The prognostic impact of vascular biomarkers and supine blood pressure (BP) is not well understood. The multicenter, prospective Coupling study determined the prognostic impact of vascular biomarkers and supine BP in outpatients aged ≥30 years with ≥1 cardiovascular risk factor. Occurrence of major cardiovascular events during follow-up was recorded. The primary outcome was time to onset of a major cardiovascular event. Office and supine BP, the cardio-ankle vascular index (CAVI), and the ankle-brachial index (ABI) were determined annually. Of the 5109 participants in the Coupling study, 4716 were analyzed (51.9

BACKGROUND:Home blood pressure (BP) is an important component of digital strategies for hypertension management. However, no studies have used the same device to investigate 24-hour BP control status in relation to different home BP control thresholds.METHODS:Participants in the general practitioner-based, multicenter HI-JAMP study (Home-Activity Information and Communication Technology-Based Japan Ambulatory Blood Pressure Monitoring Prospective) underwent office BP measurement, then 24-hour ambulatory BP monitoring, then home BP monitoring for 5 days. A validated all-in-one BP monitoring device was used to measure office, home, and ambulatory BP. Baseline data were used to investigate ambulatory BP control status in individuals with well-controlled home BP based on the different guideline thresholds (125/75 mm Hg, 130/80 mm Hg, and 135/85 mm Hg).RESULTS:Data from 2269 patients were analyzed. For individuals with well-controlled home BP <135/85 mm Hg (59.5% of the total population), the prevalence of uncontrolled 24-hour (≥130/80 mm Hg), daytime (≥135/85 mm Hg), and nighttime ambulatory BP (≥120/70 mm Hg) was 19.9%, 18.5%, and 33.6%, respectively. Corresponding prevalence rates in the 42.7% of participants with well-controlled home BP <130/80 mm Hg were 13.4%, 12.9%, and 26.0%, and when well-controlled home BP was strictly defined as <125/75 mm Hg (23.9% of the population), prevalence of rates of uncontrolled 24-hour, daytime, and nighttime ambulatory BP were 7.0%, 9.0%, and 15.3%, respectively.CONCLUSIONS:Home BP control status defined using different thresholds could predict 24-hour ambulatory BP control status in treated hypertension. One-third of individuals still had uncontrolled nocturnal hypertension when home BP was controlled to <135/85 mm Hg, but ambulatory BP was quite well controlled when home BP was <125/75 mm Hg.

There is limited evidence on the blood pressure (BP)-lowering effect of esaxerenone on home BP, including nighttime BP. Using two newly developed nocturnal home BP monitoring devices (brachial and wrist), this multicenter, open-label, prospective study investigated the nighttime home BP-lowering effect of esaxerenone in patients with uncontrolled nocturnal hypertension being treated with an angiotensin receptor blocker (ARB) or calcium-channel blocker (CCB). In total, 101 patients were enrolled. During the 12-week study period, change in nighttime home systolic/diastolic BP from baseline to end of treatment measured by the brachial device was −12.9/−5.4 mmHg in the total population and −16.2/−6.6 and −10.0/−4.4 mmHg in the ARB and CCB subcohorts, respectively (all p < 0.001). For the wrist device, the change was −11.7/−5.4 mmHg in the total population and −14.6/−6.2 and −8.3/−4.5 mmHg in each subcohort, respectively (all p < 0.001). Similar significant reductions were shown for morning and bedtime home BP and office BP. Urinary albumin-to-creatinine ratio, N-terminal pro-brain natriuretic peptide, and cardio-ankle vascular index improved in the total population and each subcohort. Incidences of treatment-emergent adverse events (TEAEs) and drug-related TEAEs were 38.6% and 16.8%, respectively; most were mild or moderate. The most frequent drug-related TEAEs were associated with serum potassium elevation (hyperkalemia, 9.9%; blood potassium increased, 3.0%); however, no new safety concerns were raised. Esaxerenone was effective in lowering nighttime home BP as well as morning and bedtime home BP and office BP, safe, and showed organ-protective effects in patients with uncontrolled nocturnal hypertension. Caution is warranted regarding elevated serum potassium levels. This study investigated the effect of esaxerenone on nighttime home BP and organ damage (UACR and NT-proBNP) in patients with uncontrolled nocturnal hypertension despite treatment with an ARB or CCB. Our results show that safe 24-h BP control and organ protection are possible with esaxerenone.

