A Review of Current Approaches to Evaluating and Reimbursing New Medicines in a Subset of OECD Countries.

OBJECTIVES: The aim of this study was to review the current evaluation and funding processes for new drugs in different developed countries, to provide a comparative framework with detailed, homogeneous, and up-to-date information. METHODS: Scientific publications, reports and websites were reviewed between July and December 2021 using PubMed, Google Scholar, and grey literature sources. The main items searched were actors and processes, including timelines, characteristics of clinical and economic evaluations, participation of stakeholders, elements of price and reimbursement decisions, cost-effectiveness thresholds and specific funds. The analysed 13 countries were Australia, Canada, England, France, Germany, Italy, Japan, the Netherlands, Portugal, Scotland, South Korea, Spain and Sweden. RESULTS: Eight countries perform the assessment process separated from the pricing decision. Countries measure each drug's added therapeutic value through multi-attribute value scales, algorithms, non-prescriptive lists of criteria, or quality-adjusted life years (QALYs). Health technology assessment (HTA) methodologies differ in their outcome measures, elicitation techniques, comparators, and perspectives. The criteria used for pricing and reimbursement include humanistic, clinical, and economic aspects. Only Scotland, England, the Netherlands, Canada and Portugal use explicit efficiency thresholds. Health care professionals participate in all assessment committees, and patients are becoming increasingly involved in most countries. The official time from marketing authorisation to the completion of the evaluation and pricing processes varied from 126 to 540 days. CONCLUSIONS: Most analysed countries show a trend towards value-based approaches that consider value for money to society, but also other economic, clinical, and humanistic criteria. Good practices included robustness, transparency, independence, and participation.

Comparison of GLP-1 receptor agonists and other Glucose-Lowering agents on cardiovascular outcomes in individuals with type 2 diabetes and Obesity: A Spanish Real-World Population-Based study.

AIMS: Assess the impact of glucagon-like peptide receptor agonists (GLP-1RA) compared to other glucose-lowering agents on cardiovascular outcomes in individuals with type 2 diabetes and obesity in a Spanish metropolitan area. METHODS: A retrospective population-based type 2 diabetes cohort was identified from the Valencia Clinic-Malvarrosa Department electronic databases (2014-2019). Study groups included GLP-1RA, sodium-glucose co-transporter-2 inhibitors (SGLT2i), Insulin, and Miscellany (other glucose-lowering agents). 1:1:1:1 propensity score matching was conducted. The primary outcome was a composite of major adverse cardiovascular events (4-point MACE) comprising myocardial infarction, stroke, all-cause mortality, and heart failure. Secondary outcomes included individual 4-point MACE components. Hazard ratios were estimated using Cox regression analyses against the Miscellany group. RESULTS: From 26,944 subjects, 1,848 adults were selected per group. GLP-1RA did not show a significant reduction in 4-point MACE risk (HR 1.05 [95%CI 0.82-1.34]). SGLT2i significantly reduced the risk of heart failure (HR 0.16 [95%CI 0.05-0.54]) and atrial fibrillation (HR 0.58, [95%CI 0.35-0.95]). The Insulin group exhibited a higher risk for 4-point MACE and most individual outcomes compared to GLP-1RA and SGLT2i. CONCLUSIONS: Our findings do not provide evidence of a reduced cardiovascular risk, as assessed by 4-point MACE, with GLP-1RA. In contrast, SGLT2i demonstrated protective effects against heart failure and atrial fibrillation.

Real-World Evaluation of GLP-1 Receptor Agonist Therapy Persistence, Adherence and Therapeutic Inertia Among Obese Adults with Type 2 Diabetes.

