Necessity for a System Implementing Therapeutic Drug Monitoring in Outpatient Settings Based on the Actual Use of Voriconazole Using the National Database of Health Insurance Claims and Specific Health Checkups of Japan: A Descriptive Epidemiological Study.

Voriconazole (VRCZ) is an antifungal drug that necessitates therapeutic monitoring (TDM). Typically, TDM is recommended for patients undergoing long-term outpatient treatment. However, in Japan, insurance reimbursement for TDM is only permitted for inpatients. There is a concern that VRCZ use is growing among outpatients, although information regarding this issue remains unavailable. Therefore, we aimed to clarify the use of VRCZ by utilizing data from the National Database of Health Insurance Claims and Specific Health Checkups in Japan. The use of branded and generic oral VRCZ from 2013 to 2019 was calculated using the defined daily doses/1000 inhabitants/d (DID) for each receipt type. Oral VRCZ was used more frequently in the outpatient setting than that in the inpatient setting, with use increasing over time. The use of generic drugs began in 2016 and accounted for 52.5% of the use in 2019 among outpatients. Considering outpatient prescriptions, 76.4-81.0% were dispensed at insurance pharmacies, indicating the need for community pharmacist involvement. Accordingly, the appropriate use of VRCZ in ambulatory care should be promoted in collaboration with community pharmacists, and a reimbursement system should be established to implement TDM in ambulatory care.

The Use of Topical Antibiotics Based on the National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB) Open Data in 2017.

The national action plan on antimicrobial resistance (AMR) in Japan emphasizes the importance of understanding antimicrobial use (AMU). Some studies have been conducted on oral and parenteral AMU in Japan. However, there are few studies on the use of topical antimicrobials, such as in dermatology and ophthalmology. Therefore, the purpose of this study was to investigate the use of topical AMU in Japan. Data on AMU in dermatology and ophthalmology were obtained from the 2017 National Database of Health Insurance Claims and Specific Health Checkups of Japan Open Data. The number of dermatological products used was 58,396,530 in 2017. The proportions of betamethasone/gentamicin and gentamicin used were 50.5% and 16.7%, respectively, whereas that of the ingredient quantity in gentamicin was 7.8%. It has been suggested that topical AMU should be evaluated based on the number of products being used. The number of ophthalmological products used was 24,655,653 in 2017, and the proportion of quinolones used was 95.9%. The high prescription rate of quinolones may cause an increase in quinolone resistance in the ophthalmologic field. Topical AMU, which is a potential "blind spot" in the measures against AMR, needs to be continuously monitored, together with systemic AMU.

The intended purpose and regional patterns of use of antibiotics for managing Clostridioides (Clostridium) difficile infections: An analysis of the National Database of Health Insurance Claims and Specific Health Checkups data of Japan.

INTRODUCTION: We previously showed the trend of antimicrobial use (AMU) for Clostridioides (Clostridium) difficile infection (CDI) using sales data. However, the details of the prescribing medical institutions and regional characteristics are unknown. Therefore, the purpose of this study was to clarify the details of the medical institutions where antibiotics for CDI were prescribed, and evaluate the AMU for CDI and the regional characteristics. METHODS: Antibiotics for CDI, including oral vancomycin (VCM), oral metronidazole (MNZ), and intravenous (IV) MNZ, were collected from the National Database of Health Insurance Claims and Specific Health Checkups (NDB) between 2013 and 2016. The PID (patients/1000 inhabitants/day) was used as an evaluation index for AMU. The PID was calculated using the claim types: inpatient, outpatient, dental, and pharmacy. The PID of each prefecture was calculated for inpatient claims in 2016. RESULTS: The AMU of oral VCM and IV MNZ were observed mainly in the inpatient claims. For oral MNZ, the total AMU in the outpatient and pharmacy claims accounted for approximately 80% per year throughout the study period. For inpatient claims of each prefecture in 2016, the PID of the antibiotics used for CDIs was approximately 3.5 times the difference between the highest and lowest prefectures. CONCLUSIONS: The AMU for CDI that takes into account the purpose of use was clarified by using the information of the prescribed medical institutions that were included in the NDB. Oral MNZ was used frequently in outpatients, and attention should be paid to the acquisition of resistance.

