Pharmacoeconomics of Cyclamen europaeum in the management of acute rhinosinusitis

To carry out a pharmacoeconomic analysis of Cyclamen europaeum (CE) in the management of acute rhinosinusitis (ARS) in Spain using data from the PROSINUS (PROspective epidemiological study of the diagnosis and treatment of acute rhinoSINUSitis) study.


INTRODUCTION
Rhinosinusitis is an inflammatory process of the paranasal sinuses with high prevalence in clinical practice. 1,2 Acute rhinosinusitis (ARS) is an inflammatory alteration of the nose and paranasal sinuses. ARS is usually caused by a viral infection, although other processes such allergic rhinitis, pathological abnormalities, nasal polyps, or nasal decongestant abuse can constitute predisposing factors. Inflammation in nasal cavity mucosa results in some disorders of the absorption, protection, and transport functions, and complications such as asthma flare-ups, chronification of ARS, meningitis, vision problems, and ear infections. In ARS, the most common symptoms experienced by patients are nasal obstruction, mucopurulent rhinorrhea, and localized frontal or facial pain.
It is currently accepted that ARS is a frequent disease, and therefore has a considerable impact on general public health and economic resources, both in terms of those allotted to treatment disease as well as those related to patient labor productivity. In the United States, it was estimated that in 1996 the costs that could be attributable to rhinosinusitis reached $3.390 million dollars. 3 The number of cases in Spain could range between 440,000 and 1,760,000 per year, with a considerable associated cost. 2 ARS treatment goals should be symptomatic relief, accelerating remission and preventing complications. Indeed, there is a weak body of clinical evidence about treatment effectiveness, and controlled clinical trials of ARS therapies are not numerous. 4 Most authors and consensus articles show little evidence on the effectiveness of treatments based on antibiotics, 5 oral steroids, 6 antihistamines, nasal irrigation, mucolytics, and phytotherapy. 7 The treatment recommended for ARS by the European Position Paper on Rhinosinusitis and Nasal Polyps Group (EPOS) 7 is based on symptomatic relief (analgesics, saline serum, and decongestants) or on the use of topical nasal steroids and antibiotics for the specific patients that can respond, depending on the etiology, severity, and evolution of the clinical pattern. 8 Upon analyzing evidence of adjuvant treatment aimed to relief symptoms, it can be concluded that it is low. In Spain, the large observational PROSINUS (PROspective epidemiological study of the diagnosis and treatment of acute rhinoSINUSitis) study, 9 showed that less than one-fourth (24%) of 2,610 patients with ARS followed EPOS guidelines, and a number of different treatments and drug combinations were used.
Cyclamen europaeum (CE), Nasodren V R , has been used for a very long time, particularly in Southeast Europe, as a traditional treatment for nasopharyngeal diseases. CE is prepared on the basis of an aqueous extract of tubers of CE that contain a mixture of saponins, which characteristically causes local osmosis and stimulation of the ending terminal of the trigeminal nerve and increases the secretion of the nasal mucus. 10,11 CE has shown its efficacy in two placebo-controlled clinical trials and 13 head-to-head studies (nine in adults and five in children) that compared CE with other active treatments, which seems to indicate that CE may contribute to reducing disease progression time, improving symptoms relief and objective response (computed tomography [CT] scan), decreasing the need for antibiotics or boosting their effects, as well as reducing the number of complications and chronification. 12 The present study has analyzed data from the PRO-SINUS study to carry out a pharmacoeconomic analysis of CE in the management of ARS in Spain.

Subjects
The PROSINUS study included 2,610 patients visited by 287 specialists in otorhinolaryngology throughout Spain. Patients had to fulfill all inclusion criteria: either sex, 18 years of age, reporting to the otorhinolaryngologist's office with symptoms compatible with the epidemiological diagnosis of ARS according to the EPOS consensus of "sudden onset of two or more symptoms, one of which should be either nasal blockage/ obstruction/congestion or nasal discharge (anterior/posterior nasal drip), 6 facial pain/pressure, 6 reduction or loss of smell; for a duration of <12 weeks." Patients voluntarily gave their consent to take part in this study, and they had none of the exclusion criteria such as established diagnosis of chronic rhinosinusitis (with or without nasal polyps and presenting with a new event or acute exacerbation of their disease), concurrent use of medication for other conditions that could interfere with the sinonasal disease, existing social or cognitive features indicating the possibility of problems in the follow-up, or a high risk of withdrawing prematurely from the study. Data on the previous management by primary care physicians was also recorded.