INTRODUCTION: In type 2 diabetes (T2D), key barriers to optimal glycaemic control include lack of persistence with treatment, reduced medication adherence and therapeutic inertia. This study aimed to assess the impact of these barriers in obese adults with type 2 diabetes treated with a GLP-1 receptor agonist (GLP-1RA) and compare them against other glucose-lowering agents in a real-world setting. METHODS: A retrospective study was conducted using electronic medical records from 2014 to 2019 for adults with T2D at the Valencia Clínico-Malvarrosa Department of Health (Valencia, Spain). Four study groups were established: all GLP-1RA users, SGLT2i users, insulin users and other glucose-lowering agent users (miscellany group). To account for imbalance between groups, propensity score matching (PSM) including age, gender and pre-existing cardiovascular disease was performed. Chi-square tests were used for comparisons between groups. Time to first intensification was calculated using competing risk analysis. RESULTS: Among the 26,944 adults with T2D, 7392 individuals were selected following PSM, with 1848 patients in each group. At 2 years, GLP-1RA users were less persistent than non-users (48.4% versus 72.7%, p < 0.0001) but more adherent (73.8% versus 68.9%, respectively, p < 0.0001). A greater proportion of persistent GLP-1RA users than non-persistent users exhibited reduced HbA1c (40.5% versus 18.6%, respectively, p < 0.0001), but no differences in cardiovascular outcomes and death were found. Overall, therapeutic inertia was observed in 38.0% of the study population. The large majority of GLP-1RA users received treatment intensification, whereas only 50.0% of GLP-1RA non-users were intensified. CONCLUSION: Under real-life conditions, obese adults with T2D persistently treated with GLP-1RA showed improved glycaemic control. Despite benefits, persistence with GLP-1RA was limited after 2 years. Additionally, therapeutic inertia occurred in two out of three study participants. Strategies to facilitate medication adherence, persistence and treatment intensification in people with T2D should be made a priority in order to achieve and maintain glycaemic targets and improve outcomes in this population. TRAIL REGISTRATION: Study registered in clinicaltrials.org with the identifier NCT05535322.

Incidence and impact of atrial fibrillation in heart failure patients: real-world data in a large community.

AIMS: The objective of the present study is to assess the bidirectional association between heart failure (HF) and atrial fibrillation (AF) using real-world data. METHODS AND RESULTS: From an electronic health recording with a population of 3 799 885 adult subjects, those with prevalent or incident HF were selected and followed throughout a study period of 5 years. Prevalence and incidence of AF, and their impact in the risk for acute HF hospitalization, worsening renal function, ischaemic and haemorrhagic stroke, and all-cause mortality were identified. We analysed all incident and prevalent patients with HF and AF, 128 086 patients (S1), and subsequently analysed a subset of patients with incident HF and AF, 57 354 patients (S2). We analysed all incident and prevalent patients with HF and AF, 128 086 patients (S1), and subsequently a subset of patients with incident HF and AF, 57 354 patients (S2). The prevalence of AF was 59 906 (46.7%) of the HF patients, while incidence in the S2 was 231/1000 patients/year. In both cohorts, S1 and S2, AF significantly increases the risk of acute heart failure hospitalization [incidence 79.1/1000 and 97.5/1000 patients/year; HR 1.53 (1.48-1.59 95% CI) and HR 1.32 (1.24-1.41 95% CI), respectively], risk of decreased renal function (eGFR reduced by >20%) [66.2/1000 and 94.0/1000 patients/year; HR 1.13 (1.09-1.18 95% CI) and HR 1.22 (1.14-1.31 95% CI), respectively] and all-cause mortality [203/1000 and 294/1000 patients/year; HR 1.62 (1.58-1.65 95% CI) and HR 1.65 (1.59-1.70 95% CI), respectively]. The number of episodes of hospitalization for acute heart failure was also significantly higher in the AF patients (27 623 vs. 10 036, P < 0.001). However, the risk for ischaemic stroke was reduced in the AF subjects [HR 0.66 (0.63-0.74 95% CI)], probably due to the anticoagulant treatment. CONCLUSIONS: AF is associated with an increment in the risk of episodes of acute heart failure as well as decline of renal function and increment of all-cause mortality.

Real world data of anticoagulant treatment in non-valvular atrial fibrillation across renal function status.

The objective is to assess the impact of anticoagulant treatment in non-valvular atrial fibrillation (AF) and different categories of renal dysfunction in real world. Electronic Health recordings of patients with diagnosis of AF and renal function collected throughout 5 years and classified according to KDIGO categories. Stroke, transitory ischemic attack (TIA), intracranial hemorrhage and all-cause mortality were identified. Anticoagulant treatments during the study period were classified in untreated (never received therapy), VKA, NOAC and Aspirin. The risk of events was calculated by Cox-proportional hazard models adjusted by confounders. A total of 65,734 patients with AF, mean age 73.3 ± 10.49 years old and 47% females and follow-up of 3.2 years were included. KDIGO classification were: G1 33,903 (51.6%), G2 17,456 (26.6%), G3 8024 (12.2%) and G4 6351 (9.7%). There were 8592 cases of stroke and TIA, 437 intracranial hemorrhage, and 9603 all-cause deaths (incidence 36, 2 and 38 per 103 person/year, respectively). 4.1% of patients with CHA2DS2-VASc Score 2 or higher did not receive anticoagulant therapy. Risk of stroke, TIA, and all-cause mortality increased from G1 to G4 groups. Anticoagulant treatments reduced the risk of events in the four categories, but NOAC seemed to offer significantly better protection. Renal dysfunction increases the risk of events in AF and anticoagulant treatments reduced the risk of stroke and all-cause mortality, although NOAC were better than VKA. Efforts should be done to reduce the variability in the use of anticoagulants even in this high risk group.

