Comparison of utilization,cost, adherence,and hypoglycemia in patients with type 2 diabetes initiating rapid-acting insulin analog with prefilled pen versus vial/syringe

Abstract

Background:

Studies examining outcomes of different insulin delivery systems are limited. The objective of this study was to compare healthcare utilization, costs, adherence, and hypoglycemia rates in patients with type 2 diabetes mellitus (T2DM) initiating rapid-acting insulin analog (RAIA) using prefilled pen versus vial/syringe.

Methods:

A retrospective analysis was conducted using a US claims database (1/1/2007 to 12/31/2008). Inclusion criteria were: ≥18 years old, with T2DM, ≥12 months of continuous eligibility, and new to RAIA. Difference-in-difference analyses after propensity score matching were conducted to compare changes in outcomes from 6 months prior to and 6 months after initiating RAIA with a prefilled pen versus vial/syringe (Wilcoxon rank-sum test for costs and t-test for other outcomes). Categories of utilization and costs (2009 USD) included total and diabetes-related inpatient, outpatient, and emergency room. Adherence was measured by proportion of days covered (PDC). Hypoglycemia was identified using ICD-9-CM codes.

Results:

Baseline characteristics were similar between the prefilled pen (n?=?239) and vial/syringe (n?=?590) cohorts after matching. Adherence to RAIA was greater in the prefilled pen cohort than the vial/syringe cohort (PDC: 54.6 vs. 45.2%, p?<?0.001). While the increase in diabetes-related pharmacy costs from before to after initiating RAIA was greater in the prefilled pen cohort than the vial/syringe cohort (+$900 vs. +$607, p?<?0.001), the prefilled pen cohort was associated with greater reductions in the total diabetes-related costs (–$235 vs. +$61, p?=?0.006) and the utilization of oral anti-hyperglycemic agents (–1.3 vs. –0.7, p?=?0.016). There were no significant differences in other outcomes.

Limitations:

Claims databases do not provide optimal measures for adherence or T2DM severity, and only capture hypoglycemia events requiring clinical intervention.

Conclusion:

Initiating RAIA with a prefilled pen was associated with better adherence and greater reduction in total diabetes-related costs than a vial/syringe. There was no significant difference in total healthcare costs.     

Guidelines-based treatment associated with improved economic outcomes in nontuberculous mycobacterial lung disease

Abstract

Background: The prevalence of nontuberculous mycobacterial lung disease (NTMLD) in the US has increased; however, data characterizing the associated healthcare utilization and expenditure at the national level are limited.

Objective: To examine associations between economic outcomes and the use of anti-Mycobacterium avium complex (MAC) guidelines-based treatment (GBT) for newly-diagnosed NTMLD in a US national managed care claims database (Optum^® Clinformatics^® Data Mart).

Methods: NTMLD was defined as having ≥2 claims for NTMLD (ICD-9 031.0; ICD-10 A31.0) on separate occasions ≥30?days apart (between 2007 and 2016). The cohort included patients insured continuously over a period of at least 36?months (12?months before initial NTMLD diagnostic claim and for the subsequent 24?months). Treatment was classified as GBT (consistent with American Thoracic Society/Infectious Diseases Society of America guidelines), non-GBT, or untreated. All-cause hospitalization rates and total healthcare expenditures at Year 2 were assessed as outcomes of the treatment prescribed in Year 1 after NTMLD diagnosis.

Results: A total of 1,039 patients met study criteria for NTMLD (GBT, n?=?294; non-GBT, n?=?298; untreated, n?=?447). After adjustment for baseline characteristics, GBT was associated with a significantly lower all-cause hospitalization risk vs non-GBT (odds ratio [OR]?=?0.53; 95% CI = 0.33–0.85, p?=?0.008), and vs being untreated (OR = 0.57; 95% CI = 0.35–0.91, p?=?0.020). Adjusted total healthcare expenditure in Year 2 with GBT ($69,691) was lower than that with non-GBT ($77,624) with a difference of ?$7,933 (95% CI = ?$14,968 to ?$899; p?=?0.03).

Conclusions: Patients with NTMLD in a US managed care claims database who were prescribed GBT had lower hospitalization risk than those who were prescribed non-GBT or were untreated. GBT was associated with lower total healthcare expenditure compared with non-GBT.     