Effects of the cefazolin shortage on the sales, cost, and appropriate use of other antimicrobials.

BACKGROUND: Shortages of antimicrobials lead to treatment failures, increase medical costs, and accelerate the development of antimicrobial resistance. We evaluated the effects of the serious cefazolin shortage in 2019 in Japan on the sales, costs, and appropriate use of other antimicrobials. METHODS: We evaluated monthly defined daily doses/1000 inhabitants/day (DID) values of antimicrobial sales from January 2016 to December 2019 using wholesaler's sales databases. Using 2016-2018 sales data, we generated a prediction model of DID in 2019 under the assumption that the cefazolin shortage did not occur. We then compared the predicted DID and actual DID. Cefazolin, government-recommended alternatives, and government-not-recommended broad-spectrum alternatives were assessed. Antimicrobial groups according to the AWaRe classification were also assessed to evaluate the effect on appropriate antimicrobial use. In addition, we evaluated changes in costs between 9 months before and after the cefazolin shortage. RESULTS: DID values of total antimicrobials increased sharply 1 month before the decrease in cefazolin. Actual DIDs were higher than predicted DIDs for ceftriaxone, flomoxef, clindamycin, cefotiam, piperacillin/tazobactam, and meropenem. Actual DID values were higher than the predicted DID values in the Watch group. The costs of antimicrobials between pre- and post- cefazolin shortage were unchanged. CONCLUSION: The cefazolin shortage brought confusion to the antimicrobial market and led to a setback in the appropriate use of antimicrobials. Early recognition and structures for prompt reactions to antimicrobial shortages are needed. Moreover, development of a system to secure the supply of essential antimicrobials is required.

Characteristics and limitations of national antimicrobial surveillance according to sales and claims data.

PURPOSE: Antimicrobial use (AMU) is estimated at the national level by using sales data (S-AMU) or insurance claims data (C-AMU). However, these data might be biased by generic drugs that are not sold through wholesalers (direct sales) and therefore not recorded in sales databases, or by claims that are not submitted electronically and therefore not stored in claims databases. We evaluated these effects by comparing S-AMU and C-AMU to ascertain the characteristics and limitations of each kind of data. We also evaluated the interchangeability of these data by assessing their relationship. METHODS: We calculated monthly defined daily doses per 1,000 inhabitants per day (DID) using sales and claims data from 2013 to 2017. To assess the effects of non-electronic claim submissions on C-AMU, we evaluated trends in the S-AMU/C-AMU ratio (SCR). To assess the effects of direct sales of S-AMU, we divided AMU into generic and branded drugs and evaluated each SCR in terms of oral versus parenteral drugs. To assess the relationship between S-AMU and C-AMU, we created a linear regression and evaluated its coefficient. RESULTS: Median annual SCRs from 2013 to 2017 were 1.046, 0.993, 0.980, 0.987, and 0.967, respectively. SCRs dropped from 2013 to 2015, and then stabilized. Differences in SCRs between branded and generic drugs were significant for oral drugs (0.820 vs 1.079) but not parenteral drugs (1.200 vs 1.165), suggesting that direct sales of oral generic drugs were omitted in S-AMU. Coefficients of DID between S-AMU and C-AMU were high (generic, 0.90; branded, 0.84) in oral drugs but relatively low (generic, 0.32; branded, 0.52) in parenteral drugs. CONCLUSIONS: The omission of direct sales information and non-electronically submitted claims have influenced S-AMU and C-AMU information, respectively. However, these data were well-correlated, and it is considered that both kinds of data are useful depending on the situation.

Effect of population inflow and outflow between rural and urban areas on regional antimicrobial use surveillance.