Therapeutic inertia in patients with type 2 diabetes treated with non-insulin agents.

AIMS: To analyze therapeutic inertia in type 2 diabetes (T2D) subjects with suboptimal glycemic control and treated with ≥2 non-insulin antidiabetic agents in a primary care setting. METHODS: A retrospective study was conducted using electronic medical records from subjects with HbA1c ≥7.0% (≥53 mmol/mol). Therapeutic inertia was defined as the absence of treatment intensification despite suboptimal glycemic control where intensification should have been implemented (HbA1c ≥7.5% [≥58 mmol/mol]). Time to the first intensification with non-insulin antidiabetic agent or insulin and HbA1c values at the time of intensification were evaluated by competing risk analysis. RESULTS: 2652 adults with T2D and HbA1c ≥7.0% (≥53 mmol/mol) were included. During the 4-year follow-up, among 1628 individuals with HbA1c ≥7.5% [≥58 mmol/mol], therapeutic inertia was present in 42.9% of cases. Median time to intensification was 14.5 months (IQR25-75, 4-24 months). In this subgroup, 72.7% of subjects initiated non-insulin agents whereas 27.3% initiated insulin. Mean HbA1c values at initiation of treatment intensification were 8.6% (70 mmol/mol) and 9.2% (77 mmol/mol), respectively. CONCLUSIONS: Therapeutic inertia occurred in over 40% of subjects. Treatment intensification took longer and was performed at higher HbA1c than recommended in clinical guidelines. Reducing therapeutic inertia is a priority to achieve therapeutic goals and prevent chronic complications in T2D.

Real-World Data of Anticoagulant Treatment in Non-valvular Atrial Fibrillation.

AIMS: To assess the impact of anticoagulant treatment on risk for stroke and all-cause mortality of patients with atrial fibrillation using real-world data (RWD). METHODS: Patients with prevalent or incident atrial fibrillation were selected throughout a study period of 5 years. Stroke, transitory ischemic attack, hemorrhagic stroke, and all-cause mortality were identified in the claims of the electronic health records (EHRs). Subjects were classified according to the anticoagulant treatment in four groups: untreated, vitamin K antagonists (VKAs), New Oral Anticoagulants (NOACs), and antiplatelet (AP). Risk of events and protection with anticoagulant therapy were calculated by Cox proportional hazard models adjusted by potential confounders. RESULTS: From a total population of 3,799,884 patients older than 18,123,227 patients with incident or prevalent atrial fibrillation (AF) were identified (mean age 75.2 ± 11.5 years old; 51.9% women). In a follow-up average of 3.2 years, 17,113 patients suffered from an ischemic stroke and transitory ischemic attack (TIA), 780 hemorrhagic stroke, and 42,558 all-cause death (incidence of 46, 8, 2, and 120 per 1,000 patients/year, respectively). Among CHA2DS2, VASc Score equal or >2, 11.7% of patients did not receive any anticoagulant therapy, and a large proportion of patients, 47%, shifted from one treatment to another. Although all kinds of anticoagulant treatments were significantly protective against the events and mortality, NOAC treatment offered significantly better protection compared to the other groups. CONCLUSION: In the real world, the use of anticoagulant treatments is far from guidelines recommendations and is characterized by variability in their use. NOACs offered better protection compared with VKAs.

Impact of Acute Hemoglobin Falls in Heart Failure Patients: A Population Study.