Impact of a step-therapy protocol for pregabalin on healthcare utilization and expenditures in a commercial population

Abstract

Objective:

To compare changes in healthcare resource utilization and costs among members with painful diabetic peripheral neuropathy (pDPN), postherpetic neuralgia (PHN), or fibromyalgia (FM) in a commercial health plan implementing pregabalin step-therapy with members in unrestricted plans.

Methods:

Retrospective study of outcomes associated with implementation of a pregabalin step-therapy protocol using claims data from Humana (‘restricted’ cohort) and Thomson Reuters MarketScan (‘unrestricted’ cohort). Members aged 18–65 years receiving treatment for pDPN, PHN, or FM during 2008 or 2009 were identified; cohorts were matched on diagnosis and geographic region. Baseline to follow-up changes in healthcare resource utilization and costs were determined using difference-in-differences (DID) analysis. Statistical models adjusting for covariates explored relationships between restricted access and outcomes.

Results:

A total of 3876 restricted cohort members were identified and matched to 3876 unrestricted cohort members. FM was the predominant diagnosis (84.7%). The unrestricted cohort was older (mean?=?49.0 (SD?=?10.4) years vs 47.6 (SD?=?10.5) years; p?<?0.001), and had greater comorbidity (RxRisk-V score?=?5.4 (SD?=?3.2) vs 4.4 (SD?=?2.9), p?<?0.001) than the restricted cohort. Compared with the unrestricted cohort, the restricted cohort demonstrated a greater year-over-year decrease in pregabalin utilization (?2.6%, p?=?0.008), and greater increases in physical therapy and disease-related outpatient utilization (3.7%, p?=?0.010 and 3.6%, p?=?0.022, respectively). There were no statistically significant net differences in all-cause or disease-related total healthcare, medical, or pharmacy costs between cohorts. After adjusting for baseline compositional differences between cohorts, restricted plan membership was associated with a net increase in all-cause medical ($1222; p?=?0.016) and disease-related healthcare costs ($859; p?=?0.002). Limitations include use of a combined analysis for pDPN, PHN, and FM, especially since the observed results were likely driven by FM; an inability to link the prescribing of a medication with the condition of interest, which is common to claims analyses; and lack of pain severity information.

Conclusions:

Implementation of a pregabalin step-therapy protocol resulted in lower pregabalin utilization, but this restriction was not associated with reductions in total healthcare costs, medical costs, or pharmacy costs.     

Examining the association between pain severity and quality-of-life,work-productivity loss,and healthcare resource use among European adults diagnosed with pain

Objective: The goal of this research was to quantify the association between pain severity and several health outcomes in a large sample of patients diagnosed with some form of pain.

Methods: Responses from patients who had been diagnosed with some form of pain (n?=?14,459) were drawn from the 2013 EU National Health and Wellness Survey (NHWS; n?=?62,000). Respondents reported their subjective pain severity in the past week on a numerical rating scale (0–10) as well as the Medical Outcomes Study Short Form (SF-36), Work Productivity and Activity Impairment Questionnaire (WPAI), and healthcare resource utilization in the past 6 months (healthcare professional (HCP) visits, emergency room (ER) visits, and hospitalizations). Associations between pain severity and health outcomes were examined via a series of regression models controlling for a set of demographic and health-related covariates.

Results: After controlling for demographics and comorbidities, pain severity in the past week was shown to be significantly negatively associated with Health Utilities (b = ?0.022, p?b?=?0.18, p?b?=?0.13, p?b?=?0.14, p?b?=?0.08, p?Limitations: This study was a self-report cross-sectional study which may have biased the results and does not allow for causal inferences to be made. Finally, the regression models run were limited to available covariates and, hence, some potentially important covariates may not have been included in these models.

Conclusions: The findings suggest that reducing pain severity could result in an increase in patients’ quality-of-life and work productivity, and a decrease in healthcare resource use. The equations, linking pain and outcomes, were presented in an accessible format so they could be readily applied in healthcare decision-making.     

Exenatide BID and liraglutide QD treatment patterns among type 2 diabetes patients in Germany

Abstract

Objectives:

This study evaluated patient and prescriber characteristics, treatment patterns, average daily dose (ADD), and glycemic control of patients initiating glucagon-like peptide 1 (GLP-1) receptor agonists in Germany.