PURPOSE: Regional-level measures can complement national antimicrobial stewardship programs. In Japan, sub-prefectural regions called secondary medical areas (SMAs) provide general inpatient care within their borders, and regional antimicrobial stewardship measures are frequently implemented at this level. There is therefore a need to conduct antimicrobial use (AMU) surveillance at this level to ascertain antimicrobial consumption. However, AMU estimates are generally standardized to residence-based nighttime populations, which do not account for population mobility across regional borders. We examined the impact of population in/outflow on SMA-level AMU estimates by comparing the differences between standardization using daytime and nighttime populations. METHODS: We obtained AMU information from the National Database of Health Insurance Claims and Specific Health Checkups of Japan. AMU was quantified at the prefectural and SMA levels using the number of defined daily doses (DDDs) divided by (a) 1,000 nighttime population per day or (b) 1,000 daytime population per day. We identified and characterized the discrepancies between the two types of estimates at the prefectural and SMA levels. RESULTS: The national AMU was 17.21 DDDs per 1,000 population per day. The mean (95% confidence interval) prefectural-level DDDs per 1,000 nighttime and daytime population per day were 17.27 (14.10, 20.44) and 17.41 (14.30, 20.53), respectively. The mean (95% confidence interval) SMA-level DDDs per 1,000 nighttime and daytime population per day were 16.12 (9.84, 22.41) and 16.41 (10.57, 22.26), respectively. The nighttime population-standardized estimates were generally higher than the daytime population-standardized estimates in urban areas, but lower in the adjacent suburbs. Large differences were observed in the main metropolitan hubs in eastern and western Japan. CONCLUSION: Regional-level AMU estimates, especially of smaller regions such as SMAs, are susceptible to the use of different populations for standardization. This finding indicates that AMU standardization based on population values is not suitable for AMU estimates in small regions.

An alternative index for evaluating AMU and anti-methicillin-resistant Staphylococcus aureus agent use: A study based on the National Database of Health Insurance Claims and Specific Health Checkups data of Japan.

INTRODUCTION: Anti-methicillin-resistant Staphylococcus aureus (MRSA) agents have different doses and administration periods. Thus, it is difficult to evaluate antimicrobial use (AMU) of anti-MRSA agents using defined daily doses per 1000 inhabitants per day (DID) or days of therapy per 1000 inhabitants per day (DOTID). This study aimed to evaluate the relationship between anti-MRSA agent use and resistant bacteria using the number of patients per 1000 inhabitants per day (PID) as an alternative index of AMU. METHODS: AMU data for anti-MRSA agents were collected from the National Database of Health Insurance Claims and Specific Health Checkups (NDB) in 2016. The relationship between PID and DID or DOTID was evaluated. The number of patients with MRSA isolated was obtained from Japan Nosocomial Infections Surveillance, and their correlation with PID was analyzed. The rate of anti-MRSA agent use in each prefecture was investigated. RESULTS: PID showed a significant linear relationship with both DID and DOTID (all p < 0.0001). PID was significantly correlated with the number of patients with MRSA isolated. Additionally, the rate of anti-MRSA agent use was markedly different in each region. CONCLUSIONS: PID is not affected by doses and administration periods, and thus may be an alternative index for the selective pressure of antibiotics. Evaluating AMU using PID based on NDB data will help in the development of effective antimicrobial resistance measures.

The first national survey of antimicrobial use among dentists in Japan from 2015 to 2017 based on the national database of health insurance claims and specific health checkups of Japan.

PURPOSE: To counter the global health threat of antimicrobial resistance, effective antimicrobial stewardship programs are needed to improve antimicrobial use (AMU) among dentists in addition to physicians. This study aimed to investigate the nationwide epidemiology of AMU among Japanese dentists to facilitate the development of dentist-centered programs. METHODS: We conducted a retrospective population-based study using the National Database of Health Insurance Claims and Specific Health Checkups of Japan to analyze the AMU among Japanese dentists between 2015 and 2017. AMU was quantified as the defined daily doses per 1,000 inhabitants per day (DID). The trends in dentist-prescribed AMU were examined according to antimicrobial category and administration route. We also compared outpatient oral AMU between dentists and physicians as well as between on-site and off-site dispensing. RESULTS: The DID values of dentist-prescribed AMU were 1.23 in 2015, 1.22 in 2016, and 1.21 in 2017. During this study period, outpatient oral antimicrobials comprised the majority (approximately 99%) of dentist-prescribed AMU, and cephalosporins were the most frequently prescribed antimicrobials (>60% of all antimicrobials). The DID values of outpatient oral AMU were 1.21 for dentists and 12.11 for physicians. The DID value for on-site dispensing was 0.89 in 2017, in which cephalosporins were the predominantly used antimicrobials (DID: 0.60). CONCLUSIONS: Interventions that target dentists in Japan should focus on on-site dispensing of oral antimicrobials (especially cephalosporins) for outpatients. Further studies are needed to ascertain the underlying factors of oral cephalosporin prescriptions to guide the development of effective antimicrobial stewardship programs.

