented by the reduced number and duration of hospitalizations observed in the SPC compared to the FEC group. Particularly, we reported a significant reduction in the number and duration of hospitalizations related to CVD. This might depend on several factors, including greater adherence to the SPC treatment leading to better prevention of the most severe forms of CVD, better control of risk factors and greater protection from complications during acute decompensations. All these factors could substantially reduce the risk of hospitalization and time necessary to restore a physiologic cardiovascular homeostasis during hospital admissions. Previous studies have documented that SPC might reduce hospital admissions, although the comparison was done with monotherapy rather than the FEC of the same drugs [32]. Therefore our results extend previous findings, and this is important as one of the most common reasons taken forward by the NHSs to monitor the prescription of SPC scrupulously is related to their higher costs than the use of the FEC of the same drugs. Such immediate increase in the economic costs is often regarded as an unnecessary expansion of the NHS budget, while the potential advantages derived by a better adherence and persistence in the treatment could be seen only in the very long term. We now show that the use of SPC is associated with a significant reduction of the NHS costs for managing CVD and that such economic impact emerges already within 1 year from the original prescription. This is combined with evident benefits for the patients, with a lower risk of hospitalizations. Another important result emerging from our analysis is the evidence that the use of SPC is associated with an improved treatment persistence than the use of FEC. Beyond the simplification of the treatment achieved with the SPC that might explain this result, it also suggests that the prescription of bisoprolol/perindopril as SPC is well tolerated, leading to a low discontinuation rate.

This study has several important strengths. First, rigorous pharmacoepidemiologic methods that have been previously validated were used to minimize confounding. We also performed extensive adjustments for covariates using propensity score matching. Second, this study provides high generalizability based on the nationally representative database used for the analyses, which includes approximately 10% of the Italian population. Finally, we utilized previously validated claims-based algorithms to define CV outcomes to minimize misclassification bias. Some limitations should also be recognized. Although the new European Society of Hypertension guidelines extended the use of BB to several conditions, the combination of ACE-IS and BB did not represent the standard of care for hypertension during the study period, therefore the patients analyzed may not be representative of all the hypertensive patients [8]. When looking at characteristics pre-PSM, SPCs tend to be prescribed to younger patients and with fewer comorbidities. PSM minimized the risk of selection bias, obtaining an appropriate balance for age, gender, drug history and comorbidities. However, its inability to balance unmeasured confounding variables or to adjust for disease severity when working with coded variables might have influenced the results of our analyses. Despite these limitations, information about unmeasured confounders may have been captured indirectly through proxies, such as using older age as a proxy for frailty or examining pharmacologic treatment as a proxy for the presence of specific diseases. Previous studies have also documented that propensity score sometimes achieves better balance than in groups randomly assigned to treatment [33]. For these reasons, PSM is increasingly used in real-world analyses [34], and large initiatives of trial emulation have placed this approach at the center of their conceptual framework [35]. While associated with better adherence and persistence, the short follow-up and limited number of hard outcomes did not provide us with the opportunity to test the benefits in terms of cardiovascular risk reduction potentially obtained with the use of bisoprolol/perindopril as FEC or SPC. For the same reasons, we could not test the efficacy of the SPC vs FEC in reducing the cardiovascular risk in different clinical settings where perindopril and bisoprolol are commonly used, including patients with hypertension, ischemic heart disease and heart failure. However, the positive impact of the SPC on the risk of hospitalization provides clear evidence of the potential advantages for the patients of using this treatment approach. Furthermore, when the analysis on the average days per hospitalization was limited to hospitalized patients only, the significant difference in this parameter between SPC and FEC groups was substantially attenuated, likely because the sample decreased significantly. Another limitation related to the use of an administrative database for our analyses is the lack of information on the absolute value of cardiovascular risk factors, making it impossible to test whether the impact of the SPC or FEC on hospitalizations and healthcare costs is effectively mediated by improved control of the patient's cardiovascular risk. In addition, information on the reasons for non-adherence were not retrievable from the databases, nor were those related to the type of therapeutic strategies at index date and reasons behind the discontinuation of therapies. Moreover, pharmacologic databases do not provide information on drugs prescribed during hospitalizations. A further limitation is the lack of information on clinical or other potential confounders that could have influenced our results, especially not-measurable variables, including patient attitude towards medication or social status, which could have affected the level of adherence in both cohorts. Finally, the study was conducted only on an Italian population; therefore, its results should be confirmed in other populations.

The current results support the use of SPC as opposed to FEC in patients requiring treatment with ACE-I combined with a BB as this is associated with better adherence and persistence, lower risk of hospitalization and reduced healthcare costs. The benefits related to the prescription of SPC are already evident 1 year after the original prescription, making its utilization highly cost-effective for patients and National Health Systems.