Methods:

The LifeLink? EMR-EU database was searched to identify patients initiating exenatide twice daily (BID) or liraglutide once daily (QD) during the index period (January 1, 2009–April 4, 2010). Eligible patients had ≥180 days pre-index history, ≥90 days post-index follow-up, and a pre-index type 2 diabetes diagnosis. Univariate tests were conducted at α?=?0.05.

Results:

Six hundred and ninety-two patients were included (exenatide BID 292, liraglutide QD 400): mean (SD) age 59 (10) years, 59% male. Diabetologists prescribed liraglutide QD to a larger share of patients (65% vs 35% exenatide BID) than non-diabetologists (51% vs 49%). GLP-1 receptor agonist choice was not associated with age (p?=?0.282), gender (p?=?0.960), number of pre-index glucose-lowering medications (2.0 [0.9], p?=?0.159), pre-index HbA1c (8.2 [1.5%], p?=?0.231) or Charlson Comorbidity Index score (0.45 [0.78], p?=?0.547). Mean (SD) ADD was 16.7?mcg (9.2, label range 10–20?mcg) for exenatide BID and 1.4?mg (0.7, label range 0.6–1.8?mg) for liraglutide QD. Among patients with post-index HbA1c tests, mean unadjusted values did not differ between cohorts. Exenatide BID patients were more likely than liraglutide QD patients to continue pre-index glucose-lowering medications (67.1% vs 60.3%, p?=?0.027) or to start concomitant glucose-lowering medications at index (32.2% vs 25.0%, p?=?0.013); exenatide BID patients were less likely to augment treatment with another drug post-index (15.8% vs 22.5%, p?=?0.027).

Limitations:

Results may not be generalizable. Lab measures for clinical outcomes were available only for a sub-set of patients.

Conclusions:

Results suggested that some differences exist between patients initiating exenatide BID or liraglutide QD, with respect to prescribing physician specialty and pre- and post-index treatment patterns. Both GLP-1 receptor agonists showed comparable post-index HbA1c values in a sub-set of patients.     

Treatment patterns and resource utilization and costs among patients with pulmonary arterial hypertension in the United States

Abstract

Objective:

To explore treatment patterns and resource utilization and cost for subjects with pulmonary arterial hypertension (PAH).

Research design:

Retrospective claims database analysis of 706 patients with PAH enrolled in a large, geographically diverse US managed-care organization.

Results:

In the final sample of PAH patients treated with bosentan (n?=?251) or sildenafil (n?=?455), average age was 57 years, 86% of patients were commercially insured, and 52% of patients were male. Gender distribution varied significantly across subgroups, with a lower proportion of males in the bosentan (30%) subgroup compared with the sildenafil group (64%) (p?<?0.001). Average baseline Charlson comorbidity score was 2.4. Average numbers of fills per month were 0.8 and 0.4 for bosentan and sildenafil patients, respectively (p?<?0.001). Over 80% of patients received only one PAH treatment in the first 90 days following the index date, with 28% of bosentan and 13% of sildenafil patients receiving combination therapy (p?<?0.001). Over one-third of bosentan patients and one-quarter of sildenafil patients experienced a dose increase in the follow-up period (p?=?0.009). Sixteen percent of sildenafil patients experienced a dose decrease in the follow-up period, while a smaller proportion of patients receiving bosentan (4%) experienced a dose decrease (p?<?0.001). On average, number of PAH-related per subject per month (PSPM) inpatient stays and emergency department visits and PSPM length of inpatient stays were statistically similar between the subgroups. PAH-related PSPM healthcare costs were high for both subgroups, with average monthly costs of $5,332 and $3,632 among bosentan and sildenafil patients, respectively (p?=?0.003). Differences in total costs were driven mainly by differences in pharmacy expenditures.

Conclusions:

Of the oral agents approved for treating PAH at the time of this study, sildenafil was most commonly prescribed as index therapy and was also associated with the lowest costs, largely due to significantly lower pharmacy costs. This study is characterized by limitations inherent to claims database analyses, such as the potential for coding errors and lack of information on whether a drug was taken as prescribed. Furthermore, PAH severity (WHO functional class) was not assessed.     