Background Blood pressure (BP) thresholds for diagnosing and managing hypertension vary for office, home, and ambulatory readings, and between guideline documents. This analysis determined corresponding office, home, and ambulatory BP thresholds using baseline data from the HI‐JAMP (Home‐Activity Information and Communication Technology–Based Japan Ambulatory Blood Pressure Monitoring Prospective) study, which used a validated “all‐in‐one” BP monitoring device. Methods and Results Data from 2322 treated patients with hypertension who underwent office BP measurement, then 24‐hour ambulatory BP monitoring, then home BP monitoring for 5 days were analyzed. Corresponding BP thresholds for office, home, and ambulatory measurements were determined using Deming regression. Values equivalent to office systolic BP (SBP) of 120 and 140 mm Hg were as follows: 115.9 and 127.7 mm Hg for 24‐hour ambulatory SBP; 120.8 and 134.0 mm Hg for daytime ambulatory SBP; 104.9 and 117.9 mm Hg for nighttime ambulatory SBP; and 122.0 and 134.2 mm Hg for morning‐evening average home SBP. Deming regression showed that morning‐evening average home SBP and daytime ambulatory SBP were almost the same (home SBP=0.99×daytime ambulatory SBP+0.27 mm Hg; r=0.627). Morning‐evening average home SBP values of 120 and 135 mm Hg were equivalent to daytime ambulatory SBP values of 119.1 and 133.9 mm Hg, respectively. A home SBP threshold of 130 mm Hg corresponded to 24‐hour and nighttime ambulatory SBP values of 123.5 and 113.6 mm Hg, whereas a home SBP threshold of 135 mm Hg corresponded to 24‐hour and nighttime ambulatory SBP values of 128.0 and 119.2 mm Hg. Conclusions Ambulatory and home BP thresholds in this analysis were similar to those proposed by existing guidelines. The similarity between the home BP and daytime ambulatory BP thresholds was a clinically relevant finding.

BACKGROUND Inconsistencies between the office and out-of-office blood pressure (BP) values (described as white-coat hypertension or masked hypertension) may be attributable in part to differences in the BP monitoring devices used. METHODS We studied consistency in the classification of BP control (well-controlled BP vs. uncontrolled BP) among office, home, and ambulatory BPs by using a validated "all-in-one" BP monitoring device. In the nationwide, general practitioner-based multicenter HI-JAMP study, 2,322 hypertensive patients treated with antihypertensive drugs underwent office BP measurements and 24-hour ambulatory BP monitoring (ABPM), consecutively followed by 5-day home BP monitoring (HBPM), for a total of seven BP measurement days. RESULTS Using the thresholds of the JSH2019 and ESC2018 guidelines, the patients with consistent classification of well-controlled status in the office (<140 mmHg) and home systolic BP (SBP) (<135 mmHg) (n = 970) also tended to have well-controlled 24-hour SBP (<130 mmHg) (n = 808, 83.3%). The patients with the consistent classification of uncontrolled status in office and home SBP (n = 579) also tended to have uncontrolled 24-hour SBP (n = 444, 80.9%). Among the patients with inconsistent classifications of office and home BP control (n = 803), 46.1% had inconsistent ABPM-vs.-HBPM out-of-office BP control status. When the 2017 ACC/AHA thresholds were applied as an alternative, the results were essentially the same. CONCLUSIONS The combined assessment of the office and home BP is useful in clinical practice. Especially for patients whose office BP classification and home BP classification conflict, the complementary clinical use of both HBPM and ABPM might be recommended.

Objective: Inconsistencies between office and out-of-office blood pressure (BP) values (described as white-coat hypertension or masked hypertension) may be attributable in part to differences in the BP monitoring devices used. We studied the inconsistency of the classification of BP control (well-controlled BP vs. uncontrolled BP) among office, home, and ambulatory BPs by using a validated all-in-one BP monitoring device. Design and method: In the nationwide, general practitioner-based multicenter HI-JAMP study, 2,322 hypertensive patients treated with antihypertensive drugs underwent office BP measurements and 24-h ambulatory BP monitoring (ABPM), consecutively followed by 5-day home BP monitoring (HBPM), using the same all-in-one device over a total of seven BP measurement days. Results: Using the thresholds of the JSH2019 and ESC2018 guidelines, the subjects with consistently well-controlled office (<140mmHg) and home systolic BP (SBP) (<135mmHg) (n = 970) also tended to have well-controlled 24-h SBP (<130mmHg) (n = 808, 83.3%). The subjects with consistently uncontrolled office and home SBP (n = 579) also tended to have uncontrolled 24-h SBP (n = 444, 80.9%). Among the subjects with inconsistent classifications of office and home BP control (n = 803), 46.1% had inconsistent ABPM-vs.-HBPM out-of-office BP control status. When the 2017 ACC/AHA thresholds or JSH2019 target BP thresholds were applied as an alternative, the results were essentially the same. Conclusions: The combined assessment of office and home BP is useful in clinical practice. Especially for patients whose office BP classification and home BP classification conflict, the complementary clinical use of both HBPM and ABPM might be recommended.