Trends of the Use of Anti-methicillin-Resistant Staphylococcus aureus Agents in Japan Based on Sales Data from 2006 to 2015.

Patterns of the use of anti-methicillin-resistant Staphylococcus aureus (MRSA) agents in Japan might be influenced by the launch of new anti-MRSA agents, the publication of relevant guidelines, and the increase in the number of generic medicines. However, as anti-MRSA agents are included in multiple anatomical therapeutic chemical classifications, such as glycopeptides and aminoglycosides, the trends of the use of individual anti-MRSA agents remain unclear. Here, we aimed to clarify the trends of anti-MRSA agent use in Japan from 2006 to 2015 based on sales data. Total anti-MRSA agent use was found to have significantly increased from 2006 to 2015 (Pfor trend = 0.027, r = 0.00022). Individual trends for vancomycin (VCM), daptomycin, and linezolid (LZD) use showed significant increases, while those for arbekacin (ABK) and teicoplanin (TEIC) showed decreases. In addition, oral LZD use significantly increased, while there was no significant change in intravenous LZD use. The ratio of oral LZD use to total LZD use increased from 25.5% in 2006 to 39.9% in 2015. Meanwhile, TEIC and ABK use decreased, while VCM use increased, following the launch of generic medicines. These results might reflect the status of guideline compliance, the launch of new anti-MRSA agents, and the decline in the sales promotion of the original medicines. It is extremely important to investigate trends for the use of not only different antibiotic groups but also individual antibiotics to develop and implement antimicrobial resistance countermeasures.

Trends of Antifungal Use Based on Sales Data in Japan from 2006 to 2015.

The detailed epidemiology of invasive mycoses and superficial mycoses has not been clarified in Japan. In addition, treatment options have increased because of novel antifungals and/or guidelines for fungal infection. In the present study, we aimed to clarify the trends of antifungal use in Japan from 2006 to 2015 based on sales data to serve as an alternative indicator of fungal infection trends. We found that the total antifungal use decreased over time (r = -0.057, Pfor trend < 0.0001). Oral and parenteral use significantly decreased by 44.1% (r = -0.056, Pfor trend < 0.0001) and 27.1% (r = -0.0012, Pfor trend = 0.00061), respectively. The trend of antifungal use for superficial mycoses significantly decreased by 49.8% (r = -0.061, Pfor trend < 0.0001). However, the trend of antifungal use for invasive mycoses was significantly increased by 19.9% (r = 0.0032, Pfor trend = 0.00045). In Japan, the increase in the number of immunocompromised patients might be associated with the increase in the frequency of antifungal use for invasive mycoses. This is the first study to clarify the trends of antifungal use in Japan. Further research is needed to establish a continuous surveillance system to compare fungal infections between Japan and the world.

Impact of antimicrobial stewardship fee on prescribing for Japanese pediatric patients with upper respiratory infections.

BACKGROUND: In 2018, the Japanese medical reimbursement system was revised to introduce a fee for the implementation of an antimicrobial stewardship (AS) fee for pediatric patients. The purpose of this study was to evaluate physicians' prescription behavior following this revision. METHODS: We conducted a retrospective observational study from January 1, 2017 to September 30, 2018 of pediatric (< 15 years) outpatients with upper respiratory tract infections (URIs). To assess the pattern of antibiotic prescription for the treatment of pediatric URIs before and after the introduction of the AS fee, we extracted data on pediatric URIs, diagnosed during the study period. Patients were divided based on whether medical facilities claimed AS fees. We defined antibiotic use as the number of antibiotics prescribed, and evaluated the proportion of each class to the total number of antibiotics prescribed. We also recorded the number of medical facilities that each patient visited during the study period. RESULTS: The frequency of antibiotic prescription decreased after AS fee implementation, regardless of whether the facility claimed the AS fee, but tended to be lower in facilities that claimed the fee. Additionally, the frequency of antibiotic prescription decreased in all age groups. Despite the reduced frequency of antibiotic prescription, consultation behavior did not change. CONCLUSIONS: The AS fee system, which compensates physicians for limiting antibiotic prescriptions, helped to reduce unnecessary antibiotic prescription and is thus a potentially effective measure against antimicrobial resistance.