Perioperative outcomes and hospital costs associated with flowable gelatin hemostatic matrix for lumbar surgeries in real world hospital setting

Abstract

Background: Efficient hemostasis during lumbar surgery (LS) is associated with better perioperative outcomes. Flowable gelatin hemostatic matrix (FGHM) is a new type of absorbable hemostatic agent, which is effective to control bleeding during spinal surgery. This study aimed to assess the impact of FGHM on perioperative outcomes and hospital costs associated with LS.

Methods: This study retrospectively analyzed medical and billing records of patients who underwent LS for spinal degenerative disease in a Chinese tertiary care hospital from 2014 to 2016. The identified patients were further stratified into a FGHM group (n?=?108) (using the combination of FGHM and gelatin sponge) and a historical control group (using oxidized cellulose and/or collagen, n?=?82) for the adjusted comparisons of the perioperative outcomes using a propensity score matching method. Multiple generalized linear regression was conducted to assess the impact of using FGHM on total hospitalization costs.

Results: Comparisons of 64 propensity score matched pairs showed a significantly lower blood transfusion rate (34.4% vs 64.1%, p?=?0.005), lower blood transfusion volume (182.7?±?312.4 vs 301.3?±?281.0?mL, p?=?0.045), reduced post-surgery drainage tube placement rate (82.8% vs 93.8%, p?=?0.046), and shorter post-operative days on antibiotics (6.0?±?2.6 vs 7.1?±?2.4 days, p?=?0.010) in the FGHM group. Although with a relatively high acquisition price, the use of FGHM for hemostasis in LS did not increase the total hospitalization costs (coefficient = ?0.001, p?=?0.972).

Conclusions: The use of FGHM in LS improved perioperative outcomes related to hemostatic effects without increasing overall hospital costs in a real-world hospital setting.     

Glycemic control among patients with type 2 diabetes who initiate basal insulin: a retrospective cohort study

Objective:

To examine changes in glycemic control for patients with type 2 diabetes mellitus (T2DM) after initiation of basal insulin and factors associated with improved glycemic control.

Methods:

An analysis of retrospective medical records of patients with T2DM was examined using Humedica’s electronic medical records database (January 2007–August 2012). Patients with T2DM, initiating basal insulin, age ≥21 years, with a recorded HbA1c test in both the 1 year prior and the 2 years post-initiation were included. A multivariate regression examined factors associated with changes in glycemic control. Logistic regressions examined factors associated with improvements or worsening of glycemic control, compared to relatively unchanged glycemic control.

Results:

Many (14,457) individuals met the inclusion–exclusion criteria. Multivariate analyses revealed that older age (p?p?p?=?0.0138), and higher household income (p?=?0.0065) were associated with improved glycemic control. Patients diagnosed with comorbid peripheral vascular disease (p?=?0.0072), cancer (p?=?0.0019), obesity (p?=?0.0002), moderate (p?=?0.0103), and severe chronic kidney disease (p?p?=?0.0075) in the pre-period were found to have significantly improved glycemic control in the post-period. Use of prandial insulin (p?=?0.0087), pre-mix insulin (p?=?0.0003) in the pre-period, a higher pre-period HbA1c score (p?p?Limitations:

Analyses rely on electronic medical records which cannot capture patient healthcare utilization occurring outside of the data capture system. Analyses do not control for insulin dosage or type of basal insulin prescribed.

Conclusions:

Among patients with T2DM treated with basal insulin, a number of factors may influence glycemic outcomes. These findings suggest a role for a more personalized approach to the treatment of patients with T2DM.     

Humanistic and economic impacts of hepatitis C infection in the United States

Abstract

Objective:

Prior research examining the effect of hepatitis C virus (HCV) on health-related quality of life (HRQoL) and healthcare costs is flawed because non-patient controls were not adequately comparable to HCV patients. The current study uses a propensity score matching methodology to address the following research question: is the presence of diagnosed hepatitis C (HCV) associated with poorer health-related quality of life (HRQoL) and greater healthcare resource use?

Methods:

Using data from the 2009 US National Health and Wellness Survey, patients who reported a HCV diagnosis (n?=?695) were compared to propensity-matched controls (n?=?695) on measures of HRQoL and healthcare resource use. All analyses applied sampling weights to project to the US population.

Results:

HCV patients reported significantly lower levels of HRQoL relative to the matched-control group, including the physical component score (39.6 vs. 42.7, p?<?0.0001) and health utilities (0.63 vs. 0.66, p?<?0.0001). The number of emergency room visits (0.59 vs. 0.44, p?<?0.05) and physician visits (7.7 vs. 5.9, p?<?0.05) in the past 6 months were significantly higher for the HCV group relative to matched controls.