HomeCirculationVol. 145, No. 9Efficacy and Safety of Edoxaban 15 mg According to Renal Function in Very Elderly Patients With Atrial Fibrillation: A Subanalysis of the ELDERCARE-AF Trial Open AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toOpen AccessLetterPDF/EPUBEfficacy and Safety of Edoxaban 15 mg According to Renal Function in Very Elderly Patients With Atrial Fibrillation: A Subanalysis of the ELDERCARE-AF Trial Tetsuro Yoshida, MD, PhD, Akihiro Nakamura, MD, PhD, Junichi Funada, MD, PhD, Mari Amino, MD, PhD, Wataru Shimizu, MD, PhD, Masayuki Fukuzawa, MS, Saori Watanabe, BS, Takuya Hayashi, MS, Takeshi Yamashita, MD, PhD, Ken Okumura, MD, PhD and Masaharu Akao, MD, PhD Tetsuro YoshidaTetsuro Yoshida Correspondence to Tetsuro Yoshida, MD, PhD, Department of Cardiovascular Medicine, Onga Nakama Medical Association Onga Hospital, 1725-2 Ooaza-Ozaki, Onga-cho, Onga-gun, Fukuoka 811-4342, Japan. Email E-mail Address: [email protected] https://orcid.org/0000-0002-6259-1403 Department of Cardiovascular Medicine, Onga Nakama Medical Association Onga Hospital, Japan (T. Yoshida). Search for more papers by this author , Akihiro NakamuraAkihiro Nakamura Department of Cardiology, Iwate Prefectural Central Hospital, Morioka, Japan (A.N.). Search for more papers by this author , Junichi FunadaJunichi Funada https://orcid.org/0000-0001-8810-0425 Department of Cardiology, National Hospital Organization Ehime Medical Center, Toon, Japan (J.F.). Search for more papers by this author , Mari AminoMari Amino Department of Cardiology, Tokai University, Isehara, Japan (M.A.). Search for more papers by this author , Wataru ShimizuWataru Shimizu https://orcid.org/0000-0001-9941-8973 Department of Cardiovascular Medicine, Nippon Medical School, Tokyo, Japan (W.S.). Search for more papers by this author , Masayuki FukuzawaMasayuki Fukuzawa Cardiovascular Group, Primary Medical Science Department, Japan Business Unit (M.F.), Daiichi Sankyo Co., Ltd., Tokyo, Japan. Search for more papers by this author , Saori WatanabeSaori Watanabe Clinical Development Department III, Development Function, Research and Development Division (S.W.), Daiichi Sankyo Co., Ltd., Tokyo, Japan. Search for more papers by this author , Takuya HayashiTakuya Hayashi The Data Intelligence Group, Data Intelligence Department, Digital Transformation Management Division (T.H.), Daiichi Sankyo Co., Ltd., Tokyo, Japan. Search for more papers by this author , Takeshi YamashitaTakeshi Yamashita https://orcid.org/0000-0002-2544-8464 Department of Cardiovascular Medicine, The Cardiovascular Institute, Tokyo, Japan (T. Yamashita). Search for more papers by this author , Ken OkumuraKen Okumura Division of Cardiology, Saiseikai Kumamoto Hospital, Kumamoto, Japan (K.O.). Search for more papers by this author and Masaharu AkaoMasaharu Akao https://orcid.org/0000-0002-2348-7646 Department of Cardiology, National Hospital Organization Kyoto Medical Center, Kyoto, Japan (M.A.). Search for more papers by this author Originally published28 Feb 2022https://doi.org/10.1161/CIRCULATIONAHA.121.057190Circulation. 2022;145:718–720The ELDERCARE-AF trial (The Edoxaban Low-Dose for Elder Care in AF Patients) demonstrated that a once-daily 15-mg dose of edoxaban was superior to placebo in preventing stroke or systemic embolism and did not result in a significantly higher incidence of major bleeding than placebo in very elderly Japanese patients with nonvalvular atrial fibrillation (NVAF) who were not appropriate candidates for standard doses of oral anticoagulants.1 In this prespecified subanalysis of the ELDERCARE-AF trial, we evaluated the association of renal function with the efficacy and safety of edoxaban 15 mg in these patients.Eligible patients were ≥80 years of age and had a history of NVAF and a CHADS2 score of ≥2. Patients had to be considered ineligible for oral anticoagulants (warfarin, dabigatran, rivaroxaban, apixaban, or edoxaban) at the recommended therapeutic strength or approved dose for ≥1 of the following reasons: low creatinine clearance (CrCl; 15–30 mL/min), history of bleeding from a critical area or organ, low body weight (≤45 kg), continuous use of nonsteroidal anti-inflammatory drugs, and current use of an antiplatelet drug. The primary efficacy end point was the incidence of stroke or systemic embolism, and the primary safety end point was the International Society on Thrombosis and Haemostasis major bleeding. Other end points were all-cause mortality and net clinical outcome (the composite of stroke, systemic embolism, major bleeding, or all-cause mortality). Anonymized trial data will be made available at https://search.vivli.org/ to researchers on reasonable request to the corresponding author with approval by Daiichi Sankyo Co., Ltd.In this trial, 984 patients were randomly assigned to treatment (edoxaban group, n=492; placebo group, n=492) and 681 completed the trial. For this analysis, patients in the ELDERCARE-AF trial were classified into 3 subgroups on the basis of their baseline renal function: severe renal dysfunction (CrCl 15 to <30 mL/min, n=401), moderate renal dysfunction (CrCl 30–50 mL/min, n=422), and normal renal function/mild renal dysfunction (CrCl >50 mL/min, n=161). The median duration of follow-up was 466.0 days (interquartile range, 293.5–708.0). Event rates for primary end points were calculated for each renal function subgroup. The cumulative incidences of stroke or systemic embolism and major bleeding were estimated using the Kaplan-Meier method. A Cox proportional hazards model was used to compare outcomes between the treatment groups, with the results expressed as a hazard ratio with a 95% confidence interval. Proportionality of hazards for the primary end point was confirmed by inspection of log-log survival plots. Interaction effects between treatment arms and CrCl subgroups were tested on the basis of a joint test using Wald statistics. The protocol was approved by the institute ethics committee. Written informed consent was obtained from all participants (or legal representatives for patients with cognitive impairment) before enrollment.Kaplan-Meier curves and forest plots showing the risk of stroke/systemic embolism (primary efficacy end point) and major bleeding (primary safety end point) in the edoxaban and placebo groups according to baseline CrCl subgroups are shown in the Figure. The