Population Health Model Predicting the Long-Term Impact of Sotatercept on Morbidity and Mortality in Patients with Pulmonary Arterial Hypertension (PAH).

INTRODUCTION: Pulmonary arterial hypertension (PAH) is a rare, progressive disease associated with significant morbidity and mortality. The phase 3 STELLAR trial tested sotatercept plus background therapy (BGT) versus placebo plus BGT. BGT was comprised of mono-, double-, or triple-PAH targeted therapy. Building on STELLAR findings, we employed a population health model to assess the potential long-term clinical impact of sotatercept. METHODS: Based on the well-established ESC/ERS 4-strata risk assessment approach, we developed a six-state Markov-type model (low risk, intermediate-low risk, intermediate-high risk, high risk, lung/heart-lung transplant, and death) to compare the clinical outcomes of sotatercept plus BGT versus BGT alone over a lifetime horizon. State-transition probabilities were obtained from STELLAR. Risk stratum-adjusted mortality and lung/heart-lung transplant probabilities were based on COMPERA PAH registry data, and the post-transplant mortality probability was obtained from existing literature. Model outcomes were discounted at 3% annually. Sensitivity analyses were conducted to examine model robustness. RESULTS: In the base case, sotatercept plus BGT was associated with longer life expectancy from model baseline (16.5 vs 5.1 years) versus BGT alone, leading to 11.5 years gained per patient. Compared with BGT alone, sotatercept plus BGT was further associated with a gain in infused prostacyclin-free life years per patient, along with 683 PAH hospitalizations and 4 lung/heart-lung transplant avoided per 1000 patients. CONCLUSIONS: According to this model, adding sotatercept to BGT increased life expectancy by roughly threefold among patients with PAH while reducing utilization of infused prostacyclin, PAH hospitalizations, and lung/heart-lung transplants. Real-world data are needed to confirm these findings. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT04576988 (STELLAR).

Longitudinal changes in risk status in pulmonary arterial hypertension.

AIMS: Low-risk status in pulmonary arterial hypertension (PAH) predicts better survival. The present study aimed to describe changes in risk status and treatment approaches over multiple clinical assessments in PAH, taking age and comorbidity burden into consideration. METHODS AND RESULTS: The study included incident patients from the Swedish PAH registry, diagnosed with PAH in 2008-2019. Group A (n = 340) were ≤75 years old with <3 comorbidities. Group B (n = 163) were >75 years old with ≥3 comorbidities. Assessments occurred at baseline, first-year (Y1) and third-year (Y3) follow-ups. The study used an explorative and descriptive approach. Group A: median age was 65 years, 70% were female, and 46% had no comorbidities at baseline. Baseline risk assessment yielded low (23%), intermediate (66%), and high risk (11%). Among patients at low, intermediate, or high risk at baseline, 51%, 18%, and 13%, respectively, were at low risk at Y3. At baseline, monotherapy was the most common therapy among low (68%) and intermediate groups (60%), while dual therapy was the most common among high risk (69%). In patients assessed as low, intermediate, or high risk at Y1, 66%, 12%, and 0% were at low risk at Y3, respectively. Of patients at intermediate or high risk at Y1, 35% received monotherapy and 13% received triple therapy. In low-risk patients at Y1, monotherapy (40%) and dual therapy (43%) were evenly distributed. Group B: median age was 77 years, 50% were female, and 44% had ≥3 comorbidities at baseline. At baseline, 8% were at low, 80% at intermediate, and 12% at high risk. Monotherapy was the most common therapy (62%) in Group B at baseline. Few patients maintained or reached low risk at follow-ups. CONCLUSIONS: Most patients with PAH did not meet low-risk criteria during the 3 year follow-up. The first year from diagnosis seems important in defining the longitudinal risk status.

Poor outcome of patients with pulmonary arterial hypertension with insufficient response to phosphodiesterase-5 inhibitors alone or in combination with other specific therapy: a registry-based study.