Study Design
The PROSINUS study was an epidemiological, observational, prospective, health outcomes study aimed to describe the diagnostic, treatment, and clinical monitoring procedures applied in ARS in clinical practice in Spain. Because this was an observational study aimed at identifying current practice real failure rates and costs associated with usual medical care, and not under experimental conditions, treatment of the ARS was left to the criteria of the attending physician. The present study was carried out as a secondary analysis of the PROSI-NUS database, combining healthcare resource use, productivity losses, and health outcomes from the observational study with updated unit costs representative of the Spanish National Health System. Data for both clinical and economic variables (see below) were recorded prospectively by the investigators (from symptoms onset until first study visit and from first study visit to final study visit, 2 to 4 weeks after first visit).

Comparative Options
Costs and outcomes of CE in monotherapy and combination therapy were compared to both monotherapies and combination therapies as follows: CE in monotherapy versus other pooled monotherapies and versus combinations of two or more pooled drug combinations without CE CE added to different combinations, specifically: CE added to one single drug, CE added to two drug combination, and CE added to three or more combined drugs Additional analysis was carried out to address the effect of adding CE to antibiotics and antibiotics plus corticosteroids. 8 In all cases, comparison options were defined by means of the treatments prescribed by the patients at the first visit of the study, irrespective of treatments taken previously (from event onset to first physician visit).

Clinical Outcomes
Cure rate was defined following the EPOS consensus for epidemiological definition 7 as the complete clinical resolution of ARS symptoms of the ARS episode at the end of the study follow-up (visit 2 at 2-4 weeks) and was calculated for each comparison option. For the primary analysis, the patient sample that met all of the inclusion criteria and none of the exclusion criteria, and which had valid data for the primary end point, was used. No provision was made for interpolating missing data or loss to follow-up.

Economic Outcomes
Both direct and indirect costs were included in the analysis. Direct costs included medical visits (general practitioner, otorhinolaryngologist, and emergency visits), diagnostic tests (rhinoscopy or nasal endoscopy, sinus x-ray, sinus CT, bacteria culture, and allergy tests) and drugs (oral antibiotics, nasal corticosteroids, antihistamines, nasal decongestants, mucolytics, saline solutions and phytotherapy including CE). Indirect costs included sick leaves (absenteeism) and reduced productivity at work (presenteeism). In the PROSINUS study, resources use from the onset of the ARS event to the date of the visit was also recorded at the first study visit. At the second visit, resources uses from first visit to the end of the event were recorded. Thus, otorhinolaryngologists could have influence in the resources use after but not before the first visit since symptoms' onset.
Unit costs applied to the health resources utilization data are shown in Table I. The data sources were the Medicine Database of the General Council of Pharmacists Official Colleges 13 for drug costs, and the health costs database eSalud 14 for healthcare resources (medical visits and tests). Regarding the medication, it was assumed that a patient would purchase one pack of each type of drug that he/she used. All costs were expressed in euros of year 2011.

Perspective, Time Horizon, and Discount Rate
The main analysis was carried out from the societal perspective (including both direct and indirect costs). Additional analysis adopted the healthcare perspective (direct costs only). Because study follow-up was short (1 month), no discounting was applied in the analysis.

Statistical Analysis
Statistical analysis was performed with SPSS version 15.0 for Windows (SPSS Inc., Chicago, IL). Analysis of variance was carried out to see if there was any difference between subgroups, and logistic regression models were built to determine whether specific drugs had a significant influence in the cure rate of pooled options, to discard relevant heterogeneity of comparison options in the analysis.
Student t test and v 2 test were used to compare mean costs and cure rates of CE-based therapies with respect to comparators. The level of statistical significance was established at .05.