effect of edoxaban versus placebo on stroke/systemic embolism was consistent among all CrCl subgroups (P value for interaction=0.91). The increase in major bleeding with edoxaban was nonsignificant, and there was no heterogeneity between the CrCl groups (P value for interaction=0.63). Regarding all-cause mortality, the hazard ratios of the edoxaban groups were 0.97 for the CrCl 15 to <30 mL/min subgroup, 1.12 for the CrCl 30 to 50 mL/min subgroup, and 0.86 for the CrCl >50 mL/min subgroup (P value for interaction=0.90), and those for net clinical outcome were 0.91, 0.87, and 0.77 for each CrCl subgroup, respectively (P value for interaction=0.96). No heterogeneity was observed between the groups.Download figureDownload PowerPointFigure. Relationship between stroke/systemic embolism or major bleeding and renal function in patients with nonvalvular atrial fibrillation. Kaplan-Meier curves and forest plots for stroke/systemic embolism and major bleeding in the edoxaban and placebo groups according to baseline creatinine clearance. CI indicates confidence interval; CrCl, creatinine clearance; and HR, hazard ratio.In a subanalysis of the ENGAGE AF-TIMI 48 trial (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction Study 48), the advantage of edoxaban over warfarin was consistent across the range of renal function in patients with NVAF (the minimum renal function was CrCl 30 mL/min).2 Another study showed that edoxaban 15 mg in patients with NVAF and severe renal dysfunction (CrCl 15 to <30 mL/min) exhibited safety and plasma concentration similar to the 30-mg dose in patients with normal renal function or mild dysfunction (CrCl ≥50 mL/min).3 In the present study, edoxaban 15 mg reduced the incidence of stroke/systemic embolism regardless of the level of renal dysfunction. There was no increase in intracranial hemorrhage or fatal bleeding events in the edoxaban group.1 Thus, the use of edoxaban 15 mg may be a feasible and clinically acceptable therapy even in very elderly patients with severe renal dysfunction, under appropriate measures for preventing bleeding.In addition to the study limitations described in our previous report,1 the sample size of this subanalysis was small, our findings are limited to very elderly patients, and the event rates were low, which may result in indeterminate conclusions. Further studies are warranted.In conclusion, the efficacy and safety of edoxaban 15 mg compared with placebo was broadly consistent across renal function subgroups in very elderly Japanese patients with NVAF who were not appropriate candidates for standard doses of oral anticoagulants.Article InformationRegistration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02801669.AcknowledgmentsWe thank Michelle Belanger, MD, of Edanz (www.edanz.com) for providing medical writing support, which was funded by Daiichi Sankyo Co., Ltd. All authors meet the ICMJE’s authorship criteria.Sources of FundingThis study was supported by Daiichi Sankyo Co., Ltd.Nonstandard Abbreviations and AcronymsCrClcreatinine clearanceNVAFnonvalvular atrial fibrillationDisclosures Dr Yoshida has received funding for research expenses (Onga Hospital) from Daiichi Sankyo Co., Ltd. Dr Shimizu has received grants from Daiichi Sankyo Co., Ltd. and Nippon Boehringer Ingelheim Co., Ltd.; and honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Daiichi Sankyo Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Bristol-Meyers Squibb, K.K., Bayer Yakuhin, Ltd., Pfizer Japan, Inc., Ono Pharmaceutical Co., Ltd., and Otsuka Pharmaceutical Co., Ltd. M. Fukuzawa, S. Watanabe, and T. Hayashi are employees at Daiichi Sankyo Co., Ltd. Dr Yamashita has received personal fees (as a medical expert) from Daiichi Sankyo Co., Ltd. for this study; and grants and lecture fees from Daiichi Sankyo Co., Ltd., Bristol-Myers Squibb K.K., and Bayer Yakuhin Ltd.; lectures fees from Pfizer Japan Inc., Nippon Boehringer Ingelheim Co., Ltd., and Ono Pharmaceutical Co., Ltd.; medical advisory fees from Toa Eiyo Ltd.; and lecture and medical advisory fees from Novartis Pharma K.K. outside the submitted work. Dr Okumura has received grants and a commission fee for the study design from Daiichi Sankyo Co., Ltd. for the submitted work; and lecture fees from Daiichi Sankyo Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Bristol-Myers Squibb K.K., Medtronic Japan Co., Ltd., Johnson & Johnson K.K., and Bayer Yakuhin Ltd. outside the submitted work. Dr Akao has received funding support for the present manuscript from Daiichi Sankyo Co., Ltd. and grants from Bayer Yakuhin, Ltd., Pfizer Japan, Inc., Bristol-Meyers Squibb, K.K., Nippon Boehringer Ingelheim Co., Bayer Yakuhin, Ltd., and Daiichi Sankyo Co., Ltd. The other authors report no conflicts.FootnotesCirculation is available at www.ahajournals.org/journal/circFor Sources of Funding and Disclosures, see page 720.Correspondence to Tetsuro Yoshida, MD, PhD, Department of Cardiovascular Medicine, Onga Nakama Medical Association Onga Hospital, 1725-2 Ooaza-Ozaki, Onga-cho, Onga-gun, Fukuoka 811-4342, Japan. Email [email protected]comReferences1. Okumura K, Akao M, Yoshida T, Kawata M, Okazaki O, Akashi S, Eshima K, Tanizawa K, Fukuzawa M, Hayashi T, et al.; ELDERCARE-AF Committees and Investigators. Low-dose edoxaban in very elderly patients with atrial fibrillation.N Engl J Med. 2020; 383:1735–1745. doi: 10.1056/NEJMoa2012883CrossrefMedlineGoogle Scholar2. Bohula EA, Giugliano RP, Ruff CT, Kuder JF, Murphy SA, Antman EM, Braunwald E. Impact of renal function on outcomes with edoxaban in the ENGAGE AF-TIMI 48 Trial.Circulation. 2016; 134:24–36. doi: 10.1161/CIRCULATIONAHA.116.022361LinkGoogle Scholar3. Koretsune Y, Yamashita T, Kimura T, Fukuzawa M, Abe K, Yasaka M. Short-term safety and plasma concentrations of edoxaban in Japanese patients with non-valvular atrial fibrillation and severe renal impairment.Circ J. 2015; 79:1486–1495. doi: 10.1253/circj.CJ-14-0942CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails March 1, 2022Vol 145, Issue 9Article InformationMetrics © 2022 The Authors. Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.https://doi.org/10.1161/CIRCULATIONAHA.121.057190PMID: 35226559 Originally publishedFebruary 28, 2022 Keywordsanticoagulantsagedthromboembolismedoxabankidneyhemorrhageatrial fibrillationPDF download Advertisement SubjectsAtrial FibrillationHeart Failure