The Trend for Antibiotic Use for Clostridioides (Clostridium) difficile Infection in Japan.

In Japan, there is no national surveillance study of Clostridioides (Clostridium) difficile infection (CDI), and details about the epidemiology and treatment status of CDI are unknown. Additionally, clinical practice guidelines (CPGs) for CDI are published by four different institutions. All CPGs recommend that the antimicrobials, vancomycin (VCM) and metronidazole (MNZ), should be selected according to disease severity. However, the trends for VCM and MNZ use in Japan remain unclear. Therefore, this study was aimed at clarifying the secular trends for VCM and MNZ use based on sales data from 2006 to 2015 and discussing its impact on CDI status and drug costs. This is the first study to clarify the antibiotic use trends for CDI treatment. We found that the total use increased over time (r = 0.0013, Pfor trend < 0.0001). While VCM use significantly decreased (r = -0.0003, Pfor trend = 0.0002), MNZ use increased (r = 0.0017, Pfor trend < 0.0001). These results show that although treatment for CDI was in line with CPGs, CDI incidence might be on an increasing trend. Additionally, despite the increased total use, the total drug costs decreased by 55% ($ 25 million) from 2006 to 2015. It was also surmised that CDI treatment in compliance with CPGs would lead to a reduction in drug costs. Hence, to understand the epidemiology of CDI, it is important to continuously investigate the use of drugs used for CDI therapy.

Cost of inappropriate antimicrobial use for upper respiratory infection in Japan.

BACKGROUND: Antibiotics are often prescribed inappropriately to patients with upper respiratory infection (URI) in ambulatory care settings; however, the economic burden of such prescription has not been quantitatively assessed. Here, we aimed to evaluate the additional cost of antimicrobial prescription for URI at the population level in Japan. METHODS: We conducted a retrospective observational survey using longitudinal claims data between 2013 and 2016 obtained from JMDC Claims Database, which contains data from 5·1 million corporate employees and family members under the age of 65 years. Appropriateness of antibiotic prescription was assessed by a panel of six infectious disease physicians according to ICD-10 code in JMDC Claims Database. Total additional cost of antibiotic prescription for URI at the national level was estimated by weighting of age-structured population data. RESULTS: The annual additional cost of inappropriate antibiotic prescription for URI was estimated at 423·6 (95% CI: 416·8-430·5) million USD in 2013, 340·9 (95% CI: 335·7-346·2) million USD in 2014, 349·9 (95% CI: 344·5-355·3) million USD in 2015, and 297·1 (95% CI: 292·4-301·9) million USD in 2016. Three classes of broad-spectrum oral antibiotics (third-generation cephalosporins, macrolides, and fluoroquinolones) accounted for > 90% of the total additional cost. CONCLUSIONS: Although a decreasing trend was observed, annual additional costs of inappropriate antibiotic prescriptions for URI could be a substantial economic burden in Japan. Appropriately prescribing broad-spectrum oral antibiotics might be an important issue to reduce unnecessary medical costs in Japanese ambulatory care.

Relationship between drug formulary and frequently used cephalosporins, macrolides and quinolones in Japanese hospitals.