Aims: This study assessed the impact of acute hemoglobin (Hb) falls in heart failure (HF) patients. Methods: HF patients with repeated Hb values over time were included. Falls in Hb greater than 30% were considered to represent an acute episode of anemia and the risk of hospitalization and all-cause mortality after the first episode was assessed. Results: In total, 45,437 HF patients (54.9% female, mean age 74.3 years) during a follow-up average of 2.9 years were analyzed. A total of 2892 (6.4%) patients had one episode of Hb falls, 139 (0.3%) had more than one episode, and 342 (0.8%) had concomitant acute kidney injury (AKI). Acute heart failure occurred in 4673 (10.3%) patients, representing 3.6/100 HF patients/year. The risk of hospitalization increased with one episode (Hazard Ratio = 1.30, 95% confidence interval (CI) 1.19-1.43), two or more episodes (HR = 1.59, 95% CI 1.14-2.23, and concurrent AKI (HR = 1.61, 95% CI 1.27-2.03). A total of 10,490 patients have died, representing 8.1/100 HF patients/year. The risk of mortality was HR = 2.20 (95% CI 2.06-2.35) for one episode, HR = 3.14 (95% CI 2.48-3.97) for two or more episodes, and HR = 3.20 (95% CI 2.73-3.75) with AKI. In the two or more episodes and AKI groups, Hb levels at the baseline were significantly lower (10.2-11.4 g/dL) than in the no episodes group (12.8 g/dL), and a higher and significant mortality in these subgroups was observed. Conclusions: Hb falls in heart failure patients identified those with a worse prognosis requiring a more careful evaluation and follow-up.

A Multiple Stakeholder Multicriteria Decision Analysis in Diabetic Macular Edema Management: The MULTIDEX-EMD Study.

BACKGROUND: The clinical and economic management of retinal diseases has become more complex following the introduction of new intravitreal treatments. Multicriteria decision analysis (MCDA) offers the potential to overcome the challenges associated with traditional decision-making tools. OBJECTIVES: A MCDA to determine the most relevant criteria to decision-making in the management of diabetic macular edema (DME) based on the perspectives of multiple stakeholders in Spain was developed. This MCDA was termed the MULTIDEX-EMD study. METHODS: Nineteen stakeholders (7 physicians, 4 pharmacists, 5 health authorities and health management experts, 1 psychologist, and 2 patient representatives) participated in this three-phase project. In phase A, an advisory board defined all of the criteria that could influence DME treatment decision-making. These criteria were then screened using a discrete choice experiment (DCE) (phase B). Next, a multinomial logit model was fitted by applying the backward elimination algorithm (relevant criteria: p value < 0.05). Finally, the results were discussed in a deliberative process (phase C). RESULTS: Thirty-one criteria were initially defined (phase A) and grouped into 5 categories: efficacy/effectiveness, safety, organizational and economic impact, patient-reported outcomes, and other therapeutic features. The DCE results (phase B) showed that 10 criteria were relevant to the decision-making process for a 50- to 65-year-old DME patient: mean change in best corrected visual acuity (p value < 0.001), percentage of patients with an improvement of ≥ 15 letters (p value < 0.001), effect duration per administration (p value = 0.008), retinal detachment (p value < 0.001), endophthalmitis (p value = 0.012), myocardial infarction (p value < 0.001), intravitreal hemorrhage (p value = 0.021), annual treatment cost per patient (p value = 0.001), health-related quality of life (HRQoL) (p value = 0.004), and disability level (p value = 0.021). CONCLUSIONS: From a multi-stakeholder perspective, the selection of an appropriate treatment for DME patients should guarantee patient safety and maximize the visual acuity improvement and treatment effect duration. It should also contribute to system sustainability by being affordable, it should have a positive impact on HRQoL, and it should prevent disability.

Acute kidney injury in heart failure: a population study.