Non-dipper and riser patterns of nocturnal blood pressure (BP) are risk factors for cardiovascular disease (CVD), including heart failure (HF). However, the risk associated with a disrupted nocturnal pattern of heart rate is not well known. To investigate whether the nighttime heart rate is a risk factor for HF, alongside nighttime BP phenotype. The practitioner-based, nationwide, prospective Japan Ambulatory Blood Pressure Monitoring Prospective (JAMP) study included patients with ≥ 1 CVD risk factor but without symptomatic CVD at baseline. All patients underwent 24-h ambulatory BP monitoring at baseline and were followed annually. Nocturnal heart rate dipping ( https://www.umin.ac.jp/ctr/ ; Unique identifier: UMIN000020377.

The value of the cardio-ankle vascular index (CAVI) increases with age. All large-scale studies of the CAVI have investigated patients <80 years old. Thus, the clinical characteristics of high CAVI in patients aged 80 or more remain unclear. Therefore, we investigated (1) the CAVI in very elderly patients and (2) the determinants of a high CAVI in high-risk patients, including very elderly patients. The Cardiovascular Prognostic Coupling Study in Japan (Coupling Registry) is a prospective observational study of Japanese outpatients with any cardiovascular risk factors. We enrolled 5109 patients from 30 institutions (average age 68.7 +/- 11.4 years, 52.4% males). We investigated the determinants of the CAVI by separating the patients into three groups: 970 middle-aged (<60 years), 3252 elderly (60-79 years), and 887 very elderly (>= 80 years) patients. The CAVI values of the males were significantly higher those of the females in all age groups (<60 years: 7.81 +/- 1.11 vs. 7.38 +/- 0.99,P < .001; 60-79 years: 9.20 +/- 1.29 vs. 8.66 +/- 1.07,P < .001; >= 80 years: 10.26 +/- 1.39 vs. 9.51 +/- 1.12,P < .001). In all age groups, the CAVI of the patients with diabetes/glucose tolerance disorder was higher than that of the patients without diabetes/glucose tolerance disorder (<60 years: 7.82 +/- 1.22 vs 7.58 +/- 1.03,P = .002; 60-79 years: 9.23 +/- 1.20 vs 8.78 +/- 1.19,P < .001; >= 80 years: 10.04 +/- 1.24 vs 9.75 +/- 1.32,P = .002). The determinants of the CAVI in these very elderly patients were age, male sex, low BMI, and mean blood pressure. Diabetes/glucose tolerance disorder and glucose were independently associated with the CAVI in the patients aged <60 years and 60-79 years, but not in those aged >= 80 years after adjusting for other covariates.