In Japan, hospitals' pharmaceutical affairs committees freely select the drugs to be purchased depending on the regulations of each hospital. This system poses a risk of the absence of essential drugs or an excess of similar drugs, and may promote inappropriate use of third-generation cephalosporins (3GCs) and quinolones. Against this backdrop, we researched availability of antibacterial agents in Japanese hospitals. We conducted a questionnaire-based study in eastern Shizuoka Prefecture, Japan. Questionnaires were sent to 33 hospitals that had established an interactive regional partnership on infection control. We analyzed the number of available oral cephalosporins, macrolides, and quinolones in each hospital, and the correlation between the number of total available antibacterial agents and the hospital scale and cephalexin availability. Thirty-one hospitals participated in this study. First-generation cephalosporin (1 GC) was available in only 22.5% of them. In all participating hospitals, 3GCs were available, with more than one 3 GC available in 74.2%. Quinolones were available in all hospitals, and more than one quinolone in 67.7%. The numbers of hospital beds and total available antibacterial agents were positively correlated and hospitals that owned cephalexin available also significantly more often owned other available antibacterial agents. 1 GC were available in only a few hospitals, while multiple 3GCs and quinolones were available in most. This situation may lead to excess use of 3GCs or quinolones in Japan. A low number of available drugs was associated with cephalexin unavailability. Outpatient antimicrobial stewardship may focus not only on the quality of medicine, but also on the prescribing environment.

Longitudinal trends of and factors associated with inappropriate antibiotic prescribing for non-bacterial acute respiratory tract infection in Japan: A retrospective claims database study, 2012-2017.

BACKGROUND: Inappropriate antibiotic prescribing is a cause of antimicrobial resistance. Acute Respiratory Tract Infections (ARTI) are common diseases for those antibiotics are most likely prescribed in outpatient setting. OBJECTIVES: To clarify factors associated with antibiotic prescribing for non-bacterial acute respiratory tract infections (NB-ARTI) and identify targets for reducing inappropriate prescribing for NB-ARTI in Japan. METHODS: We conducted a retrospective, observational study using longitudinal claims data between April 2012 and June 2017. We assessed the rate of and factors associated with inappropriate antibiotic prescribing in outpatient settings for all NB-ARTI consultations included in the database. RESULTS: The mean monthly antibiotic prescribing rate per 100 NB-ARTI consultations during the study period was 31.65. The monthly antibiotic prescribing rate per 100 NB-ARTI consultations decreased by 19.2% from April 2012 to June 2017. Adolescents (13-18 years) and adults of working age (19-29 and 30-39 years) were more likely prescribed antibiotics compared with elderly patients ≥ 60 years (aOR: 1.493 [95%CI: 1.482-1.503], 1.585 [95%CI: 1.575-1.595], and 1.507 [95%CI: 1.498-1.516], respectively). Outpatient clinics registered as internal medicine or ear, nose, and throat specialty were more likely to prescribe antibiotics than those of paediatric specialty or other specialties. Among health facility type, clinics without beds (aOR 2.123 [95%CI: 2.113-2.133]) and clinics with beds (aOR: 1.752 [95%CI: 1.7371-1.767]) prescribed significantly more antibiotics for NB-ARTI than outpatient departments inside general hospitals. CONCLUSIONS: Inappropriate antibiotic prescribing for NB-ARTI is common in Japan. Although the antibiotic prescribing rate has decreased, further interventions are required to promote antimicrobial stewardship (ASP). Education and awareness for adults and promotion of ASP among physicians in clinics without beds are key drivers to reduce inappropriate antibiotic prescribing in Japan.

Relationship between left ventricular dyssynchrony and systolic dysfunction is independent of impaired left ventricular myocardial perfusion in heart failure: assessment with 99mTc-sestamibi gated myocardial scintigraphy.

BACKGROUNDS: Left ventricular (LV) dyssynchrony reduces LV systolic function in patients with heart failure (HF). However, it remains unknown whether this relationship is independent of impaired LV myocardial perfusion. METHODS AND RESULTS: A total of 105 patients with chronic HF (age 71 ± 13 years; 71 men) were enrolled in the present study. (99m)Tc-sestamibi (MIBI) gated myocardial scintigraphy was performed at rest to assess LV myocardial perfusion as evaluated by the total defect score of perfusion Single Photon Emission Computed Tomography images (TDS-MIBI), LV systolic function as evaluated by LV ejection fraction (LVEF), and LV systolic dyssynchrony as evaluated by the maximal difference of time to end systole (MD-TES), which is the time lag between the earliest and the latest end systole among 17 LV segments analyzed with a novel program, "cardioGRAF". The mean ± SD (minimum and maximum range) of the MD-TES was 147.8 ± 117.5 (14.0-458.3)ms. The MD-TES was significantly higher in patients with LVEF<45% (199.4 ± 117.6 ms) than in those with LVEF ≥ 45% (60.5 ± 41.2 ms, p<0.001). In a multiple logistic regression analysis, the MD-TES showed an increased odds ratio for LVEF<45% (2.46 [95% CI; 1.51-4.01] per increment in decile of MD-TES rank, p<0.001), after adjusting for the TDS-MIBI, history of myocardial infarction, and other potential confounders. CONCLUSIONS: LV dyssynchrony is a significant determinant of LV systolic dysfunction in patients with HF, and this relationship is independent of impaired LV myocardial perfusion and history of myocardial infarction.