Phosphodiesterase-5 inhibitors are commonly used in pulmonary arterial hypertension but, as suggested by the RESPITE study, phosphodiesterase-5 inhibitor therapy (mono-/combination) does not always have a satisfactory treatment effect. This study aimed to investigate the clinical course of pulmonary arterial hypertension patients not at treatment goal after at least 90 days of treatment with phosphodiesterase-5 inhibitors, alone or in combination with other pulmonary arterial hypertension therapies. The study included 106 incident patients from the Swedish Pulmonary Arterial Hypertension Registry, treated with phosphodiesterase-5 inhibitors for ≥90 days, who were not at a pre-specified treatment goal, i.e. in World Health Organisation functional class III, with 6-min walking distance 165-440 m, and N-terminal prohormone of brain natriuretic peptide >300 ng/L. Changes in World Health Organisation functional class, 6-min walking distance, N-terminal prohormone of brain natriuretic peptide, and risk group between index and follow-up were assessed. Of patients with complete follow-up data, (n = 53) 77% were on combination therapy and risk assessment yielded 98% at intermediate risk at index. At follow-up, 11 patients transitioned from World Health Organisation functional class III to World Health Organisation functional class II, the median (Q1; Q3) change in 6-min walking distance was 6 (-30; 42) meters and in N-terminal prohormone of brain natriuretic peptide 47 (-410; 603) ng/L, while 89% remained at an intermediate risk. Of those without complete follow-up data, 11 patients died and 2 underwent lung transplantation. In conclusion, pulmonary arterial hypertension patients treated with phosphodiesterase-5 inhibitors, as single or combination therapy and not achieving the pre-specified treatment goals after ≥90 days have an unfavourable clinical course.

Rates of pneumonia among children and adults with chronic medical conditions in Germany.

BACKGROUND: The objective of this study is to evaluate rates of all-cause pneumonia among "at-risk" and "high-risk" children and adults in Germany-in comparison with age-stratified healthy counterparts-during the period following the 2006 recommendation for universal immunization of infants with pneumococcal conjugate vaccine. METHODS: Retrospective cohort design and healthcare claims information for 3.4 M persons in Germany (2009-2012) were employed. Study population was stratified by age and risk profile (healthy, "at-risk" [with chronic medical conditions], and "high-risk" [immunocompromised]). At-risk and high-risk conditions, as well as episodes of all-cause pneumonia, were identified via diagnosis, procedure, and drug codes. RESULTS AND DISCUSSION: Rates of all-cause pneumonia were 1.7 (95 % CI 1.7-1.8) to 2.5 (2.4-2.5) times higher among children and adults with at-risk conditions versus healthy counterparts, and 1.8 (1.8-1.9) to 4.1 (4.0-4.2) times higher among children and adults with high-risk conditions. Rates of all-cause pneumonia among at-risk persons increased in a graded and monotonic fashion with increasing numbers of conditions (i.e., risk stacking). CONCLUSIONS: An increased risk for all-cause pneumonia in German children and adults with a spectrum of medical conditions persists in the era of widespread pneumococcal vaccination, and pneumonia risk in persons with ≥2 at-risk conditions is comparable or higher than those with high-risk conditions.

Optimising assessments of the epidemiological impact in The Netherlands of paediatric immunisation with 13-valent pneumococcal conjugate vaccine using dynamic transmission modelling.

This work is the first attempt to quantify the overall effects of a 13-valent pneumococcal conjugate vaccine (PCV13) vaccination programme in the Dutch population taking into account all the direct and indirect effects of the vaccine on invasive pneumococcal disease. Using available Dutch data, a dynamic transmission model for the spread of pneumococci and potential subsequent invasive pneumococcal disease has been adapted to the Dutch setting. Overall, invasive pneumococcal disease cases in the Netherlands are predicted to decrease from a pre-vaccination level of 2623 cases annually to 2475, 2289, 2185, 2179, and 2178 cases annually 5-, 10-, 20-, 30-, and 40-years, respectively, post-vaccination. Therefore, vaccination with PCV13 in the Netherlands is predicted to lower invasive pneumococcal disease cases per year by up to 445 cases in the medium- to long-term. The results are quite robust for the sensitivity analyses performed on the parameters that regulate herd immunity and competition between vaccine and non-vaccine types.

Cost-effectiveness of a 10- versus 13-valent pneumococcal conjugate vaccine in Denmark and Sweden.