BACKGROUND Implementation of appropriate oral anticoagulant treatment for the prevention of stroke in very elderly patients with atrial fibrillation is challenging because of concerns regarding bleeding. METHODS We conducted a phase 3, multicenter, randomized, double-blind, placebo-controlled, event-driven trial to compare a once-daily 15-mg dose of edoxaban with placebo in elderly Japanese patients (≥80 years of age) with nonvalvular atrial fibrillation who were not considered to be appropriate candidates for oral anticoagulant therapy at doses approved for stroke prevention. The primary efficacy end point was the composite of stroke or systemic embolism, and the primary safety end point was major bleeding according to the definition of the International Society on Thrombosis and Haemostasis. RESULTS A total of 984 patients were randomly assigned in a 1:1 ratio to receive a daily dose of 15 mg of edoxaban (492 patients) or placebo (492 patients). A total of 681 patients completed the trial, and 303 discontinued (158 withdrew, 135 died, and 10 had other reasons); the numbers of patients who discontinued the trial were similar in the two groups. The annualized rate of stroke or systemic embolism was 2.3% in the edoxaban group and 6.7% in the placebo group (hazard ratio, 0.34; 95% confidence interval [CI], 0.19 to 0.61; P<0.001), and the annualized rate of major bleeding was 3.3% in the edoxaban group and 1.8% in the placebo group (hazard ratio, 1.87; 95% CI, 0.90 to 3.89; P = 0.09). There were substantially more events of gastrointestinal bleeding in the edoxaban group than in the placebo group. There was no substantial between-group difference in death from any cause (9.9% in the edoxaban group and 10.2% in the placebo group; hazard ratio, 0.97; 95% CI, 0.69 to 1.36). CONCLUSIONS In very elderly Japanese patients with nonvalvular atrial fibrillation who were not appropriate candidates for standard doses of oral anticoagulants, a once-daily 15-mg dose of edoxaban was superior to placebo in preventing stroke or systemic embolism and did not result in a significantly higher incidence of major bleeding than placebo. (Funded by Daiichi Sankyo; ELDERCARE-AF ClinicalTrials.gov number, NCT02801669.).