Prognostic value of heart rate variability in comparison with annual health examinations in very elderly subjects.

The prognostic value of heart rate variability (HRV) in patients with cardiac conditions has been investigated for many years. However, the HRV is superior to annual health examinations for predicting the longevity of very elderly residents of long-term care facilities is unknown. Annual health examinations and subsequently ambulatory Holter ECG recording were performed in 2008 for 71 very elderly subjects, who were then followed up for 3 to 48 months. The patients were divided into 2 groups on the basis of whether they were alive (86 ± 14 years, n=37) or deceased (90 ± 16 years, n=34) at end of follow-up. To assess cardiac autonomic function, HRV was obtained with the MemCalc/Chiram software program after Holter ECG. Age, sex, body-mass index, plasma levels of C-reactive protein and albumin, and the low-frequency/high-frequency ratio did not differ between the 2 groups. However, the standard deviation of all NN intervals (SDNN) and the coefficient of variation of RR intervals (CVRR) were higher in living subjects than in deceased subjects (SDNN: 73.2 ± 13.5 milliseconds vs. 53.2 ± 9.8 milliseconds, CVRR: 9.3% ± 1.7% vs. 7.6% ± 1.3%, p<0.05). The relative risks with an SDNN <65 milliseconds was 1.85 (p<0.05) and that with a CVRR <8% was 1.84 (p<0.05). Kaplan Meier analysis showed that SDNN and CVRR were useful markers for the longevity of very elderly subjects. The present data suggest that annual health examination data does not predict longevity, but that HRV does. The modulation of parasympathetic tone in daily activities plays an important role in the longevity of very elderly residents of long-term care facilities.

Radial arterial wave reflection is associated with the MEGA risk prediction score, an indicator of coronary heart disease risk, in middle-aged men with mild to moderate hypercholesterolemia.

AIM: The present study examined the association between the radial augmentation index (AI), a marker of arterial wave reflection, and the MEGA risk prediction score (MEGA score), an indicator of coronary heart disease (CHD) risk, in middle-aged men with mild to moderate hypercholesterolemia. METHODS: Radial AI was measured during a company health examination in 266 men (age: 47+/-5 years) with total cholesterol levels ranging 220-270 mg/dL who were not taking antihypertensive, lipid-lowering, or antidiabetic agents. The MEGA score was calculated based on sex, age, low- and high-density lipoprotein cholesterol, blood pressure, glucose level, and smoking status. The higher MEGA score indicates increased CHD risk. A MEGA score > or = 22 corresponds to a 5-year CHD risk > or = 2.5% and we defined a MEGA score > or = 22 as a high estimated CHD risk. RESULTS: The mean AI was 74.4+/-12.6%. A high estimated CHD risk was seen in 32 subjects (12.0%). After adjusting for height and heart rate, the AI was higher in subjects with a high estimated CHD risk (81.5+/-10.6%) than in those without (73.4+/-10.4%, p<0.001). The odds ratio for high estimated CHD risk in the highest tertile of AI was 8.14 (p=0.002) in comparison to the lowest tertile, after adjusting for multiple potential confounders which did not constitute the MEGA score. CONCLUSION: The radial AI was positively associated with the estimated risk of CHD. These results suggest the usefulness of radial AI as a risk marker for future onset of CHD in middle-aged men with mild to moderate hypercholesterolemia.