BACKGROUND: The introduction of a 7-valent pneumococcal polysaccharide-protein conjugate vaccine (PCV7) had profound public health effects across the globe. PCV7 vaccination in a national immunization program is generally considered cost-effective and potentially cost-saving. Two new PCVs have been launched, a 10-valent pneumococcal conjugate vaccine (PCV10) and a 13-valent pneumococcal conjugate vaccine (PCV13). OBJECTIVE: This article examines the public health and economic effects of pediatric national immunization programs of PCV10 and PCV13 in Denmark and Sweden. METHODS: A previously published decision-analytic model was used to estimate the impact of PCV10 and PCV13 on reducing cases of invasive pneumococcal disease (IPD), pneumonia (PNE), and acute otitis media (AOM) by using country-specific incidence, serotype coverage, disease sequelae, mortality, vaccine effectiveness, indirect effects, costs, and utilities. Direct effects for PCV13- and PCV10-covered serotypes were assumed similar to PCV7. PCV13 was assumed to confer an indirect effect, similar to PCV7, whereas PCV10 was not. Assumptions were tested in sensitivity analyses. RESULTS: PCV13 is expected to save 280.7 million DKK (Danish kroner) in Denmark and 288.2 million SEK (Swedish kronor) in Sweden in direct costs compared with a vaccination program with PCV10. In both Denmark and Sweden, the results of this study indicate that, compared with PCV10, PCV13 will have a greater impact on disease in life-years gained (LYG), quality-adjusted life-years (QALYs) gained, IPD cases avoided, PNE cases avoided, AOM cases avoided, and in deaths avoided. For Denmark PCV13, it was estimated to result in 10,051 LYG; 9063 QALYs gained; 237 additional IPD cases avoided; 12,094 additional PNE cases avoided; 958 additional cases of AOM avoided; and 882 additional deaths avoided. For Sweden PCV13, it was estimated to result in 4245 LYG; 3953 QALYs gained; 379 additional IPD cases avoided; 8210 additional PNE cases avoided; 1459 additional cases of AOM avoided; and 378 additional deaths avoided. In all sensitivity analyses, PCV13 was less costly and more effective compared with PCV10. CONCLUSIONS: In this analysis, a national immunization program with PCV13 was found to be good value for money and estimated to prevent additional cases of disease among children and nonvaccinated individuals and save additional costs due to treatment of pneumococcal disease, when compared with PCV10 in Denmark and Sweden.

Cost-effectiveness models of pneumococcal conjugate vaccines: variability and impact of modeling assumptions.

Currently, 13-valent pneumococcal conjugate vaccine (PCV); and ten-valent PCV vaccine are marketed. Neither vaccine obtained regulatory approval based on efficacy trials, but instead were approved based on a surrogate end point: immunogenicity data measuring effective antibody levels. Therefore, direct measures of efficacy were unavailable at the time economic analyses were conducted. The authors systematically reviewed cost-effectiveness studies of ten-valent PCV and 13-valent PCV from the literature to analyze the methodologies and compare the assumptions made about vaccine effectiveness. The following three inputs were found the most variant across analyses: efficacy against acute otitis media; inclusion of indirect effects; and cross protection. These assumptions are discussed with regard to the validity of supporting data and implications on decision-making.

Cost-effectiveness of 13-valent pneumococcal conjugate vaccine: Germany, Greece, and The Netherlands.

BACKGROUND: Seven-valent pneumococcal conjugate vaccine (PCV7) had profound public-health impacts and is considered cost-effective and potentially cost saving. Two new PCVs have been launched, a 10-valent vaccine (PCV10) and a 13-valent vaccine (PCV13). We examined public-health and economic impacts of PCV pediatric national immunization programs (NIPs) in Germany, Greece, and the Netherlands. METHODS: A decision-analytic model was developed to estimate the impact of PCV13, PCV7, and 10-valent pneumococcal conjugate vaccine (PCV10) on invasive pneumococcal disease (IPD), pneumonia (PNE), and acute otitis media (AOM). Using epidemiological data, we calculated the cases of IPD, PNE, and AOM, using country-specific incidence, serotype coverage, disease sequelae, mortality, vaccine effectiveness, indirect effects, costs, and utilities. Direct effects for PCV13- and PCV10-covered serotypes were assumed similar to PCV7. PCV13 was assumed to confer an indirect effect, while PCV10 was not. Assumptions were tested in sensitivity analyses. RESULTS: In a NIP, PCV13 was estimated to eliminate 31.7%, 46.4%, and 33.8% of IPD in Germany, Greece, and the Netherlands, respectively. Compared with PCV7 and PCV10, PCV13 was found to be cost-effective or cost saving in all cases when PCV13 indirect effects were included. CONCLUSIONS: Pediatric NIPs with PCV13 in Europe are expected to have dramatic public-health impacts and be cost-effective or cost saving.