Conclusion:

The results of this study suggest that HCV represents a substantial burden on patients by having a significant and clinically-relevant impact on key dimensions of HRQoL as well as on utilization of healthcare resources, the latter of which would result in increased direct medical costs.

Limitations:

Due to limitations of the internet survey approach (e.g., inability to confirm HCV diagnosis), future research is needed to confirm these findings.     

Indirect costs associated with metastatic breast cancer

Abstract

Objective:

To compare the indirect costs of productivity loss between metastatic breast cancer (MBC) and early stage breast cancer (EBC) patients, as well as their respective family members.

Methods:

The MarketScan® Health and Productivity Management database (2005–2009) was used. Adult BC patients eligible for employee benefits of sick leave and/or short-term disability were identified with ICD-9 codes. Difference in sick leave and short-term disability days was calculated between MBC patients and their propensity score matched EBC cohort and general population (controls) during a 12-month follow-up period. Generalized linear models were used to examine the impact of MBC on indirect costs to patients and their families.

Results:

A total of 139 MBC, 432 EBC, and 820 controls were eligible for sick leave and 432 MBC, 1552 EBC, and 4682 controls were eligible for short-term disability (not mutually exclusive). After matching, no statistical difference was found in sick leave days and the associated costs between MBC and EBC cohorts. However, MBC patients had significantly higher short-term disability costs than EBC patients and controls (MBC: $6166?±?$9194 vs EBC: $3690?±?$6673 vs Controls: $558?±?$2487, both p?<?0.001). MBC patients had more sick leave cost than controls ($2383?±?$5539 vs $1282?±?$2083, p?<?0.05). Controlling for covariates, MBC patients incurred 47% more short-term disability costs vs EBC patients (p?=?0.009). Older patients (p?=?0.002), non-HMO payers (p?<?0.05), or patients not receiving chemotherapy during follow-up (p?<?0.001) were associated with lower short-term disability costs. MBC patients’ families incurred 39.7% (p?=?0.06) higher indirect costs compared to EBC patients’ families after controlling for key covariates.

Conclusion:

Productivity loss and associated costs in MBC patients are substantially higher than EBC patients or the general population. These findings underscore the economic burden of MBC from a US societal perspective. Various treatment regimens should be evaluated to identify opportunities to reduce the disease burden from the societal perspective.     

Pharmacological control of secondary hyperparathyroidism in hemodialysis subjects: a cost consequences analysis of data from the FARO study

Abstract

Background and objectives:

Secondary hyperparathyroidism (SHPT) is a frequent complication of CKD with incidence, prevalence, and costs increasing worldwide. The objective of this analysis was to estimate therapy cost of SHPT in a sub-population of the FARO study.

Materials and Methods:

In the FARO study, an observational survey aimed to evaluate patterns of treatment in patients with SHPT who had undergone hemodialysis, pharmacological treatments and biochemical parameters evolution data were collected in four surveys. Patients maintaining the same treatment in all sessions were grouped by type of treatment and evaluated for costs from the Italian National Health Service perspective.

Results:

Four cohorts were identified: patients treated with oral (PO) calcitriol (n?=?182), intravenous (IV) calcitriol (n?=?34), IV paricalcitol (n?=?62), and IV paricalcitol?+?cinacalcet therapy (n?=?20); the cinacalcet monotherapy group was not analysed due to low number of patients (n?=?9). Parathyroid hormone (PTH) level at baseline and effectiveness of treatments in suppressing PTH level were assessed to test comparability among cohorts: calcitriol PO patients were significantly less severe than others (PTH level at baseline lower than 300?pg/ml; p?<?0.0001); calcitriol IV patients did not reach significant reduction in PTH level. Paricalcitol and paricalcitol?+?cinacalcet treatment groups results were comparable, while only the IV paricalcitol cohort’s PTH level, weekly dosage, and cost decreased significantly from the first to the fourth survey (p?=?0.020, p?=?0.012, and p?=?0.0124, respectively). Total costs per week of treatment (including calcium-based phosphate binder and sevelamer) were significantly lower in the paricalcitol vs paricalcitol?+?cinacalcet cohort (p?<?0.001). Major limitations of this study are related to the survey design: not controlled and lack of comparability between cohorts; however, reflective of true practice patterns.