RESULTS
On average, patients reported to the first PROSI-NUS study visit 11.2 days (66.2 days) after onset of the ARS event, whereas the average total duration of the event was 13.7 days (68.8 days). At visit 2, 82.9% of patients presented complete clinical resolution of the symptomatic episode. Table II shows the clinical results of the comparison of CE-based therapies with respect to other therapies in the management of ARS. CE in monotherapy appeared to be more effective in terms of cure rate than other pooled monotherapies (15.3% higher, P <.05) and combination therapies (10.3% higher, P <.05).
The addition of CE to other monotherapies or combination therapies showed a significant improvement when adding CE to two-drug combinations (93.9% vs. 76.5%; P <.05), but no significant effect when added to combinations of three or more drugs (81.1% vs. 79.8%; nonsignificant).
Patients receiving CE monotherapy were e98 less costly than patients receiving other monotherapies (e682 vs. e584, P <.05) and e61 less costly than combination therapies (e645 vs. e584, P <.05). Figure 1 shows the breakdown of these results in terms of direct and indirect costs. CE as an add-on treatment was associated with lower total costs when used in combination with one single drug (e626 vs. e682, P 5.29), even though these differences did not reach the statistical significance, probably because of the limited sample size. The combination of CE with two or more drugs produced similar total costs than the same combinations without CE. In all situations, cost reductions associated to CE-based therapies were mainly explained by indirect costs, whereas direct healthcare costs were similar in all subgroups (Table III). The proportion of patients treated with CE who were visited by a primary care physician or a primary care physician and otorhinolaryngologist was slightly higher than for patients not taking CE, but differences were only significant versus patients treated with antibiotics (which accounted for a small subgroup of patients). This fact could yield to higher costs for CE patients, but this is not the case because of the lower number of total visits in this group.
The combination of total costs and cure rates provides an estimate of the balance between cost and  outcomes, showing lower cost per cured patient in CEbased therapies in almost all comparisons (except when added to combinations of three or more drugs) (Fig. 2).

Special Situations
Because only antibiotics, either in monotherapy or combined with corticosteroids, have demonstrated a clinical efficacy in the management of ARS, a specific analysis was carried out to compare these options with and without CE. The results of this analysis showed that adding CE to one antibiotic, with or without nasal corticosteroid, increased the success rate and reduced total costs, due to a significant reduction of indirect costs. Both compared to antibiotic in monotherapy or to antibiotic plus nasal corticoid, the addition of CE resulted in a lower cost per success ratio (Table IV).