BACKGROUND:Ambulatory and home blood pressure (BP) monitoring parameters are better predictors of cardiovascular events than are office BP monitoring parameters, but there is a lack of robust data and little information on heart failure (HF) risk. The JAMP study (Japan Ambulatory Blood Pressure Monitoring Prospective) used the same ambulatory BP monitoring device, measurement schedule, and diary-based approach to data processing across all study centers and determined the association between both nocturnal hypertension and nighttime BP dipping patterns and the occurrence of cardiovascular events, including HF, in patients with hypertension. METHODS:This practitioner-based, nationwide, multicenter, prospective, observational study included patients with at least 1 cardiovascular risk factor, mostly hypertension, and free of symptomatic cardiovascular disease at baseline. All patients underwent 24-hour ambulatory BP monitoring at baseline. Patients were followed annually to determine the occurrence of primary end point cardiovascular events (atherosclerotic cardiovascular disease and HF). RESULTS:A total of 6,359 patients (68.6±11.7 years of age, 48% men) were included in the final analysis. During a mean±SD follow-up of 4.5±2.4 years, there were 306 cardiovascular events (119 stroke, 99 coronary artery disease, 88 HF). Nighttime systolic BP was significantly associated with the risk of atherosclerotic cardiovascular disease and HF (hazard ratio adjusted for demographic and clinical risk factors per 20-mm Hg increase: 1.18 [95% CI, 1.02-1.37], P=0.029; and 1.25 [95% CI, 1.00-1.55], P=0.048, respectively). Disrupted circadian BP rhythm (riser pattern, nighttime BP higher than daytime BP) was significantly associated with higher overall cardiovascular disease risk (1.48 [95% CI, 1.05-2.08]; P=0.024), and especially HF (2.45 [95% CI, 1.34-4.48]; P=0.004) compared with normal circadian rhythm. CONCLUSIONS:Nighttime BP levels and a riser pattern were independently associated with the total cardiovascular event rate, in particular for HF. These findings suggest the importance of antihypertensive strategies targeting nighttime systolic BP. Registration: URL: https://www.umin.ac.jp/ctr/; Unique identifier: UMIN000020377.

Background: Ambulatory and home blood pressure (BP) monitoring parameters are better predictors of cardiovascular events than are office BP monitoring parameters, but there is a lack of robust data and little information on heart failure (HF) risk. The JAMP study (Japan Ambulatory Blood Pressure Monitoring Prospective) used the same ambulatory BP monitoring device, measurement schedule, and diary-based approach to data processing across all study centers and determined the association between both nocturnal hypertension and nighttime BP dipping patterns and the occurrence of cardiovascular events, including HF, in patients with hypertension. Methods: This practitioner-based, nationwide, multicenter, prospective, observational study included patients with at least 1 cardiovascular risk factor, mostly hypertension, and free of symptomatic cardiovascular disease at baseline. All patients underwent 24-hour ambulatory BP monitoring at baseline. Patients were followed annually to determine the occurrence of primary end point cardiovascular events (atherosclerotic cardiovascular disease and HF). Results: A total of 6,359 patients (68.6±11.7 years of age, 48% men) were included in the final analysis. During a mean±SD follow-up of 4.5±2.4 years, there were 306 cardiovascular events (119 stroke, 99 coronary artery disease, 88 HF). Nighttime systolic BP was significantly associated with the risk of atherosclerotic cardiovascular disease and HF (hazard ratio adjusted for demographic and clinical risk factors per 20-mm Hg increase: 1.21 [95% CI, 1.03–1.41], P =0.017; and 1.36 [95% CI, 1.08–1.71], P =0.009, respectively). Disrupted circadian BP rhythm (riser pattern, nighttime BP higher than daytime BP) was significantly associated with higher overall cardiovascular disease risk (1.48 [95% CI, 1.05–2.08]; P =0.024), and especially HF (2.45 [95% CI, 1.34–4.48]; P =0.004) compared with normal circadian rhythm. Conclusions: Nighttime BP levels and a riser pattern were independently associated with the total cardiovascular event rate, in particular for HF. These findings suggest the importance of antihypertensive strategies targeting nighttime systolic BP. Registration: URL: https://www.umin.ac.jp/ctr/ ; Unique identifier: UMIN000020377.

Vascular biomarkers, including the cardio-ankle vascular index (CAVI), are increasingly being recognized as important indicators of cardiovascular risk. CAVI has been shown to have good discriminative ability for detecting new-onset hypertension, but results of studies investigating cardiovascular risk prediction are inconsistent. Furthermore, there is a lack of data on the prognostic value of changes in CAVI over time. The Cardiovascular Prognostic Coupling study was designed to determine the impact of baseline CAVI and changes in CAVI on cardiovascular events in a Japanese cohort. The design of the ongoing, multicenter, prospective, observational registry and baseline characteristics of the enrolled population are reported. Eligible consecutive patients were aged ≥30 years, had ≥1 cardiovascular risk factor, and were being treated according to relevant Japanese guidelines. The primary outcome is time to onset of a major cardiovascular event (a composite of cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage, stroke of unknown etiology, myocardial infarction, cardiovascular intervention for angina pectoris, and sudden death). Screening and enrollment occurred over a period of 3 years, followed by ≥7 years of follow-up, with CAVI determined annually. A total of 5279 patients were registered, of whom 5109 had baseline data available and will be included in future analyses. Mean CAVI at baseline was 8.8 ± 1.4. The proportion of patients with CAVI of <8, 8-10 or >10 was 25.3%, 57.0%, and 17.7%, respectively. Data from this registry should provide information on the significance of baseline CAVI and change in CAVI as indicators of cardiovascular prognosis in a representative patient population.