Quality of life in relation to constipation among opioid users.

OBJECTIVE: Opioid users often experience constipation. In this study the impact of constipation on QoL was assessed in patients using opioids either for non-advanced illness or advanced illness. METHODS: Patients using opioids, recruited via public pharmacies, were asked to complete questionnaires on opioid use, constipation and the EuroQol five-dimension questionnaire (EQ-5D). Patients with a severe non-curable disease and relatively short life-expectancy were classified as having an advanced illness; a disabling yet not directly life-threatening condition was defined as non-advanced illness. Constipation was assessed based on questions on opioid side-effects and laxative use. EQ-5D index scores were compared between patients with and without constipation using Wilcoxon two-samples test. RESULTS: Questionnaires were returned by 588 patients with non-advanced illness, of whom 326 (55%) were classified as having constipation and by 113 patients with advanced illness, of whom 76 (67%) were classified as having constipation. The median EQ-5D index, a weighted health state index score with 1 = full health, was lower in patients with constipation than in patients without constipation (0.31 vs. 0.65, p< 0.01 for non-advanced illness and 0.41 vs. 0.61, p=0.12 for advanced illness). CONCLUSION: The results of this study suggest that, in patients using opioids either for non-advanced illness or advanced illness, constipation negatively influences QoL. By separately analysing patients with advanced illness and patients with non-advanced illness, possible selective non-response and confounding was accounted for, but not completely solved.

Cost-effectiveness of a potential future Helicobacter pylori vaccine in the Netherlands: the impact of varying the discount rate for health.

To estimate the cost-effectiveness of a potential Helicobacter pylori (HP) vaccine for the Dutch situation, we developed a Markov model. Several HP prevalence scenarios were assessed. Additionally, we assessed the impact of the discount rate for health on the outcomes, as this influence can be profound for vaccines. When applying the current discount rate of 1.5% for health, the expected cost-effectiveness of HP vaccination is estimated below the informal Dutch threshold of euro 20,000/LYG when the HP prevalence is assumed > or =20% in the Dutch population. In conclusion, we showed that HP vaccination could possibly be a cost-effective intervention. However, this depends to a large extend on the prevalence of HP in the population. Furthermore, we showed the large impact of the discount rate for health on the cost-effectiveness of a HP vaccination program, illustrative for other vaccination programs.

Incremental cost effectiveness of proton pump inhibitors for the prevention of non-steroidal anti-inflammatory drug ulcers: a pharmacoeconomic analysis linked to a case-control study.

INTRODUCTION: We estimated the cost effectiveness of concomitant proton pump inhibitors (PPIs) in relation to the occurrence of non-steroidal anti-inflammatory drug (NSAID) ulcer complications. METHODS: This study was linked to a nested case-control study. Patients with NSAID ulcer complications were compared with matched controls. Only direct medical costs were reported. For the calculation of the incremental cost effectiveness ratio we extrapolated the data to 1,000 patients using concomitant PPIs and 1,000 patients not using PPIs for 1 year. Sensitivity analysis was performed by 'worst case' and 'best case' scenarios in which the 95% confidence interval (CI) of the odds ratio (OR) and the 95% CI of the cost estimate of a NSAID ulcer complication were varied. Costs of PPIs was varied separately. RESULTS: In all, 104 incident cases and 284 matched controls were identified from a cohort of 51,903 NSAID users with 10,402 NSAID exposition years. Use of PPIs was associated with an adjusted OR of 0.33 (95% CI 0.17 to 0.67; p = 0.002) for NSAID ulcer complications. In the extrapolation the estimated number of NSAID ulcer complications was 13.8 for non-PPI users and 3.6 for PPI users. The incremental total costs were euro 50,094 higher for concomitant PPIs use. The incremental cost effectiveness ratio was euro 4,907 per NSAID ulcer complication prevented when using the least costly PPIs. CONCLUSIONS: Concomitant use of PPIs for the prevention of NSAID ulcer complications costs euro 4,907 per NSAID ulcer complication prevented when using the least costly PPIs. The price of PPIs highly influenced the robustness of the results.