DISCUSSION
This secondary analysis of the PROSINUS study, an observational, prospective, health outcomes study aimed to describe the management of ARS and its outcomes, has shown that CE-based therapies are associated with better clinical outcomes, with similar or even lower costs than comparable therapies without CE.
These results are in line with the conclusions of most of the clinical studies on ARS, including placebocontrolled clinical trials and head-to-head clinical studies. Pfaar et al., in a randomized controlled trial in patients with moderate-to-severe ARS, demonstrated that CE on top of regular antibiotic treatment added a significant improvement of facial pain/pressure and signs of nasal inflammation compared to antibiotic alone. 12 CE is a safe and well-tolerated treatment that demonstrated a great reduction in individual symptoms scores (nasal obstruction, mucus secretion, facial pain, and loss of smell), an improvement in the mucosal edema and nasal obstruction evaluated by endoscopy, and a reduction of the sinus occlusion evaluated by CT scan on day 7. 15 The effects of CE on ARS start at 3 to 5 days of treatment and complete symptom resolution at 9 to 12 days. 15 CE was able to reduce the disease  progression time, the need for antibiotics or boosting their effects, the number of complications, and the disease chronification with great satisfaction scores rated by patients and investigators compared to antibiotic treatment. 12 Several drugs, such as antibiotics, oral decongestants, antihistamines, and topical corticosteroids are used for the treatment of rhinosinusitis, but these available therapies do not have sufficient evidence to be considered efficacious and often fail to provide adequate symptoms relief and/or objective cure assessed by endoscopy or CT scan. Consequently, patients with ARS are often poorly treated and/or treated using several therapies. Despite continued development of new therapies and more accurate diagnostic procedures, there is no evidence that ARS is being better controlled. CE could be considered a recommendable option as a first-line treatment, as it has demonstrated in several clinical studies its ability to improve the signs and symptoms of the disease. In addition, Savvateeva and Lopatin 16 have recently published a review of studies that evaluated the efficacy and safety of CE and concluded that it provides a good option for ARS treatment, ensuring personalized treatment and preventing polymedication and inappropriate use of antibiotics.
As ARS frequently occurs in conjunction with asthma, allergic rhinitis, and other airway disorders, it is difficult to single out the expenditures devoted to treating rhinosinusitis only, and only a few studies have done so 17 with notably variable results. Anzai et al. 18 examined the cost-effectiveness of four treatment strategies, with and without antibiotics, for adult patients with acute sinusitis, finding a total cost per patient between $747 and $899 in 2005. Bhattacharyya et al. 19,20 have recently published two studies on the burden of rhinosinusitis (recurrent ARS and chronic rhinosinusitis, respectively), with total cost per patient per year of $1,091 and $780. These results are hardly comparable with those from our study, because we focused in costs associated with a single ARS event, whereas those mentioned studies analyzed longer time horizons. Finally, pharmacoeconomic analysis of two antibiotic therapies found a direct healthcare cost per ARS episode of $171 to $211 in 2002, 21 slightly lower than our estimates of e250 to e329.
Given the high prevalence of ARS and the eventual consequences of treatment failure, including potential disease chronification, clinical success should be pursued not only to improve the patients' quality of life but to limit the economic impact of the condition.
In our study, the use of CE was associated with a higher cure rate without increasing healthcare costs, either when compared as a monotherapy with respect to other monotherapies, or when added to different combinations. It is important to note that not properly treated, rhinosinusitis could lead to a recurrence or even to a potential chronification of the disease, whereas consequently reducing the patient's overall well being and quality of life and increasing direct and indirect costs. 19 Therefore, in this sense CE provides an added value because it reduces chronification of ARS. In addition, CE has a purely physiological effect and is not absorbed, showing a better safety profile compared to other treatments that cause more or worse adverse events, and  consequently produces a greater cost derived from adverse event management. 22 This study has two main limitations that must be considered. First, the use of the data from an observational descriptive study to derive conclusions regarding the consequences of different treatment options is risky (i.e., the PROSINUS study was not designed to compare different therapies, and patients' characteristics may be assumed equivalent irrespective of treatment received), therefore selection bias could exist. Considering the ethical and logistical weaknesses of randomized clinical trials, well-designed and conducted observational studies may be an efficient alternative to explore exposure effectiveness, even though comparability across exposure groups may not be guaranteed. Second, the comparison options built into the secondary analysis include the outcomes of patients who received different drugs in different combinations (e.g., the pooled results of CE vs. other monotherapies included a number of different drugs in the other monotherapies group). However, logistic regression techniques were applied to address whether this pooling of clinical results was justifiable (i.e., no statistical differences between individual treatments [or combinations] were stated before aggregating patients in the pool analysis). These limitations raise the need for further research to definitely establish the clinical superiority of CE in different clinical situations and combined with different treatments.
Finally, it is noteworthy that the present study is pragmatic and widely applicable in clinical practice, and although it has the mentioned limitations, especially in relation to the selection of treatments, we can conclude that the trend CE has in monotherapy for ARS is cost-efficient. However, further studies are needed with greater control to come to conclusions on the effect of CE with other treatment combinations for ARS.

CONCLUSION
The results of this study suggest that the use of CE, both as monotherapy or in combination, may be associated with better clinical outcomes, including cure rate, at no additional cost to the healthcare system, with respect to different treatment options commonly used in clinical practice for the treatment of ARS.