AIMS: The objective of the present study is to assess the prognostic value of acute kidney injury (AKI) in the evolution of patients with heart failure (HF) using real-world data. METHODS AND RESULTS: Patients with a diagnosis of HF and with serial measurements of renal function collected throughout the study period were included. Estimated glomerular filtration rate (GFR) was calculated with the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration). AKI was defined when a sudden drop in creatinine with posterior recovery was recorded. According to the Risk, Injury, Failure, Loss, and End-Stage Renal Disease (RIFLE) scale, AKI severity was graded in three categories: risk [1.5-fold increase in serum creatinine (sCr)], injury (2.0-fold increase in sCr), and failure (3.0-fold increase in sCr or sCr > 4.0 mg/dL). AKI incidence and risk of hospitalization and mortality after the first episode were calculated by adjusting for potential confounders. A total of 30 529 patients with HF were included. During an average follow-up of 3.2 years, 5294 AKI episodes in 3970 patients (13.0%) and incidence of 3.3/100 HF patients/year were recorded. One episode was observed in 3161 (10.4%), two in 537 (1.8%), and three or more in 272 (0.9%). They were more frequent in women with diabetes and hypertension. The incidence increases across the GFR levels (Stages 1 to 4: risk 7.6%, 6.8%, 11.3%, and 12.5%; injury 2.1%, 2.0%, 3.3%, and 5.5%; and failure 0.9%, 0.6%. 1.4%, and 8.0%). A total of 3817 patients with acute HF admission were recorded during the follow-up, with incidence of 38.4/100 HF patients/year, 3101 (81.2%) patients without AKI, 545 (14.3%) patients with one episode, and 171 (4.5%) patients with two or more. The number of AKI episodes [one hazard ratio (HR) 1.05 (0.98-1.13); two or more HR 2.01 (1.79-2.25)] and severity [risk HR 1.05 (0.97-1.04); injury HR 1.41 (1.24-1.60); and failure HR 1.90 (1.64-2.20)] increases the risk of hospitalization. A total of 10 560 deaths were recorded, with incidence of 9.3/100 HF patients/year, 8951 (33.7%) of subjects without AKI episodes, 1180 (11.17%) of subjects with one episode, and 429 (4.06%) with two or more episodes. The number of episodes [one HR 1.05 (0.98-1.13); two or more HR 2.01 (1.79-2.25)] and severity [risk 1.05 confidence interval (CI) (0.97-1.14), injury 1.41 (CI 1.24-1.60), and failure 1.90 (CI 1.64-2.20)] increases mortality risk. CONCLUSIONS: The study demonstrated the worse prognostic value of sudden renal function decline in HF patients and pointed to those with more future risk who require review of treatment and closer follow-up.

Number of drugs used in secondary cardiovascular prevention and late survival in the population of Valencia Community, Spain.

BACKGROUND: Drug treatment for secondary prevention of cardiovascular disease is recommended by guidelines, but it is not always followed in real life. This study wanted to assess the size of this gap and its impact on mortality in subjects after a cardiovascular event (MACE). METHODS: Patients with any of MACE in the period from January 1st 2011 to December 31st 2013, and more than one year of follow-up were selected from population of the Valencian Community. Drugs for secondary prevention were antiplatelets, renin-angiotensin system blockers and statins. Assessment of treatment was performed one year after the initial event. Mortality risk was assessed using Cox by the number of drug classes (G0 no medication, G1 one, G2 two and G3 three drugs) adjusted by confounders. RESULTS: A total of 92,436 patients (62% men, mean age 72 years) of whom 60.5% presented with stroke, 30.6% with myocardial infarction and 8.9% with revascularization were included. Among them, 4.1% were G0, 20.2% G1, 32.9% G2 and 42.7% G3. A progressive decrease in mortality was observed in G1 (HR 0.83, CI 95% 0.73-0.95), G2 (HR 0.70, CI 95% 0.60-0.82) and G3 (HR 0.61, CI95% 0.51-0.74) vs. G0. In diabetic subgroup, significant reduction of risk was observed in the G2 (0.79, CI 95% 0.63-0.98) and G3 (0.72, CI9 5% 0.56-0.95), but not in G1 (0.97, CI 95% 0.80-1.17). CONCLUSION: A gap between guidelines and reality in the use of cardiovascular protecting drugs one year after the initial event still exists and it is largely related with all-cause late mortality.

Explaining primary healthcare pharmacy expenditure using classification of medications for chronic conditions.