Direct medical costs of serious gastrointestinal ulcers among users of NSAIDs.

BACKGROUND: The occurrence and prevention of gastrointestinal ulcers during use of NSAIDs has become a major healthcare issue. OBJECTIVE: To determine the direct medical costs of serious NSAID-related ulcer complications. METHOD: An observational cost-of-illness study was conducted in a large general hospital serving a population of 152,989 persons. From November 2001 to December 2003 all consecutive patients hospitalised with serious NSAID-related ulcer complications were identified. Serious NSAID-related ulcer complications were defined as ulcerations of the stomach or proximal duodenum causing perforation, obstruction or bleeding that occurred during the use of NSAIDs, necessitating hospitalisation of the patient. Data were retrieved with respect to days hospitalised and the number and type of diagnostic and therapeutic interventions. The main outcome measure was estimated mean direct medical costs of resources used. RESULTS: A total of 104 patients were hospitalised with serious NSAID-related ulcer complications (incidence 31.4 per 100,000 persons per year). Most patients were elderly (mean 70.4 years, SD 16.7). In-hospital mortality was 10.6%. Mean direct medical costs were euro 8375 (95% CI 7067, 10 393). On the basis of these results, we estimated that approximately 5105 people are hospitalised with serious NSAID-related ulcer complications in The Netherlands each year, of whom 541 die in hospital. The total annual direct medical costs for serious NSAID-related ulcer complications in The Netherlands were estimated to be euro 42,754 375 (95% CI 36 077 035, 53 056 265). CONCLUSIONS: Serious NSAID-related ulcer complications have a mortality rate of 10.6% in The Netherlands and the annual direct medical costs to the country of such complications are approximately euro 42,750 000.

Pharmacoeconomics of quetiapine for the management of acute mania in bipolar I disorder.

Bipolar disorder (or manic depression) is a lifelong, severe and complex psychiatric illness characterized by recurrent episodes of depression and mania. The aim of this study is to explore the cost-effectiveness of quetiapine compared with other alternatives for the treatment of acute manic episodes in bipolar I disorder, with a specific focus on serious side effects. Four trials investigating quetiapine monotherapy and adjunctive therapy were performed to investigate the efficacy of quetiapine in patients with bipolar I disorder. Data were derived from The Netherlands Mental Health Survey and Incidence Study and used to construct a study population for the model. To assess the cost-effectiveness of quetiapine in the management of acute mania in bipolar I disorders, a discrete event simulation model of seven monotherapy and combination treatment options was developed. A comparison of the total costs demonstrates that all of the monotherapy options and placebo are more costly than the combination therapy options. The combinations of lithium with risperidone (euro2365) and with olanzapine (euro2429) are estimated to be less costly per patient than the combination of lithium with quetiapine (euro2555). A group of 10,000 patients switching from olanzepine/lithium to quetiapine/lithium would involve extra costs of euro1,260,000, but would prevent an estimated number of 362 serious side effects. Switching from risperidone/lithium to quetiapine/lithium would cost an additional euro1,900,000 and would prevent 1580 serious side effects. In terms of serious side effects, the combination of lithium/quetiapine was superior to the combination of lithium with olanzapine or risperidone. It must be considered whether the decreased likelihood of developing a severe side effect is worth the extra costs incurred with the combination of quetiapine/lithium.

Economic evaluation of a randomized trial comparing Helicobacter pylori test-and-treat and prompt endoscopy strategies for managing dyspepsia in a primary-care setting.