Background: The risk of cardiovascular disease and mortality in salt-sensitive patients with diabetes mellitus and uncontrolled nocturnal hypertension is high. The SACRA (Sodium-Glucose Cotransporter 2 [SGLT2] Inhibitor and Angiotensin Receptor Blocker [ARB] Combination Therapy in Patients With Diabetes and Uncontrolled Nocturnal Hypertension) study investigated changes in blood pressure (BP) with empagliflozin plus existing antihypertensive therapy. Methods: This multicenter, double-blind, parallel study was conducted in Japan. Adult patients with type 2 diabetes mellitus and uncontrolled nocturnal hypertension receiving stable antihypertensive therapy including angiotensin receptor blockers were randomized to 12 weeks’ treatment with empagliflozin 10 mg once daily or placebo. Clinic BP was measured at baseline and weeks 4, 8, and 12; 24-hour ambulatory BP monitoring was performed at baseline and week 12; and morning home BP was determined for 5 days before each visit. The primary efficacy end point was change from baseline in nighttime BP (ambulatory BP monitoring). Results: One hundred thirty-two nonobese, older patients with well-controlled blood glucose were randomized (mean age 70 years, mean body mass index 26 kg/m 2 ). Empagliflozin, but not placebo, significantly reduced nighttime systolic BP versus baseline (–6.3 mm Hg; P =0.004); between-group difference in change from baseline was –4.3 mm Hg ( P =0.159). Reductions in daytime, 24-hour, morning home, and clinic systolic BP at 12 weeks with empagliflozin were significantly greater than with placebo (–9.5, –7.7, –7.5, and –8.6 mm Hg, respectively; all P ≤0.002). Between-group differences in body weight and glycosylated hemoglobin reductions were significant, but small (–1.3 kg and –0.33%; both P <0.001). At 4 weeks, N-terminal pro-B-type natriuretic peptide levels were reduced to a greater extent in the empagliflozin versus placebo group (–12.1%; P =0.013); atrial natriuretic peptide levels decreased with empagliflozin versus placebo at weeks 4 and 12 (–8.2% [ P =0.008] and –9.7% [ P =0.019]). Changes in antihypertensive medication during the study did not differ significantly between groups. Conclusions: Nonseverely obese older diabetes patients with uncontrolled nocturnal hypertension showed significant BP reductions without marked reductions in glucose with the addition of empagliflozin to existing antihypertensive and antidiabetic therapy. Use of sodium-glucose cotransporter 2 inhibitors in specific groups (eg, those with nocturnal hypertension, diabetes, and high salt sensitivity) could help reduce the risk of heart failure and cardiovascular mortality. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT03050229.

The clinical expert consensus statement on takotsubo syndrome (TTS) part II focuses on the diagnostic workup, outcome, and management. The recommendations are based on interpretation of the limited clinical trial data currently available and experience of international TTS experts. It summarizes the diagnostic approach, which may facilitate correct and timely diagnosis. Furthermore, the document covers areas where controversies still exist in risk stratification and management of TTS. Based on available data the document provides recommendations on optimal care of such patients for practising physicians.

Takotsubo syndrome (TTS) is a poorly recognized heart disease that was initially regarded as a benign condition. Recently, it has been shown that TTS may be associated with severe clinical complications including death and that its prevalence is probably underestimated. Since current guidelines on TTS are lacking, it appears timely and important to provide an expert consensus statement on TTS. The clinical expert consensus document part I summarizes the current state of knowledge on clinical presentation and characteristics of TTS and agrees on controversies surrounding TTS such as nomenclature, different TTS types, role of coronary artery disease, and etiology. This consensus also proposes new diagnostic criteria based on current knowledge to improve diagnostic accuracy.

Background: The risk of cardiovascular disease and mortality in salt-sensitive patients with diabetes mellitus and uncontrolled nocturnal hypertension is high. The SGLT2 inhibitor and ARB Combination theRapy in pAtients with diabetes and uncontrolled nocturnal hypertension (SACRA) study investigated changes in blood pressure (BP) with empagliflozin plus existing antihypertensive therapy. Methods: This multicenter, double-blind, parallel study was conducted in Japan. Adult patients with type 2 diabetes mellitus and uncontrolled nocturnal hypertension receiving stable antihypertensive therapy including angiotensin receptor blockers were randomized to 12 weeks' treatment with empagliflozin 10 mg once daily or placebo. Clinic BP was measured at baseline, and weeks 4, 8 and 12; 24-hour ambulatory BP monitoring (ABPM) was performed at baseline and week 12; and morning home BP was determined for 5 days before each visit. Primary efficacy end point was change from baseline in nighttime BP (ABPM). Results: 132 non...