Conclusions:

The IV Paricalcitol cohort had significantly lower treatment costs compared with patients treated with paricalcitol?+?calcimemtics (p?<?0.001), without a significant difference in terms of baseline severity and PTH control.     

Respiratory-related medical expenditure and inpatient utilisation among COPD patients receiving long-acting bronchodilator therapy

Abstract

Objective:

To evaluate chronic obstructive pulmonary disease (COPD)-related expenditure and hospitalisation in COPD patients treated with tiotropium versus alternative long-acting bronchodilators (LABDs).

Methods:

Data were from the Thomson Reuters MarketScan Research Databases. COPD patients ≥35 years with at least one LABD claim between July 1, 2004 and June 30, 2006 were classified into five cohorts based on index LABD: monotherapy with tiotropium, salmeterol/fluticasone propionate, formoterol fumarate, or salmeterol or combination therapy. Demographic and clinical characteristics were evaluated for a 6-month pre-period and COPD-related utilisation and total costs were evaluated for a 12-month follow-up period. LABD relationship to COPD-related costs and hospitalisations were estimated by multivariate generalised linear modelling (GLM) and multivariate logistic regression, respectively.

Results:

Of 52,274 patients, 53% (n?=?27,457) were male, 71% (n?=?37,271) were ≥65?years, and three LABD cohorts accounted for over 90% of the sample [53% (n?=?27,654) salmeterol/fluticasone propionate, 23% (n?=?11,762) tiotropium, and 15% (n?=?7755) combination therapy]. Patients treated with salmeterol/fluticasone propionate (p?<?0.001), formoterol fumarate (p?=?0.032), salmeterol (p?=?0.004), or with combination therapy (p?<?0.001) had higher COPD-related costs and a greater risk of inpatient admission (p?<?0.01 for all) versus tiotropium.

Limitations:

These data are based on administrative claims and as such do not include clinical information or information on risk factors, like smoking status, that are relevant to this population.

Conclusions:

Patients treated with tiotropim had lower COPD-related expenditures and risk of hospitalisation than patients treated with other LABDs     

Adherence,persistence, healthcare utilization,and cost benefits of guideline-recommended hepatitis B pharmacotherapy

Abstract

Objective:

To compare pharmacotherapy adherence, persistence, and healthcare utilization/costs among US patients with chronic hepatitis B (CHB) initiated on an oral antiviral monotherapy recommended as first-line treatment by current national (US) guidelines vs an oral antiviral not recommended as first-line monotherapy.

Research design and methods:

In this retrospective cohort study, patients aged 18–64 with medical claims for CHB who initiated an oral antiviral monotherapy for CHB between 07/01/05 and 01/31/10 were identified from a large US commercial health insurance claims database. Patients were continuously enrolled for a 6-month baseline period and ≥ 90 days follow-up. They were assigned to ‘currently recommended first-line therapy’ (RT: entecavir or tenofovir) or ‘not currently recommended first-line therapy’ (NRT: lamivudine, telbivudine, or adefovir) cohorts.

Main outcome measures:

Multivariate analyses were conducted to compare treatment adherence, persistence, healthcare utilization, and costs for RT vs NRT cohorts.

Results:

Baseline characteristics were similar between RT (n?=?825) and NRT (n?=?916) cohorts. In multivariate analyses, RT patients were twice as likely as NRT patients to be adherent (OR?=?2.09; p?<?0.01) and persistent (mean: RT?=?361 days, NRT?=?298 days; p?<?0.01) and half as likely to have an inpatient stay (OR?=?0.527; p?<?0.01). Between the two oral antivirals recommended as first-line treatment, even though pharmacy cost was higher for entecavir, mean total healthcare costs for entecavir and tenofovir were similar ($1214 and $1332 per patient per month, respectively). Similar results were also observed with regard to adherence, persistence, and healthcare use for entecavir and tenofovir.

Conclusions:

A limitation associated with analysis of administrative claims data is that coding errors can be mitigated but are typically not fully eradicated by careful study design. Nevertheless, the current findings clearly indicate the benefits of initiating CHB treatment with an oral antiviral monotherapy recommended as first-line treatment by current guidelines.