BACKGROUND: In western European countries, most dyspeptic patients are initially managed by their general practitioners (GPs), who use a range of strategies to manage dyspepsia. We performed an economic analysis of a Helicobacter pylori test-and-treat strategy versus a prompt endoscopy approach in a primary care setting. METHODS: Data were used from the Strategy: Endoscopy versus Serology (SENSE) study, performed in The Netherlands from 1998 to 2001. Patients were randomized to a prompt endoscopy (n = 105) or test-and-treat (n = 118) group. Follow-up lasted 1 year. Adverse events were not recorded in the SENSE study. Health care costs were based on the total amount of dyspepsia-related drugs used, the number of dyspepsia-related GP visits, the number of diagnostic tests, and the number of dyspepsia-related referrals to specialists. The use of medical resources was calculated as standardized costs for 1999, recorded as euros. (On December 31, 1999, 1.00 Euro = 1.00 US dollar.) Quality of life was measured at inclusion and 1 year later, using the RAND-36 questionnaire. To calculate quality-adjusted life-years (QALYs), we transformed the individual scores of the RAND-36 into 1 overall score, the Health Utilities Index Mark 2, which introduced a limitation to the study. An incremental cost-effectiveness ratio (ICER) was calculated. The 95% confidence limits were calculated using a parametric bootstrap method with angular transformation. All cost data were analyzed from a third-party payer perspective. RESULTS: The total costs per patient were 511 Euros, with 0.037 QALY gained per patient, in the test-and-treat group, and 748 Euros, with 0.032 QALY gained per patient, in the endoscopy group (between groups, P < 0.001 and P = NS, respectively). The point estimate of the ICER indicated that the test-and-treat strategy yielded cost savings and QALYs gained. Parametric bootstrap confidence limits indicated cost savings per QALY gained in 75.7% of the bootstrap simulations. CONCLUSION: This analysis of data from the SENSE1026 study suggests that the H pylori test-and-treat strategy was more cost-effective than prompt endoscopy in the initial management of dyspepsia in general practice, from the perspective of a third-party payer.

Drug costs developments after patent expiry of enalapril, fluoxetine and ranitidine: a study conducted for the Netherlands.

BACKGROUND: In order to increase price competition, government regulations focus on controlling drug costs. Drug costs after patent expiry are an area of particular interest because the substitution of branded medication with generics represents an opportunity for lowering drug costs. However, drug costs may not decrease after patent expiry, because of a lack of price competition and different national pricing systems. AIM: The aim of this study was to investigate the trends in the use of generics after patent expiry for enalapril, fluoxetine and ranitidine and the subsequent changes, if any, in the costs of these medications. METHODS: A drug-utilisation study was performed using data from a large sample of Dutch pharmacies. Both volumes (measured as defined daily doses [DDD] per 1000 population) as well as drug costs (calculated per DDD) prior to and after patent expiry were calculated. Costs per DDD were compared using trend-line analysis. In addition, the relative market shares of the different trade channels (branded, parallel imported and generic) were compared before and after patent expiry. RESULTS: The costs per DDD decreased for all three drugs and, as expected, these costs decrease more rapidly after patent expiry. Significant differences in the trend lines were found for enalapril and fluoxetine. CONCLUSIONS: Despite relatively high reimbursement prices for generics in the Netherlands, this example from the Dutch pharmaceutical market demonstrates the benefit of generic substitution for containing pharmaceutical costs, which contrasts with concerns raised by the Dutch government.

Pharmacoeconomics of gastrointestinal drug utilisation prior and post Helicobacter pylori eradication.

BACKGROUND: Eradication of Helicobacter pylori prevents recurrence of peptic ulcer. In pharmacoeconomic analyses it is often presumed that after successful eradication no more gastrointestinal drugs are used. We investigated this presumed positive monetary effect using General Practitioners prescribing data, including information in diagnosis. METHODS: From the RNG-database we identified patients with a H. pylori eradication in the years 1997-2000. H. pylori eradication was defined as a prescription of two antibiotics and one gastrointestinal drug on the same day. Patients were divided into a group with diagnosed ulcers and a group without diagnosed ulcers. Gastrointestinal drug costs were calculated for 4 months prior to eradication and 9-12 months post eradication. For comparison costs in all periods were expressed per patient per period. For statistical analysis the paired t-test was used. RESULTS: One hundred and two patients were eligible for evaluation. Of these patients 35 had a diagnosed ulcer and 67 had not. Generally the number of patients on gastrointestinal drugs decreased (61% prior vs. 33% post), however, the drug costs did not change (Euro 33 prior vs. Euro 34 post). Costs for proton pump inhibitors increased post eradication (Euro 14 prior vs. Euro 28 post). The ulcer and nonulcer group showed similar results. CONCLUSION: Helicobacter pylori eradication is thought to be cost effective, however, we did not find a decrease in costs for all gastrointestinal drugs. There may be a great pharmacoeconomical advantage when it is possible to predict which patients are more likely to 'fail' eradication therapy.