BACKGROUND: The Valencian Autonomous Community (Spain) has implemented a scheme of purchasing services with the participation of public and private providers. Five districts are managed using public-private partnership. The financing model is capitation and inter-center invoice. The pharmaceutical benefits are not included in the per capita assignment. OBJECTIVES: Modeling and explaining pharmacy expenditure using electronic prescriptions drug data. METHODS: A database of electronic prescription corresponding to 625,246 patients between November 2008 and October 2009 was used to run four linear models that explain the pharmaceutical expenditures. We take as dependent variable the neperian log of total pharmacy annual cost per patient in the primary health setting. The independent variables used combined demographics with revised classification in 18 chronic conditions obtained from the anatomical therapeutic chemical classification index (ATC). RESULTS: The retrospective model selected included: gender, pharmaceutical co-payment status and 8 dummy variables for the number of chronic conditions of each patient from 1 to 8 or more. The goodness-of-fit achieved is measured in R(2) of 57%. CONCLUSIONS: These models must be considered in the current capitation system for pharmaceutical budgeting in a primary care setting established at regional level, as is the case in the Valencian Autonomous Community. The use of diagnostics and information regarding hospital encounters appears to be a complementary option for refining models of capitation of pharmaceutical and total health expenditure.

Adherence to and appropriateness of anti-osteoporotic treatments in patients aged 50 and over in the Valencia Region (Spain). The ESOSVAL-AD study.

BACKGROUND: A study to evaluate the adherence to and appropriateness of anti-osteoporotic treatments in a cohort of men and women aged 50 and over participating in the ESOSVAL-R study. DESIGN: An observational, longitudinal, prospective cohort study; STUDY SUBJECTS: Men and women aged 50 and over living in the Valencia Region (Spain) who initiated treatment between June 15, 2009, and June 15, 2011, in primary healthcare centers with electronic medical records; DATA SOURCES: The main data source will be electronic medical records. Measurement of results: Degree of compliance with and persistence of anti-osteoporotic treatments, and the proportion of patients with appropriate anti-osteoporotic treatment in accordance with the most relevant and high impact recommendations with clearly defined treatment algorithms in Spain (the Spanish National Health System guide (2010), the General Practitioners' Society (2007) and the General Directorate for Pharmacy and Medical Products of Madrid (2007)), and with the National Osteoporosis Foundation (NOF, 2010), and the International Osteoporosis Foundation guidelines (IOF, 2008); ANALYSIS: 1.) Descriptive analysis of patients undergoing treatment and the treatments prescribed; 2.) Descriptive analysis of compliance with and persistence of anti-osteoporotic treatments; 3.) ANALYSIS of factors associated with compliance with and persistence of treatments by Cox proportional hazard regression models, 4.) Descriptive analysis of appropriateness of treatment; 5.) ANALYSIS of factors associated with the appropriateness of treatment by multilevel models (4 levels: patient, doctor, Basic Healthcare Zone/Primary Healthcare Center, and Health Area variables). DISCUSSION: ESOSVAL-AD will provide information regarding adherence to osteoporosis treatments and the factors associated with a higher or lower adherence (including the appropriateness of the treatment) in the Spanish context. A better understanding of this phenomenon and the interventions needed to address it would contribute to the increased effectiveness of therapeutic measures, a reduction in morbidity and mortality, and a corresponding reduction in healthcare costs.

Antidepressant utilization in primary care in a Spanish region: impact of generic and reference-based pricing policy (2000-2004).

OBJECTIVE: To describe the evolution of antidepressant use in primary care in the Valencian region (Spain) from 2000 to 2004 and to analyze the effects of reference-based price and generic drugs introduction on drug utilization and cost saving. METHODS: Retrospective observational study in primary care using sales data collected from antidepressant group (N06A), corresponding to the period 2000-2004. Defined daily dose (DDD)/1000 inhabitants per day were obtained as consumption data. Cost and cost/DDD rate evolution was related to reference price system implantation. RESULTS: Antidepressant utilization progressively increased by 44.0% from 30.3 DDDs/1000 per day in 2000 to 43.5% in 2004. Selective serotonin reuptake inhibitors (SSRIs) comprised 77% of the total consumption where paroxetine, sertraline and fluoxetine were the most used drugs in 2004. The proportion of relative use and cost of fluoxetine declined after a reference price and the introduction of generic competitors were put into effect in 1999; cost/DDD was reduced by 1.8. Third-generation antidepressants showed a fast rising rate i.e. venlafaxine utilization multiplied by 2.2; this drug with the higher cost/DDD was not subjected to the reference price system. Reduction in citalopram utilization was related to a replacement by its recently marketed enantiomer escitalopram. CONCLUSIONS: In 2004, reference price policy and the implementation of generic drugs reduced the antidepressant cost by DDD. However, antidepressant expenditure increased since 2000 due to a continued growth in consumption (SSRIs and novel agents) and a displacement of prescriptions to drugs that were not included in the reference price policy.